Despite significant advances in the treatment of cancer overall, the mortality in melanoma remains unchanged. Ocular melanomas have a significant predilection for metastasizing to the liver, and frequently patients with ocular melanoma have the liver as the only site of metastatic disease . The outcome for patients with liver metastases from malignant melanoma (MM) is very poor with the 1-year survival estimated at 10% [2,3]. Systemic chemotherapy has shown limited tumor response rates, often in the range of 20–30%, without proof of prolonging survival . According to a recent Cochrane review, there is no clear evidence that the addition of immunotherapy to chemotherapy increases the survival of patients with MM .
The pharmacokinetic advantage of the regional isolation perfusion technique with cytostatic drugs is well established. It has been shown that a 50-fold to100-fold increase in regional drug concentration can be achieved via isolation perfusion as compared with the traditional systemic route, as the drug is distributed in a smaller volume . As it is assumed that melphalan uptake is directly proportional to the dose, the high concentration may overcome drug resistance . As it is nearly impossible to isolate any organ completely, leakage has to be taken into consideration when calculating the dose. If there is no leakage during the perfusion and the organ is rinsed from the drug after completion of the perfusion, minimal systemic toxicity complications should be expected. The synergistic effect of hyperthermia on melphalan in perfusion of extremities with MM is well recognized. In addition, the rate of complete remission has been reported at around 70% in this clinical setting [8–10].
The results of isolated hepatic perfusion (IHP) for different tumors have been reported in many communications. The most-reported indication for IHP is colorectal metastases where tumor remission rates of up to 75% have been reported [11–13]. The response rate for patients with liver metastases of ocular melanoma is reported to be 50% with the median time of progression being within 6–10 months [14–17].
The aim of this paper was to analyze and compare respective tumor responses and complications between one early retrospective IHP cohort and two later prospective IHP cohorts, in which the surgical technique was simplified, the melphalan dose was larger and the temperature in the liver lower.
Materials and methods
Patients and tumors
Twenty-seven (27) patients were included in the analysis. Three different time periods were studied: the IHP I retrospective cohort of 11 patients covered the time period from 1985 to 1994, the IHP II prospective cohort of 11 patients covered the time period from 1998 to 2005 and the IHP III prospective cohort of five patients covered the time period from 2005 to 2007. Anecdotally, five additional patients, treated under the IHP II cohort time period, were laparatomized but did not complete IHP treatment. Two of these patients presented with a liver tumor volume that was too large, one patient presented with a large subcapsular liver haematoma after biopsy, one patient experienced a perforation of the subclavian vein during catheterization for the bypass and one patient presented with an occult colon cancer. Of note here is that the data presented from the IHP I cohort are partly presented in previous communications [18,19].
The demographics and clinical characteristics of the patients from the three treatment periods are depicted in Table 1. In 74% of the patients studied, the primary tumor was of ocular origin.
Preoperative evaluation included standard liver function tests. Mandatory computed tomography (CT) or MRI of the abdomen and chest was used to evaluate the tumor volume in the liver and to exclude any major extrahepatic growth. CT or MRI of the brain was performed to exclude local recurrence of ocular melanoma. Inclusion criteria required the patient to have a Karnofsky score of 80% or above and normal liver function according to the Child–Pugh score. In the IHP III cohort, the tumor volume had to be less than 50% of the patient's total liver volume as estimated radiologically.
Under general anesthesia, a bilateral subcostal incision was made. Evaluation of the intrahepatic and extrahepatic tumor volume was performed. Incongruence existed between the tumor volume estimated radiologically and that estimated intraoperatively by the surgeon inasmuch as the liver tumor burden was estimated as being larger by the surgeon as the metastatic melanoma deposits less than 5 mm in diameter were not objectified by the radiological setup. The patients were, according to this estimation, categorized into three groups of tumor volumes in the liver: <25, 25–50, >50% (Table 1). In the IHP I series, an internal lower caval vein shunt (Perfufix; Braun, Melsungen, Germany) was applied to drain the lower part of the body and was also used as the venous liver outflow . In this same series, the splanchnic compartment was bypassed during perfusion via a catheter through the inferior mesenteric vein to the portal vein to the Perfufix. Both the portal vein and the hepatic artery proper (via the gastroduodenal artery) were cannulated for perfusion and connected to the arterial perfusion line.
In the IHP II series and in the IHP III series, wire-reinforced catheters were inserted into the iliac vein and the axillary vein. The caval vein was isolated infrahepatically above the renal veins and suprahepatically between the diaphragm and the pericardium. Tributaries from the lumbal veins and from the diaphragm were occluded, as were the veins from the right suprarenal gland.
In both the IHP II and IHP III series, the right gonadal vein was catheterized and a catheter placed in the retrohepatic portion of the caval vein for perfusion outflow. An external shunt from the iliac vein through a centrifugal pump to the axillary vein was created for lower body drainage. The perfusion system was arranged as previously described , the only modification being that the portal blood flow was clamped and no portal perfusion was performed.
The liver perfusion was performed at a rate of 15 ml per kg of body weight per minute in the IHP I cohort and 8–9 ml/kg/min in the IHP II and IHP III cohorts. The target hyperthermic liver temperatures in the IHP I cohort was ≥41 and ≥40°C for the IHP II and IHP III cohorts, respectively (Table 2). The hyperthermic temperatures were registered continuously with thermistor probes in the inflow catheter and in the liver parenchyma itself, to provide two readings. For seven patients in the IHP II cohort and in all patients in the IHP III cohort, the leakage from the system was continuously recorded as described by Barker et al. . With this leakage detection technique, radiolabeled albumin is injected into the perfusion circuit and a detector is placed over the veno-venous bypass pump, which detects the appearance of such radiolabeled albumin in systemic circulation.
All the measurements were recorded and stored via the MedicView (Systemdata, Gothenburg, Sweden) computerized system.
When steady-state conditions in the perfusion circuit were established and the target temperature had been reached in the liver, melphalan was added to the perfusion system. The perfusion was then continued for 60 min, after which the perfusion was discontinued and the liver was irrigated with low molecular weight Dextrane (Rheomacrodex; Pharmalink, Stockholm, Sweden). The shunts and the perfusion circuit were disconnected and the patients were autotransfused with blood from the veno–veno bypass circuit before the catheters were removed.
In the IHP I cohort, melphalan was added to the perfusion system at a dose of 0.25 mg/kg of body weight on two different occasions 20 min apart. Of the 11 patients in this cohort, seven received additive cisplatinum therapy at a dose of 0.5 mg/kg of body weight and two patients received additive tumor necrosis factor α (TNF-α) therapy at 30 μg. In the IHP II cohort, melphalan was administered at a dose of 2 mg/kg of body weight divided into two doses, administered 30 min apart. In the IHP III cohort, melphalan was administered at a dose of 1 mg/kg of body weight divided into two doses, given 30 min apart. The actual measured temperatures and perfusion flows are depicted in Table 2.
All measurable and nonmeasurable lesions were recorded at baseline and subsequently measured/recorded during assessments scheduled at intervals of 8–12 weeks postperfusion during the first postoperative year and then at the discretion of the patient's primary oncologist. Assessment of the lesions was done by CT or MRI scans using WHO criteria: complete response (CR) was interpreted as disappearance of measurable lesions in the liver, partial response (PR) was achieved when the overall tumor size in the liver had decreased by at least 50% or more and stable disease was estimated as no more than a 25% decrease or increase in liver tumor burden. A quantification of tumor necrosis was not done. Responses were assessed on liver lesions and when new lesions outside the liver were objectified; no consequent follow-up of the liver was done.
The survival probability was analyzed using the Kaplan–Meier method (Stat-view 5.0; Abacus Concepts Inc., Berkeley, California, USA). Time to tumor progression was calculated as the time from day of perfusion to tumor progression on CT/MRI or clinical signs of tumor progression or of clinical deterioration, that is, palpable mass in abdomen or elsewhere, clinical jaundice, anorexia and decreasing body weight.
ANOVA factorial (Stat-view 5.0) was used to analyze differences between groups.
The conduct of the protocol and patient follow-up was performed at the Department of Surgery, Unit for Transplantation and Liver Surgery, Sahlgrenska University Hospital, Gothenburg. The study was carried out in compliance with the Declaration of Helsinki principles. The IHP II and III trials were approved by the Regional Ethics Committee of the Medical Faculty of the University of Gothenburg. Following a detailed explanation of the study, informed consent was obtained for participation in the IHP II series and the IHP III series.
In the IHP I cohort, PR in the liver was objectified in six of the 11 patients for a median of 10.4 months (range 4.3–41.5 months), and stable disease was seen in two patients for 2.9 and 9.8 months, respectively (Table 3). In five of the IHP I cohort patients, melanoma metastasis was reported in extrahepatic tissue before or concomitant with progression of the liver metastases. The IHP I cohort response rate was 55%. All patients in this cohort were followed up until death.
In the IHP II cohort, a CR was objectified in two of the 11 patients. One CR patient, who is now 57 months post-liver perfusion, experienced lung metastasis at 9.3 months, which was treated with radiation and dacarbazine therapy. The other CR patient is now at 46.8 months without tumor progression. Six patients in the IHP II cohort had a PR for a median of 8.6 months (range 2.7–24.6). In this group, extrahepatic tumor metastases were reported before or concomitantly with the progression of liver metastases in six patients. The IHP II cohort response rate was 73%. The shortest follow-up time was of 26 months.
In the IHP III cohort, all patients, five of five, reported a PR rate at 3 months, and two of the five had progressed with pulmonary metastases after 3.2 and 5.5 months. The IHP III cohort response rate at 3 months was 100%. Median follow-up in this cohort was 7 months (range 4–18).
The overall response rate was 70% (19/27). The overall response rate of the two recent, prospective cohorts (IHP II and IHP III) was 81% (13/16).
A similar distribution of response rates was encountered for ocular and nonocular melanoma.
Median survival for the 27 patients was 7.5 months (range 0–57 months) (Fig. 1). If the six postoperative deaths are excluded, the median survival increases to 12.6 months (2.5–57 months).
Significant differences were found among the three cohorts in liver temperatures (IHP I vs. IHP II and IHP III; P=0.0217 vs. P=0.055) and blood perfusion rates (IHP I vs. IHP II and IHP III; P=0.004 vs. P=0.0054) (Table 2).
No statistically significant correlation was found between peak increase in bilirubin and tumor response as well as between peak increase in aspartate amino transferase and tumor response (Table 4).
Time to tumor progression or death because of any other reason is illustrated in Fig. 2.
The final cause for the six fatal outcomes was multiorgan failure (MOF) based on intractable liver insufficiency. One patient in the IHP II cohort recovered from MOF and one patient in the IHP I cohort had major bleeding on the fourth postoperative day. One patient in the IHP I cohort with a tumor volume above 75% was treated prophylactically with plasmapheresis. Eight patients experienced serious perioperative complications consistent with a large volume of bleeding (more than 6 l) (Table 2). Thirteen of the patients had an uneventful postoperative course; four of those patients with an uneventful postoperative course did have a tumor volume of greater than 50%. One of the two patients in the IHP I cohort who received TNF-α, in addition to melphalan in the perfusate, experienced a significant major postoperative bleed and the other had an uneventful course.
The nadir leukocyte count in IHP II was not significantly lower than in IHP I (P=0.07).
The preoperative median value of platelets was 261×109/l (range137–483×109/l) which declined to nadir median value of 94×109/l (20–240×109/l). The nadir value was most often reported on the third postoperative day. The nadir thrombocytes were lower in IHP II versus IHP I and IHP III (Table 5).
The leakage in the IHP II cohort and the IHP III cohort was measured in 12 patients. In nine patients no leakage was registered and in the remaining it was 0.9, 8.0 and 27%. The patient, with a 27% leakage, who was given 2 mg melphalan per kg of body weight in the perfusate, got the lowest postoperatively registered leukocyte nadir count of 0.4×109/l.
Comparison of postoperative deaths to survivors
Three patients in the IHP I cohort and three patients in the IHP II cohort died during the postoperative period (Table 5). The six patients who died in the early postoperative period also had higher preoperative serum bilirubin than the postoperative survivors and on the first postoperative day, they had significantly higher serum bilirubin values and ASAT values than the other 21 patients, but all patients were scored to Child–Pugh A. These six patients also had significantly larger relative body weight increases postoperatively than their counterparts (Table 6).
No statistical differences were present in liver temperature and in flow rate of the liver perfusion between the six patients who died postoperatively and the other 21 patients.
In this study, hyperthermic liver perfusion with melphalan demonstrated an encouraging overall response rate (CR and PR) of 70% (Table 3). This is far better than the percentages reported after traditional systemic chemotherapy, and is consistent with what has previously been reported for IHP strategies . Five patients were longtime survivors (45, 46, 46, 47 and 57 months), indicating that among a minority of patients a longtime tumor response could be achieved.
In IHP there is a delicate trade-off between efficacy and risk of the procedure. The high tumor response rates are counteracted by the high rate of postoperative mortality owing to liver insufficiency and MOF. Technically, the procedure was simplified when the portal infusion was omitted in IHP II. Further, the splanchnic shunting decompression and the internal lower caval vein bypass were substituted by external shunting from lower caval vein to upper caval vein. Undoubtedly, the major surgical trauma with complete isolation of the liver contributes to the high morbidity and further simplification is warranted. Procedures with a percutaneous approach have been given by Eggermont et al. .
The occurrence of six postoperative deaths in the IHP I and IHP II cohorts necessitated an analysis of associated factors (Table 6). Concerning laboratory values that are related to poor liver function, preoperative bilirubin was higher and preoperative thrombocytes were lower among those that succumbed (Table 6). Four of these six patients had a tumor volume estimated to be above 75% of the liver volume. Based on this, patients with a tumor volume in the liver estimated on the preoperative CT to be more than 50% of the liver volume were disqualified from entering IHP III. A similar conclusion with respect to liver toxicity that at least 50% of functional liver tissue should be present in patients subjected to IHP was stated by van Etten et al. .
Toxicity from IHP has mainly three causes: toxicity of hyperthermia that increases with temperature, the systemic toxicity in the event of leakage from the perfusion system and the liver toxicity related to the dose of melphalan or any other drug given during hyperthermia. To diminish the risk of additional toxicity from hyperthermia, which undoubtedly was high (41.4±0.8°C) in IHP I, a decision was taken to reduce the maximal temperature to 40°C in the liver parenchyma in IHP II. With this limited material, however, no statistical support could relate mortality to temperature. Eliminating systemic leakage might be technically demanding. Two of the 12 patients, in whom the leakage from the perfusate was measured, had a significant leakage. These two patients came out with significantly lower nadir leukocyte count than the other 10 patients. This advocates the leukocyte count as one indicator of leakage. Systemic toxicity was reflected mainly by the decline in thrombocytes in IHP II patients in whom a significantly lower nadir thrombocyte count was registered than in IHP II and IHP III.
Grade 3/4 hepatic toxicity is reported in 65% of the patients when using 1.5 mg/kg melphalan in the perfusate . Melphalan was the drug used, but in the first IHP I study, seven patients received additive cisplatinum in the perfusate and two patients received additive TNF-α (30 μg). Based on the less supporting experience of TNF-α perfusion in patients without melanoma indication for perfusion, the TNF-α was eliminated. Of the 11 patients who were administered 2mg/kg body weight of melphalan in the perfusate (IHP II), three patients succumbed postoperatively owing to liver and MOF although two of them had a tumor volume of less than 50%. Thus, with 2 mg/kg of melphalan, we hypothesized that the maximal tolerated dose was surpassed. Experimental evidence is found in mice that melphalan induces hepatotoxicity, which is mediated by the induction of membrane-bound tumor necrosis factor expression in Kuppfer cells and it is suggested that hyperthermia could confer protection against this toxicity .
The strategy behind the IHP III cohort was to lower the dose of melphalan (1mg/kg body weight) and to not treat patients with an estimated tumor volume above 50%. These modifications have resulted in an uneventful postoperative course and a 3 months response rate in five of five patients.
The overall reported survival rate in the 27 patients (median 7.5 months including all postoperative deaths and 12.6 months without postoperative deaths) and our report of 18.5% (5/27) of patients surviving for 45 months or more are promising data. These survival figures can be favorably compared with an analysis of 1158 stage IV melanomas in which only a minority of the patients with visceral metastases were alive beyond 1 year . Another analysis of 1362 patients with metastatic melanoma reported a median survival rate of 6.4 months (95% confidence interval, 6.1–6.9 months) and only 12% responded to protocol treatment .
In this study, 74% of the melanomas had an ocular origin, as they have a tendency for liver metastases. All but one, however, had extrahepatic tumor recurrences and were subjected to chemotherapy, IL-2 or best supportive care at recurrence. When presenting IHP as an option for patients with liver metastases from MM, it must be noted that although a temporary local control in the liver can be achieved, the tumor continues to progress in extrahepatic organs. Optimally, the rapid tumor necrosis that occurs with the perfusion should be combined with a systemically effective treatment. In the future, the isolation perfusion technique may be combined with biotherapy and gene therapy [25,26].
In conclusion, IHP has consistently demonstrated temporary partial tumor control of liver metastases from MM. So far, a dose of 1-mg/kg body weight melphalan in the perfusate and 40°C hyperthermia seem to be well tolerated. Until a more effective systemic chemotherapy is available, IHP can benefit a carefully selected group of patients with liver metastases from MM, but tumor progression at extrahepatic locations will dramatically diminish the benefit of the procedure. This analysis supports the concept that IHP with melphalan should be further explored, preferably with an additional treatment integrated to prevent the progression of extrahepatic cancer.
All the authors contributed in the conception of this study, analysis of data and in writing this communication. Per Lindner reports being an employee of Genzyme Corp. No other conflicts of interest relevant to this article were reported. The study was supported by grants from the Swedish Cancer Research Foundation (Cancerfonden) no. 5029 B06 02xBB.
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