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10.1245/s10434-006-9208-4
Annals of Surgical Oncology 14:795-801 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Synergistic Antitumor Effects of Histamine Plus Melphalan in Isolated Hepatic Perfusion for Liver Metastases

Flavia Brunstein, MD, Alexander M. M. Eggermont, MD, PhD, Gisela aan de Wiel-Ambagtsheer, Sandra T. van Tiel, Joost Rens and Timo L. M. ten Hagen, PhD

Department of Surgical Oncology, Erasmus MC, Daniel den Hoed Cancer Centre, Rotterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: Flavia Brunstein, MD, Department of Surgical Oncology, Laboratory of Experimental Surgical Oncology, Room Ee 0175a, PO Box 1738, 3000 DR Rotterdam, The Netherlands; E-mail: flis_br{at}yahoo.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Nonresectable primary and metastatic liver tumors remain an important clinical problem. Melphalan-based isolated hepatic perfusion (M-IHP) leads to more than 70% objective responses in selective groups of patients with nonresectable metastases confined to the liver. Complete responses are rare and progression-free survival is limited. Tumor necrosis factor (TNF), a very active agent in isolated limb perfusion, is linked to serious hepatotoxicity, restricting its use in IHP. Because of its vasoactive properties, histamine (Hi) is an alternative to TNF. In this article we evaluate its potential synergistic effect in M-IHP, improving response rates.

Methods: Our experimental rat IHP model is used for the treatment of soft tissue sarcoma liver metastases. Blood samples are collected for monitoring liver enzymes. Livers are excised 72 h and 7 days after treatment for histologic evaluation.

Results: After sham-IHP and Hi-IHP, tumor progression was observed in 100% of treated animals, while after M-IHP this number fell to 62% and after Hi + M-IHP it fell to only 22% (P = 0.006). Overall response rates were of 55% for Hi + M-IHP vs. 25% for M-IHP, and, more importantly, complete responses (CR) were observed only after Hi + M-IHP (22%) (P = 0.009). Hepatotoxicity peaked within 24 h after IHP, independent of the treatment administered, recovered in 48 h, and was related mainly to the elevation of transaminases (grade 3 ASAT and grade 1 ALAT for control group and grades 3 and 4, respectively, for all other treatments). No serious systemic toxicity was observed. Histology of the liver showed no serious damage.

Conclusion: Hi + M-IHP has synergistic antitumor effects without any increase in regional or systemic toxicity.

Key Words: Liver metastasis • Sarcomas • Histamine • Regional treatment


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
As many as 50% of the patients with a primary malignancy will eventually develop metastases in the liver, more than in any other organ. Primary tumors draining into the portal circulation more likely develop liver metastasis, but those arising in other sites such as breast and lungs might also develop them.1 Surgical approach, when possible, remains the best option, prolonging survival rates and even curing some patients, while unresectable primary or metastatic cancers confined to the liver still pose an important clinical challenge. Mean survival of patients with unresectable colorectal liver metastases is 12–18 months, while reported survival expectancy for those with ocular melanoma metastases is less than one year.2 The use of neoadjuvant therapies might render an unresectable tumor resectable, and these patients will still benefit from the advantages of surgical treatment. Systemic therapy has a limited role, depending on the histologic type of the primary lesion.

Regional approaches such as hepatic arterial chemotherapy infusion and perfusion allow high doses of chemotherapeutic drugs, typically delivering higher drug concentrations to the tumor compared with the hepatic parenchyma and the body as a whole. The advantages of regional delivery of chemotherapeutic drugs are direct tumor administration with limited systemic toxicity and the treatment of the whole liver including the micrometastases. Response rates are increased to 42%–62% using different chemotherapeutic agents such as 5-fluorouracil (5-FU) and melphalan. Despite promising results in a select group of patients, isolated hepatic perfusion (IHP) remains an experimental procedure and further development is needed to improve its efficacy and broaden its applicability, including the enhancement of the melphalan effect.2,3 In this scenario, despite its striking effect in isolated limb perfusion (ILP), the use of tumor necrosis factor TNF) in IHP was disappointing. Preclinical studies suggested a synergistic effect, increasing drug uptake mainly for highly vascularized tumors,4,5 but unfortunately its use in the clinical setting was hampered by serious hepatotoxicity, limiting the use of higher doses.6,7

We showed previously that histamine (Hi), an inflammatory mediator, is a potential alternative to TNF-{alpha}, strongly augmenting tumor response rates in melphalan-based ILP (overall response rates of 66%). The mechanism of action is based on (1) a direct cytotoxic effect on tumor-associated vasculature (TAV), (2) a direct cytotoxic effect on tumor cells, and (3) an indirect effect on TAV, increasing tumoral drug accumulation.8

Based on reports of systemic use of Hi combined with interleukin ( IL-2) in the treatment of stage IV melanoma patients, including those with liver metastases, no serious treatment-related hepatotoxicity was expected.

In this article we explore the synergistic effect of Hi in melphalan-based IHP (M-IHP) potentially improving the efficacy of the method. The previously described leak-free IHP experimental model in rats5,9 is used for the treatment of soft tissue sarcoma liver metastases.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animals and Tumor Cell Line
Male inbred Brown Norway (BN) rats were obtained from Harlan-CPB (Austerlitz, The Netherlands) (weight = 253–308 g, mean = 276 g). Animals were housed at the Central Animal Facility of Erasmus MC Rotterdam and fed a standard laboratory diet ad libitum (Hope Farms Woerden, Ihe Netherlands).

The syngeneic, spontaneous, rapidly growing, and metastasizing BN-175 soft tissue sarcoma10 was kept in liquid nitrogen and implanted in the dorsum of a BN rat for further growth before being inserted into the liver of the experimental animals.

All animal studies were done in accordance with protocols approved by the Animal Care Committee of the Erasmus University Rotterdam, the Netherlands.

Chemicals
Melphalan (Alkeran, 50 mg/vial, Wellcome, Beckenham, UK) was dissolved in 10 ml of diluent solvent. Further dilutions were made in phosphate-buffered saline (PBS) to a concentration of 2 mg/ml. Histamine (kindly provided by Maxim Pharmaceuticals Inc., San Diego, CA) came in vials already diluted in the concentration of 1 mg/ml.

Isolated Liver Perfusion Protocol
Small viable fragments (1–2 mm) of the syngeneic BN-175 sarcoma were implanted under the liver capsule in the left and right liver lobes of each rat using a 19-G Luer lock needle in a standardized manner.5 The fast-growing BN-175 sarcoma has a doubling time in the liver of approximately 2–3 days.11 Six days after implantation tumors reached a diameter of approximately 6 mm, being amenable to the procedure, and IHP was then performed (Fig. 1Go illustrates the liver metastasis model used for the studies). During followup tumor diameters were assessed through a small midline incision by caliper measurement. Tumor volume was calculated by the formula 0.4(A2 x B) (where B is the diameter of the largest tumor and A is the diameter perpendicular to B). When tumor diameter exceeded 20 mm, or abdominal adhesions made further assessment of tumor size impossible, or it was the end of the experiment, rats were killed by cervical dislocation under anesthesia.4,5


Figure 1
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  		FIG. 1. Liver sections from tumor-bearing BN rats showing nodules of the nonimmunogenic soft tissue sarcoma BN-175 infiltrating the liver tissue (black arrows, 2.5x). Liver with tumor was removed about four days after subcapsullary implantation. At higher magnification (16x) tumor infiltrating the liver tissue and concomitant liver parenchymal degradation (arrowheads) and the presence of vessels close to the tumor tissue become apparent. Bars correspond to 500 µm (right panel, lower magnification) and 100 µm (left panel, higher magnification).

 
The treatment consisted of a modification of the experimental IHP technique described by de Brauw et al.12 which was previously described.5,9 In brief, 6 days after implantation, tumor fragments reached a diameter of around 6 mm and were amenable to the procedure. Under anesthesia (maintained and induced with ether), a midline laparotomy was performed and the hepatic ligament was exposed. The pyloric side branch of the portal vein and the gastroduodenal side branch of the common hepatic artery were cannulated using silastic cannulas [0.025–in. outer diameter (o.d.) and 0.012–in. inner diameter (i.d.); Dow Corning, Midland, MI) Through an inguinal incision the femoral vein was exposed and cannulated retrogradely to reach the caval vein with the tip positioned at the level of the hepatic veins. Isolation of the hepatic vascular bed was obtained by temporarily ligating the common hepatic artery and the portal vein. The venous outflow limb was isolated by temporarily clamping the suprahepatic caval vein and by applying a temporary ligature around the infrahepatic caval vein containing the cannula, cranial to the right adrenal vein. During isolation, the mesenteric artery was clamped to reduce splanchnic blood pressure and the risk of translocation of intestinal bacteria. After the IHP procedure, clamps on the caval vein, portal vein, hepatic artery, and mesenteric artery were released. Gastroduodenal artery, pyloric vein, and femoral vein were ligated and gastroduodenal and pyloric cannulas were removed.

The perfusion circuit consisted of an arterial inflow limb in the hepatic artery, a venous outflow limb in the caval vein, and a collection reservoir/oxygenator. The circuit was primed with 10 ml of Haemaccell (Behring Pharma, Malburg, Germany) containing 50 IU of heparin. The perfusate was oxygenated in the reservoir with a mixture of O2:CO2 (95%:5%) and kept at 38–39°C through a heat exchanger connected to a warm water bath. A temperature probe was positioned in the lumen of the portal catheter 5 cm from the catheter tip. Arterial flow of 5 ml/min was maintained with a low-flow roller pump (Watson Marlow type 505 U, Falmouth, UK). Rats were perfused for 10 min with Haemaccell and dissolved agents followed by a washout with oxygenated Haemaccell for 2 min.

During the entire surgical procedure, which took in average 60–80 min, rats were kept at constant temperature with a heated mattress. Rats were randomly perfused with (1) Haemaccell alone, (2) Haemaccell plus 50 µg melphalan (Alkeran®, Wellcome, Beckenham, UK), (3) Haemaccell and 1000 µg Hi, or (4) Haemaccell, 50 µg melphalan, and 1000 µg Hi. Between four and six rats were included in each group, with a total of evaluable tumors ranging from 7 to 12.

Tumor dimensions were measured every four days. Volume on day 8 was compared with that on day 0 and response was classified as follows: progressive disease (PD) when there was a volume increase of more than 25%; no change (NC) when volume remained in the range of –25% to +25%; partial remission (PR) when there was a decrease between – 25% and –99%; or complete response (CR), i.e., no palpable tumor on day 8.

Weight, food and water intake, and general aspect of the animal (hair and behavior) were evaluated daily for grading toxicity of the different treatments administered.

Hepatotoxicity
Blood samples were drawn when cannulating the vessels before starting the IHP (t = 0 min), right after the end of the procedure before removing the cannulas (t = 10 min), and 24 h and 72 h after IHP. Alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), {gamma}-glutamyltranspeptidase (gGT), and alkaline phosphatase (AP) were measured at all the above-mentioned time points. Toxicity was graded according to the World Health Organization’s (WHO) common toxicity criteria (WHO Handbook for Reporting Results of Cancer Treatment, CTC v2.0, published 30 April 1999).

Histologic Evaluation After ILP
Two animals from each group were killed 72 h and one week after IHP. Tumor and liver were excised, fixed in 4% formaldehyde solution, and embedded in paraffin. The liver of a untreated BN rat was used as control. Slides were stained with hematoxylin and eosin (HE), CD-31, and periodic acid Schiff (PAS) method. In brief, for the PAS method slides were deparaffinized and hydrated to water, oxidized in 0.5% periodic acid solution, rinsed in distilled water, placed in Schiff reagent, and washed in tap water. Next, they were counterstained with hematoxylin and mounted with mowiol. HE and CD-31 staining were performed by the Pathology Department of Erasmus University. Images were taken with a Leica DM-RXA microscope supplied with a Sony 3CCD DXC camera.

Statistical Analysis
Repeated-measures analysis of variance (ANOVA) on days 4, 8, and 12 was performed with SPSS software release 11.0 for Windows 2000 (SPSS Inc., Chicago, IL). Main effects of day and treatment were included in the model as well as their interaction. Response rates were subjected to ANOVA and post hoc to the least significant difference (LSD) multiple comparison test. All statistical tests were two-sided and P < 0.05 was considered statistically significant. Whether synergy was obtained with the combined treatment was calculated as described previously.8 Calculations were performed on a personal computer using Prism v3.0 software (GraphPad Software Inc., San Diego, CA) and SPSS v11 for Windows 2000.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Tumor Response After Isolated Hepatic Perfusion
All the rats submitted to sham and Hi-alone IHP presented with progressive disease; 62% of the rats had progressive disease after M-IHP and only 22% progressed after HI + M-IHP (P = 0.03).

After M-IHP overall response rate (OR) was 25% and consisted only of PR, whereas after Hi + M-IHP the OR was 55%, including 22% CR and 33% PR (P = 0.009 for Hi vs. Hi + melphalan on day 12, and P = 0.03 for melphalan vs. Hi + M-IHP on day 12) (Fig. 2Go and Table 1Go). The increased response rates seen by the addition of Hi to melphalan was clearly synergistic (P = 0.002).


Figure 2
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  		FIG. 2. Tumor response after isolated hepatic perfusions (IHP). Brown Norway rats bearing liver implants of BN-175 soft tissue sarcoma were randomly submitted to IHP with perfusate alone (sham), 50 µg melphalan, 1000 µg Hi, or 1000 µg Hi plus 50 µg melphalan. Tumors were measured every four days with a caliper and volumes were calculated. Mean tumor volumes ± SEM are depicted in the graph. The number of independent experiments (rats) for each treatment is shown in parentheses.

 

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  		TABLE 1. Response in Brown Norway rats bearing liver metastasis of BN-175 soft tissue sarcoma after melphalan-based IHP in combination with histamine over 12 days
 
All animals had a mean weight loss in the range of 7.8%–12.4%, independent of the treatment administered. Even those who underwent a sham IHP had a 10% mean weight loss.

Liver Toxicity
Hepatotoxicity peaked at 24 h after IHP for all the different treatments administered (Fig. 3Go and Table 2Go). The control group (sham IHP) presented with a grade 3 increase of ASAT (median = 315.6 IU/L; range = 218.0–415.2 IU/L) and a grade 1 increase of ALAT (median = 109.4 IU/L; range = 59.2–124 IU/ L), which recovered to grade 0 within the following 48 h (median = 67.7 and 10.6 IU/L, respectively). All the other treatments (melphalan, Hi, and combination treatment Hi + melphalan) led to a grade 4 increase of ASAT and a grade 3 of ALAT, but the recovery pattern was similar to those described above for sham perfusions (Table 2Go).


Figure 3
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  		FIG. 3. Hepatotoxicity after IHP. Blood samples were drawn when cannulating the vessels before starting the IHP (t = 0 min), right after the end of the procedure before removing the cannulas (t = 10 min), and 24 h and 72 h after IHP. Alanine aminotrasferase (ALAT), aspartate aminotransferase (ASAT), {gamma}-glutamyltranspeptidase (GGT), and alkaline phosphatase (ALP) were measured at all the above-mentioned time points Toxicity was graded according to WHO common toxicity criteria. Median ± SEM values are depicted; n = 6 per group.

 

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  		TABLE 2. Liver enzyme ranges after different IHP treatment showing the highest and lowest value observed for each group
 
As for AP, there was a grade 1 toxicity for all the treated groups (Hi 159.9 IU/L, melphalan 145.0 IU/ L, and combination Hi + melphalan 158.4 IU/L; all values are medians). Control IHP (sham) led to a grade 0 toxicity (95.3 IU/L).

Finally, gGT presented with a grade 0 toxicity for all the different groups (medians ranged from 2.2 IU/ L for melphalan alone to 4.6 IU/L in the sham perfused group). Interestingly, the sham group still showed a trend toward increasing values 72 h after the procedure, while the three other treated groups presented a recovery profile.

Histology
HE slides showed normal liver anatomy with preserved structures similar to those seen in the normal liver. We can clearly see the lobes, portal vein, central vein, and biliary ducts. There are some mild eosinophilic deposits around the biliary ducts and some necrotic areas in melphalan-treated specimens (both alone and in combination with Hi) (Fig. 4Go).


Figure 4
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  		FIG. 4. Histologic evaluation of livers extracted from an untreated BN rat and seven days after sham, melphalan, Hi, or Hi + M-IHP. Livers were fixed in 4% formaldehyde solution and embedded in paraffin before staining with HE and periodic acid Schiff (PAS) method. HE staining show preserved anatomical structures compared with normal liver. An even reduction on glycogen for all the treatments, even sham, compared with normal untreated liver is illustrated by the PAS method. Images were taken with a Leica DM-RXA microscope equipped with a Sony 3CCD DXC camera.

 
PAS staining 72 h and 7 days after IHP showed that the same pattern, independent of the treatment administered, was maintained, disclosing negative areas around the central vein compared with the normal liver with extensive glycogen positive-stained areas.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We show here for the first time a very promising synergistic effect of the combination of histamine with melphalan in isolated hepatic perfusion for the treatment of soft tissue sarcoma metastasis with no systemic toxicity and an acceptable regional toxicity, which was not greater than that seen after IHP with melphalan alone.

IHP was first used more than 40 years ago13 but there was limited clinical experience then. Most of the early reports lacked documented efficacy and unacceptable mortality rates of 10%–25% were reported. More recently, thanks to technical advances and standardization of the techniques for vascular isolation of the liver, IHP returned as a treatment option for patients with unresectable cancers of the liver. Also, the results obtained in isolated limb perfusion (ILP) had a strong impact on the further exploration of using organ perfusion methodologies as a neoadjuvant approach for those patients with unresectable hepatic lesions.6,14–16

The number of drugs considered for IHP is still very limited because these agents must be effective after a single short exposure of no longer than 60 min, without serious hepatotoxicity. Melphalan is described as effective against both colorectal cancer and melanoma after relatively short exposure times and has a steep dose-response curve; it is widely accepted as a good option for locoregional treatment of liver metastasis.3

Although in the clinical setting melphalan is used at a concentration of 1.0 mg/kg,17 in this study we used a concentration of 0.2 mg/kg to better evaluate the effect of the combination treatment with Hi. Still, melphalan alone in this lower dosage led to 25% PR associated with grade 3 and grade 4 hepatotoxicity measured by transaminases. The combination treatment of melphalan + Hi did not add to the toxicity observed with each drug alone, yet it significantly improved response rates with 55% OR, including 22% CR. (Table 2Go).

TNF-{alpha}-related hepatotoxicity in IHP4,18 has been clearly shown and precludes its use in IHP. As previously shown, not only does it preferentially accumulate in the liver instead of in the tumor tissue, but it also leads to endogenous TNF-{alpha} production by Kupffer cells that are abundant in normal liver tissue.19 In fact, it does not come as a total surprise because the production of this cytokine is known as one of the initial events in liver injury. TNF-{alpha} recruits inflammatory cells that cause hepatocyte injury and promote production of type I collagen fibers by hepatic stellate cells as a healing response. In addition, it acts on biliary ducts to interfere with the flow of bile causing cholestasis.

The previously reported systemic combination of histamine and IL-2 for the treatment of stage IV melanoma patients with liver metastasis20 suggested a potentially safer profile in terms of hepatotoxicity. Indeed, in spite of grade 3 and grade 4 toxicity for transaminases within 24 h, we observed a satisfactory recovery 72 h after treatment with no systemic repercussion.

Histologic findings further back-up the observation of a mild and tolerable hepatotoxicity because no important anatomical damage was seen and accordingly glycogen distribution (PAS staining) showed the same mild decrease after 72 h for all the different treatments administered.

In conclusion, histamine has a synergistic antitumor effect when combined with melphalan-based isolated hepatic perfusion for the treatment of BN-175 liver metastases. Based on these results and those previously reported on the synergistic effect of histamine in melphalan-based isolated limb perfusion, a phase I–II study to explore its therapeutic efficacy in the clinic is worthwhile and currently in development.


   ACKNOWLEDGMENTS
 
The authors thank Maxim Pharmaceuticals Inc. (San Diego, CA) for kindly providing histamine dihydrochloride for this study. This study was supported by the Translational Research grant of the Erasmus MC.

Received for publication July 25, 2006. Accepted for publication July 26, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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 Ann. Surg. Oncol.Home page
C. Verhoef, J. H. W. deWilt, F. Brunstein, A. W. K. S. Marinelli, B. vanEtten, M. Vermaas, G. Guetens, G. de Boeck, E. A. de Bruijn, and A. M. M. Eggermont
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