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10.1245/s10434-006-9108-7
Annals of Surgical Oncology 14:802-809 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Correlation Between Melphalan Pharmacokinetics and Hepatic Toxicity Following Hyperthermic Isolated Liver Perfusion for Unresectable Metastatic Disease

Simone Mocellin, MD1, Pierluigi Pilati, MD1, Pierpaolo Da Pian, MD1, Marco Forlin, MD1, Susanna Corazzina, MD1, Carlo Riccardo Rossi, MD1, Federico Innocente, MD2, Carlo Ori, MD2, Dario Casara, MD3, Francesca Ujka, MD4, Donato Nitti, MD1 and Mario Lise, MD1

1 Surgery Branch, Department of Oncological and Surgical Sciences, University of Padova, via Giustiniani 2, 35128, Padova, Italy
2 Department of Anesthesiology and Pharmacology, University of Padova, via Giustiniani 2, 35128, Padova, Italy
3 Department of Radiotherapy, Section of Nuclear Medicine, University of Padova, via Giustiniani 2, 35128, Padova, Italy
4 Laboratory and Clinical Medicine, University of Padova, via Giustiniani 2, 35128, Padova, Italy

Correspondence: Address correspondence and reprint requests to: Pierluigi Pilati, MD, Clinica Chirurgica 2, Dipartimento di Scienze Oncologiche e Chirurgiche, Università di Padova, Via Giustiniani 2, 35128, Padova, Italy; E-mail: pl.pilati{at}unipd.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 STUDY DESIGN
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: In the present work, we report on the results of our pilot study of hyperthermic isolated hepatic perfusion (IHP) with melphalan alone for patients with unresectable metastatic liver tumors refractory to conventional treatments, with particular regard to the correlation between pharmacokinetic findings and hepatic toxicity.

Patients and methods: Inclusion criteria were unresectable liver metastases, hepatic parenchyma replacement ≤50%, normal liver function, and previous failure of at least one conventional treatment. IHP was performed under hyperthermic conditions with melphalan (1.5 mg/kg body weight). Completeness of vascular isolation of the liver and drug distribution volumes of the perfusion circuit were assessed by a radiolabeled albumin-based method. Drug concentrations in perfusate and plasma were measured by means of high-performance liquid chromatography (HPLC).

Results: Twenty patients with unresectable liver metastases underwent IHP. No intraoperative mortality occurred. Treatment-related systemic toxicity was minimal and reversible. Three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Other six patients had significant (grade 3–4) but transitory hepatic toxicity. Complete and partial responses were observed in three and nine out of 17 evaluable patients, respectively (overall response rate = 70%). The pharmacokinetics study showed a 3% mean perfusate-to-plasma drug leakage (range 1–6%). Logistic regression analysis showed that drug concentration in the perfusate circuit, but not preoperative tests, significantly and independently correlated with hepatic toxicity (P = 0.028).

Conclusions: Following melphalan-based IHP, objective tumor regression could be observed in a remarkable percentage of patients refractory to standard treatments. However, hepatic toxicity and related mortality were significant. Our findings suggest that drug dosage personalization based on the measurement of drug distribution volumes might minimize hepatic toxicity.

Key Words: Isolated hepatic perfusion • Liver metastasis • Locoregional treatment • Pharmacokinetics • Treatment personalization


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
STUDY DESIGN
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Surgery is the therapeutic option associated with the best chance of cure for patients with liver metastatic disease originating from different types of solid malignancies. In case of unresectable liver disease, the therapeutic management is challenging, particularly when systemic chemotherapy has failed.1 Since the 1950s, clinicians have sought to concentrate anti-neoplastic agents selectively in the diseased liver by means of locoregional drug delivery systems. The largest experience has been reached with hepatic arterial infusion (HAI) in patients with colorectal carcinoma metastases.2 With this strategy, intratumoral drug concentrations are ten-fold higher than those achievable with systemic drug administration. However, although high tumor response rates (up to 40–50%) have been reported, no significant impact on overall survival has been demonstrated.

Isolated hepatic perfusion (IHP) has been proposed as a locoregional treatment based upon the complete vascular isolation of the liver from the systemic circulation, which allows attainment of tumor drug concentrations about 50- to 100-fold higher than those achievable through the systemic route though maintaining low systemic levels of drug and thus minimizing systemic toxicity.3 The near-complete vascular isolation of the liver obtained during IHP also allows administration of antineoplastic drugs [e.g., tumor necrosis factor (TNF)] that cannot be used through the systemic route owing to the fact that their minimal effective dose is higher than their maximal tolerated dose.4 Furthermore, IHP performed under hyperthermic conditions permits exploitation of the antineoplastic synergism between some chemotherapeutic agents (e.g., melphalan) and heat. The early clinical experiences with IHP were associated with high morbidity and mortality rates along with a weak proof of efficacy, which hampered acceptance of this surgically demanding procedure by the scientific community. In the early 1990s, Lienard et al. reported complete remission in more than 80% of patients treated with isolated limb perfusion with melphalan and TNF for locally advanced melanomas and sarcomas of the extremities:5 these results renewed the interest in locoregional chemotherapy based on isolated perfusion and, as a consequence, in IHP. This led to refinement of the surgical procedure, to definition of the maximum tolerated dose of melphalan, and ultimately to significant decrease in postoperative toxicity and mortality rates, which, however, remain the major concern among oncologists. Moreover, encouraging results have been reported in terms of antitumor activity, with overall response rates ranging from 40% to 75% in patients affected with different types of cancers and often treated heavily and unsuccessfully with standard chemotherapy before IHP.

The complexity, the cost, and the still significant morbidity rate associated with this surgical procedure limit the performance of IHP to highly specialized centers. In the present work, we report on the results of our pilot study of hyperthermic IHP with melphalan alone for patients with unresectable metastatic liver tumors resistant to conventional treatments, with particular regard to the correlation between the pharmacokinetic findings and hepatic toxicity.


   STUDY DESIGN
TOP
 ABSTRACT
 INTRODUCTION
 STUDY DESIGN
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This was a pilot study aimed at determining feasibility of IHP for treatment of patients with unresectable liver tumors refractory to conventional therapeutic options. Patient enrollment started in March 2003; after that, the treatment protocol was approved by the Local Ethical Committee Board. According to including criteria, all patients had histologically or cytologically proven metastatic cancers of any origin limited to liver parenchyma with no evidence of extrahepatic disease by preoperative radiological studies. Patients underwent standard staging studies that included computed tomography (CT) of the chest, abdomen, and pelvis, and, as clinically indicated, hepatic and bone magnetic resonance imaging (MRI). Eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of two or less and an adequate hepatic, renal, and bone marrow function. Patients in whom elevations in hepatic transaminases were thought to be secondary to the presence of metastatic disease in the liver were considered eligible. Patients were excluded who had evidence of extrahepatic disease, biopsy-proven cirrhosis, evidence of significant portal hypertension, history of venous occlusive disease, or portal and/or inferior vena cava thrombosis. In addition, before operative procedure, patients were submitted to green indocyanine test in order to evaluate hepatic metabolic function, with a clearance ≥ 450 ml/min being required for eligibility.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 STUDY DESIGN
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between March 2003 and December 2005, 30 patients meeting the above-mentioned preoperative eligibility criteria were enrolled at our institution. Patients were fully informed of the investigational nature, risks, and potential benefits of the procedure. A signed informed consent form was obtained from all patients.

IHP: Technical Procedure
The surgical procedure for IHP, which was performed as described by Alexander et al.,6 has been reported by us in detail elsewhere.7 Briefly, the circulation of the liver was completely isolated by ligating and dividing all posterior phrenic and retro-peritoneal tributaries of the inferior vena cava from the level of the renal veins to the diaphragm and subsequently placing an inflow cannula in the gastroduodenal artery and an outflow cannula in the retrohepatic inferior vena cava. Infrahepatic and portal blood flow was shunted to the right axillary vein by an extracorporeal circuit. The hepatic perfusion circuit was obtained by connecting the inflow cannula with the infrahepatic venous outflow cannula. The circuit included a roller pump, a membrane oxygenator, and a heat exchanger. The liver perfusate consisted of a balanced salt solution (700 ml) primed with 300 ml packed red blood cells; sodium bicarbonate was added to the perfusate during the procedure to maintain pH in the range of 7.2–7.4. Flow rates were adjusted according to acceptable perfusion pressures. The perfusion circuit was used to deliver melphalan at high dosages (1.5 mg/kg) as well as to increase liver temperature to about 41°C, thus exploiting the antiblastic synergism between melphalan and heat. Since no obese patients were enrolled [body mass index (BMI) range: 21–29), no melphalan dosage adjustment was performed. Perfusion time was 60 min. Perfusate-plasma drug leakage was measured/calculated in real time immediately before drug administration and then at 5-min interval throughout IHP by means of a scintigraphic method, as described below. Drug leakage ≥10% was considered the cutoff to interrupt IHP.

Toxicity Evaluation
For assessment of IHP-related toxicity, the National Cancer Institute Common Toxicity Criteria (NCI-CTC) were adopted. In order to correlate liver toxicity with drug concentrations and tumor response, the four NCI-CTC grades for liver toxicity were categorized as follows: grade 1 or 2 = low toxicity; grade 3 or 4 = high toxicity. Liver toxicity was measured 48 h after IHP: this time point was chosen based on the observation that, on average, the peak of toxicity was observed on the second postoperative day.

Definition of Response
Tumor response was evaluated with CT 3 months after IHP. A complete response (CR) was defined as complete disappearance of all established tumor on standard imaging studies without evidence of new lesions. A partial response (PR) was defined as tumor shrinkage of at least 50%. Tumor shrinkage between 25% and 50% was considered as minimal change (MC). Stable disease (SD) and progressive disease (PD) were defined as tumor shrinkage less than 25% (or no evidence of tumor change) and increase in tumor size, respectively.

Melphalan Pharmacokinetics
Concentrations of melphalan were measured in the perfusate and plasma throughout perfusion (at 15, 30, 45, and 60 min). Melphalan levels were measured by means of high-performance liquid chromatography (HPLC), as already described by our group.8 The areas under the curve (AUC) from 0 to 60 min (AUC0–60) were calculated using Graph-Pad Prism (version 2.0) software.

A modification of the Tc-99 human serum albumin leak-monitoring system used during isolated limb perfusion with TNF and melphalan9 was used in IHP perfusion. In brief, once stable perfusion parameters were established, a gamma detection camera was positioned over the centrifugal pump housing, which was a stable reservoir of systemic blood for the purpose of determining count-per-minute (CPM). A dose of 0.5 MBq/kg body weight of radiolabeled Tc-99 human albumin was administered through a central vein, and a baseline level of CPM was determined on a strip-chart recorder. After a stable baseline CPM was obtained, a tenfold higher dose of Tc-99 human serum albumin was injected into the perfusion circuit. If any increase in CPM was detected on the strip-chart recorder, this would have indicated a leak from the perfusion circuit into the systemic circulation. Leak rates as small as 0.5% can be reliably measured with this system. At the completion of the perfusion, the liver was flushed via the perfusion circuit with 1,500 ml of saline and 1,500 ml of Ringer’s lactate.

In order to calculate the perfusate volume (and consequently melphalan concentration in the hepatic perfusion circuit), we utilized a simple dilution method based on the first dose of radiolabeled albumin (0.5 MBq/kg body weight) injected in the hepatic perfusion circuit. The same amount of radiotracer had been previously diluted in a known volume (1 l) of an experimental system and the radioactivity of 1 ml of such solution measured by means of a gamma counter. Knowing the radioactivity of 1 ml of such experimental solution and that of 1 ml of perfusate (withdrawn at the beginning of IHP), the volume of the hepatic perfusion circuit was calculated according to the following formula: VOLcir = CPMexp/CPMcir, where VOLcir, CPMexp and CPMcir are the volume of the hepatic perfusion circuit (expressed in liters) and the counts per minute measured in the 1-ml samples obtained from the experimental system and the perfusate circuit, respectively.

Statistical Analysis
Correlation between drug concentrations as measured with HPLC- and scintigraphy-based methods was analyzed by means of the Pearson’s product-moment correlation coefficient. The two-tailed t test was used to evaluate differences in drug concentrations in the hepatic perfusion circuit of patients with different hepatic toxicity (categorized in high vs. low, as above described) and tumor response (CR or PR vs. MC or SD). To investigate the influence of continuous (drug concentration, perfusion circuit volume, drug dose, indocyanine dye clearance, age) and categorical (gender, tumor type) variables on both tumor response and hepatic toxicity, Fisher’s exact test and binary logistic regression were fitted, as appropriate. Probability values <0.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 STUDY DESIGN
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Out of 30 enrolled patients, 20 (11 men and nine women; mean age, 56 years, range 44–69) with unresectable liver metastases from colorectal carcinoma (n = 11), breast carcinoma (n = 5), and uveal melanoma (n = 4) underwent a 60-min hyperthermic IHP using melphalan alone (1.5 mg/kg of body weight). Intraoperatively, ten patients were found to be not eligible for IHP due to liver involvement by metastatic disease greater than 50% (n = 5) or extrahepatic disease (n = 5).

Hepatic parenchyma replacement was between 25% and 50% in all treated patients as assessed by preoperative CT. Before IHP, all patients experienced no response or disease progression following at least two types of conventional treatments, mainly systemic chemotherapy (Table 1Go).


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  		TABLE 1. Patient and tumor characteristics
 
Morbidity and Mortality
There was no intraoperative mortality. In the postoperative period, complications included hemoperitoneum (n = 1), pleural effusion (n = 8), and pneumonia (n = 2). Treatment-related systemic toxicity was minimal and reversible. By contrast, three patients (15%) experienced grade 4 hepatic toxicity and died due to liver failure and subsequent multiorgan failure. Six patients had significant (grade 3–4) but transitory hepatic toxicity (median time to recovery 15 days, range 9–58). Grade 2 reversible hepatic toxicity occurred in the remaining cases. Although it must be considered that the test had a power of <80%, binary logistic regression showed that hepatic toxicity (categorized in high and low grade, as above described) did not correlate with tumor response, which was categorized as significant (CR or PR) or not significant (MC or SD). Furthermore, none of the patient-related parameters we considered (age, gender, preoperative liver function tests, percentage of hepatic replacement by metastatic disease) correlated with postoperative liver toxicity.

Tumor Response and Clinical Outcome
Excluding the three postoperative deaths, the overall response rate in the 17 evaluable patients was 70% (12/17), of whom 18% (3/17) had CR, and 52% (9/17) had PR. We observed MC in three patients while two had stable disease. The median duration of response (time to progression) was 9 months.

After a median follow-up of 18 (range: 3–31) months, seven patients died of disease progression (two with hepatic progression only, five with extra-hepatic progression only, and one with hepatic and extrahepatic progression), eight were alive with disease (one with hepatic disease only, four with extra-hepatic disease only, and three with hepatic and extrahepatic disease), and two were disease free.

Melphalan Pharmacokinetics
According to patient’s weight, 98–125 mg of melphalan were administered at the beginning of IHP. During IHP, the mean melphalan concentration in plasma and perfusate was 1.9 µg/ml (range: 0–6) and 79 µg/ml (range: 0–95), respectively. The high AUC ratio (AUCperf/AUCplasma: 52) demonstrated that vascular isolation of the liver was near complete and that most of the melphalan dose remained in the perfusate throughout IHP (Fig. 1Go).


Figure 1
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  		FIG. 1. Melphalan distribution during 60-min hyperthermic isolated hepatic perfusion (IHP) in 18 patients with unresectable liver metastasis. Drug dosage for all patients was 1.5 mg/kg of patient’s body weight. During IHP, samples of peripheral plasma and perfusate were withdrawn at different time points, and melphalan levels were measured by means of high-pressure liquid chromatography (HPLC).

 
Using the scintigraphic method, the mean perfusate-plasma leakage was 3% (range: 1–6%), which corroborates the data of HPLC-based melphalan measurements. Scintigraphy revealed that the mean volume of the perfusion circuit (and thus drug distribution volume) was 1,119 ml, with a significant variability among patients (range: 714–1,967 ml). Accordingly, in the perfusion circuit, initial melphalan concentrations estimated with the scintigraphic method (drug dosage/perfusion circuit volume) varied from 61 to 175 µg/ml (mean 110 µg/ml). These values correlated well with drug levels assessed with HPLC at time 15 min (Pearson’s correlation coefficient = 0.87, P = 0.001) (Fig. 2Go).


Figure 2
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  		FIG. 2. Correlation between perfusate melphalan concentrations measured with high-pressure liquid chromatography (HPLC) and drug levels calculated by dividing the amount of melphalan administered to each patient (1.5 mg/kg of body weight) by the distribution volume estimated by means of intraoperative scintigraphy. Pearson’s correlation coefficient was 0.87 (P = 0.001).

 
Interestingly, higher drug concentrations in the hepatic perfusion circuit were significantly associated with greater liver toxicity (t test P value = 0.007; logistic regression P value = 0.028) (Fig. 3Go) but not with tumor response rates, as mentioned above. The discrepancy between the dose per kilogram of body weight (1.5 mg of melphalan for all patients) and the wide range of drug concentrations in the perfusate was likely related to the significant variability in the perfusate volumes among patients, as supported by the highly significant inverse correlation between the two factors (Pearson’s correlation coefficient = –0.91, P < 0.0001). Of note, postoperative deaths, which were due to liver failure, occurred in three cases with the highest drug concentrations (163, 155, and 135 µg/ml, respectively) while no severe (i.e., grade 3–4) toxicity was observed in patients with melphalan levels lower than 100 µg/ml.


Figure 3
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  		FIG. 3. Correlation between liver toxicity observed after isolated hepatic perfusion and melphalan concentrations in the perfusion circuit as measured by high-pressure liquid chromatography (HPLC). Hepatic toxicity was graded as low [grade 1 or 2 according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC)] or high (grade 3 or 4). The t test P value was 0.007.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 STUDY DESIGN
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
A number of locoregional approaches have been proposed over the last few decades for the treatment of unresectable liver metastases. The aim of such approaches is to restrict the effect of chemotherapy to the tumor-bearing organ and thus minimize systemic toxicity. Some of these techniques (e.g., hepatic artery infusion), have been shown to improve overall response rates, but none of them has been demonstrated to prolong survival.1

Recently, IHP has been reconsidered as an alternative therapeutic option for patients with unresectable cancers confined to the liver who did not respond to previous systemic or locoregional treatments. The main disadvantages of IHP are that it is a technically demanding procedure and is associated with significant perioperative morbidity.10–25

Using the maximum tolerated dose of melphalan calculated in phase I studies in humans (1.5 mg/kg of body weight),11 we carried out a feasibility clinical trial, which was the objective of the present work. Although this pilot study was not designed to evaluate IHP antineoplastic activity and although different tumor types were treated, our results appear encouraging. In fact, in line with the findings reported in the literature,3,10–25 overall tumor response evaluated 3 months after IHP was 66%, with three patients experiencing complete disappearance of their metastatic disease. These results are of particular relevance considering that tumor responses were obtained in patients who had previously failed at least one type of conventional treatment, such as surgery, systemic chemotherapy, or locoregional therapies other than IHP. However, as also pointed out by other investigators,10–25 life expectancy of patients undergoing IHP does not appear significantly different from that of subjects treated with conventional therapies; moreover, after IHP most patients experience extra-hepatic disease recurrence, which questions the utility of this locoregional treatment alone and calls for the combination of IHP with systemic chemotherapy.

As regards the feasibility of IHP, no surgical complications were encountered intraoperatively, and no intraoperative deaths occurred. In the postoperative period, hepatic toxicity was significant in all cases: while in 15 patients toxicity reversed in 1–6 weeks after IHP, in another three (16.7%), liver failure was followed by multiorgan failure on the fourth to sixth postoperative day, and death occurred 5, 3, and 2 weeks after IHP was performed, respectively. According to some investigators, grade 3–4 liver toxicity and multiorgan failure might be explained by the high tumor load: in particular, De Vries et al. observed that in patients with more than 50% of liver replacement, the mortality rate within 30 days from IHP was 25%.26 Our findings do not confirm this observation, but the power of the Fisher exact test was < 80% (data not shown). Clearly, post-IHP mortality—which ranges from 0% to 33% in the series published so far3,10–25—remains a significant "deterrent" for the diffusion of this locoregional therapeutic approach. Therefore, despite the fact that phase I studies have been performed and a maximum tolerated dose of melphalan already set at 1.5 mg/kg of patient’s body weight, any effort to dissect the mechanisms underlying IHP-related liver failure is warranted.

We and others found no correlation between postoperative liver toxicity and patient, tumor, or liver function features, which underscores the need for more accurate preoperative tests for the evaluation of residual hepatic parenchyma function and thus for a better selection of patient candidates to IHP. Given the current lack of such preoperative assays, we suggest that intraoperative assessment of the drug distribution volume might be of great value to personalize drug dosage and minimize hepatic toxicity while maintaining the antineoplastic activity of IHP.

Considering the results of the present study, the first observation is that—although the priming volume is constant (1,000 ml)—the drug distribution volume can significantly vary among patients. Despite the lack of direct evidence, we hypothesize that this phenomenon may be due at least in part to interindividual variations in liver volume as well as to different percentages of hepatic parenchyma replacement by the metastatic disease.

We then observed that higher drug concentrations were associated with higher toxicity rates and that the three postoperative deaths occurred in patients with the highest drug levels in their perfusion circuits, a finding that resembles that reported by some investigators dealing with melphalan-based isolated limb perfusion.27 Interestingly, no significant correlation was observed between the total dose of melphalan or the calculated distribution volume and liver toxicity, which probably reflects the fact that drug concentration (and not its total dose or its distribution volume) is the most reliable parameter for predicting liver damage.

By contrast, the magnitude of hepatic toxicity did not correlate with tumor response rates, suggesting that beyond a certain concentration, no further antitumor effect can be obtained. Our pharmacokinetic findings also indicate that drug concentrations can vary widely between patients due to significant differences in drug distribution volumes: ultimately, this phenomenon might be responsible for hepatic damage unrelated to liver function and thus unpredictable on the basis of preoperative assessments. Since drug concentration cannot be directly measured intraoperatively (e.g., by means HPLC), calculation of drug distribution volumes by means of a scintigraphy-based real-time method could represent an alternative and effective approach to adjust drug dosage on a single-patient basis.

Obviously, the hypothesis that drug-dose adjustment according to drug-distribution volumes leads to minimize hepatic toxicity without compromising tumor response rates needs to be validated in larger prospective series, and we cannot recommend any drug dosage modification on the basis of the measurement of distribution volume. In fact, the test is still to be refined, as suggested by the fact that among calculated volumes, there were values inferior to the priming volume (1,000 ml). This phenomenon might depend upon the timing of scintigraphic measurements; for instance, if measurements are made too early (e.g., when the radiolabeled colloid is not yet homogeneously distributed), "false" levels of radioactivity can be detected in the perfusate sample. To address this issue, a time-course study is underway at our institution.


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  		TABLE 2. Morbidity, mortality and tumor response after isolated hepatic perfusion in 18 patients with unresectable liver metastasis
 

   ACKNOWLEDGMENTS
 
This work was in part supported by the AIRC [Associazione Italiana Ricerca sul Cancro (an Italian association for cancer research)] Regional Grant 2005

Received for publication May 23, 2006. Accepted for publication May 23, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 STUDY DESIGN
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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