Hyperthermic Isolated Hepatic Perfusion Using Melphalan for Patients with Ocular Melanoma Metastatic to Liver

Vol. 9, 6343–6349, December 15, 2003 Clinical Cancer Research 6343

H. Richard Alexander, Jr.,1 Steven K. Libutti,1 survival after disease progression is short. On the basis of a James F. Pingpank,1 Seth M. Steinberg,2 pattern of tumor progression predominantly in liver, con- David L. Bartlett,1 Cynthia Helsabeck,1 and tinued clinical evaluation of hepatic directed therapy in this patient population is justified. Tatiana Beresneva1 1Surgical Metabolism Section, Surgery Branch, Center for Cancer Research and 2Biostatistics and Data Management Section, Center for INTRODUCTION Cancer Research, National Cancer Institute, Bethesda, Maryland There are ϳ54,200 new cases of malignant melanoma diagnosed annually in the United States (1), of which 3–6% are ABSTRACT primary ocular melanoma representing up to 4,000 new cases/ Purpose: Liver metastases are the sole or life-limiting year (2). Metastatic disease occurs in 40–60% of patients with component of disease in the majority of patients with ocular ocular melanoma (3), and unresectable hepatic metastases rep- melanoma who recur. Because median survival after diag- resent the life-limiting component of progressive disease in nosis of liver metastases is short and no satisfactory treat- ϳ80% of patients with ocular melanoma in this setting (3–5). ment options exist, we have conducted clinical trials evalu- Even with aggressive treatment, the median survival after liver ating isolated hepatic perfusion (IHP) for patients afflicted metastases from ocular melanoma are diagnosed is between 2 with this condition. and 7 months and 1-year survival is ϳ10% (5). Therapeutic Experimental Design: Twenty-nine patients (male: 14, options are limited and none have been shown to meaningfully female: 15; mean age, 49 years) with unresectable liver alter the natural history of metastatic disease (5). metastases from ocular melanoma were treated with a 60- A variety of chemotherapeutic agents such as dacarbazine min hyperthermic IHP using 1.5 mg/kg of melphalan (mean and cisplatin or immunotherapeutic agents such as IFN, inter- total dose 105 mg). Via laparotomy, perfusion inflow was leukin 2, or monoclonal antibodies, and the antiangiogenic established with a cannula in the gastroduodenal artery and agent, thalidomide, have been administered either alone or in outflow via a cannula positioned in an isolated segment of combinations and have not been associated with remarkable the retrohepatic inferior vena cava. Portal and infra-renal antitumor efficacy (6–11). Combination regimens using chem- inferior vena cava blood flow was shunted externally to the otherapy and cytokines for patients with metastatic ocular mel- axillary vein using a veno-veno bypass circuit. Patients were anoma result in response rates of no Ͼ20% (12). assessed for toxicity, radiographic response, and survival. Regional treatment strategies for patients with unresectable Results: There was no treatment related mortality and hepatic metastases from ocular melanoma have been developed transient grade 3/4 hepatic toxicity was observed in 19 pa- because the natural history of this disease justifies measures to tients (65%). Mean length of operation and hospital stay was control tumor progression in the liver. The best results with 8.3 h and 10 days, respectively. There were 3 (10%) com- hepatic directed therapy have been with chemoembolization, plete responses (duration: 12, 14؉, 15 months) and 15 par- intra-arterial chemotherapy, and isolated hepatic perfusion tial responses (52%; mean duration: 10 months). The initial (IHP). Chemoembolization is performed using percutaneously site of disease progression included liver in 17 of 25 patients placed catheters to administer chemotherapy followed by infu- (68%) who recurred. At a median follow-up of 30.7 months sion of absorbable or nonabsorbable particles into the hepatic the median actuarial progression-free and overall survivals artery. Mavligit et al. (13) reported results of chemoemboliza- were 8 and 12.1 months, respectively. tion using cisplatin for patients with this condition and observed Conclusions: IHP with melphalan alone results in sig- a 50% response rate and a median survival time of 12 months. nificant regression of established liver metastases for pa- Leyvraz et al. (14) treated 31 patients with monthly intra-arterial 2 tients with ocular melanoma. However, after IHP, disease fotemustine (100 mg/m ) over 4 h via the hepatic artery. The progression is most commonly observed in the liver, and overall response rate (all partial) was 40%, the median duration of response was 11 months, and overall survival was 14 months. IHP has been under clinical evaluation for ϳ45 years but has not gained widespread application for a number of reasons. First, it is a complex therapy to administer, and, in initial studies Received 7/15/03; revised 9/8/03; accepted 9/22/03. The costs of publication of this article were defrayed in part by the of IHP, there was remarkable morbidity associated with the payment of page charges. This article must therefore be hereby marked procedure and no clearly documented efficacy (15). More re- advertisement in accordance with 18 U.S.C. Section 1734 solely to cently, we and others (16, 17) have reported results of IHP using indicate this fact. melphalan alone or in combination with tumor necrosis factor Requests for reprints: H. Richard Alexander, Jr., Surgical Metabolism Section, National Cancer Institute/NIH, 10 Center Drive, Building 10, (TNF) for patients with a variety of tumor histologies. We have Room 2B07, Bethesda, MD 20892-1502. Phone: (301) 496-2195; Fax: reported our initial results in 22 patients with IHP using mel- (301) 402-1788; [email protected]. phalan with or without TNF for patients with metastatic ocular

melanoma to the liver and observed an overall response rate of version 2.0 was used for toxicity and adverse event scoring. A 62% with a median duration of hepatic response of 9 months copy of the Common Toxicity Criteria version 2.0 is available (18). However, a number of treatment parameters that may have online.3 Acute systemic toxicity that corrected within 24 h of influenced outcome were used in that series of patients, includ- IHP or hepatic toxicity that corrected within 7 days of hepatic ing two doses of melphalan (1.5 and 2 mg/kg), 1 mg of TNF in perfusion were considered treatment related. 11 patients, and perfusion via the hepatic artery and portal vein IHP. The technique of IHP was performed as described in 5 patients. The current article analyzes outcome of 29 con- previously (16, 19). Briefly, via a laparotomy the liver was secutively treated patients using identical treatment parameters extensively mobilized, the inferior vena cava was isolated, and derived from previous feasibility and dose-seeking studies, the porta hepatis structures were completely dissected and pre- which includes a 60-min hyperthermic IHP with 1.5 mg/kg pared for cannulation. After heparinization, cannulae are in- melphalan alone with perfusion inflow via the hepatic artery. serted into the saphenous, portal, and axillary veins for veno- venous bypass, and the hepatic perfusion circuit is connected to cannulae positioned in the gastroduodenal artery and an isolated MATERIALS AND METHODS segment of retrohepatic inferior vena cava. Melphalan was Patient Population. Twenty-nine patients with meta- obtained from Glaxo-Wellcome (Research Triangle Park, NC), static unresectable biopsy proven ocular melanoma confined to and 1.5 mg/kg were added over 3–5 min to the arterial inflow liver underwent IHP between December 1997 and August 2002. line of the perfusion circuit and IHP continued for 60 min. After Patients were treated on three consecutively conducted clinical IHP, the liver was flushed with crystalloid and colloid solution, research protocols that were approved by the Institutional Re- and physiological blood flow was reestablished promptly to the view Board of the National Cancer Institute. Twenty-one of the liver. patients in this analysis underwent treatment on a Phase II study Statistical Analysis. An analysis of factors relating to evaluating efficacy of a 60-min hyperthermic IHP using 1.5 response and survival was performed in all patients. Patients mg/kg melphalan alone based on ideal body weight and with a were categorized as responders (partial or complete) or nonre- minimum total dose of 90 mg and a maximum total dose of 120 sponders, and continuously measured parameters were evalu- mg. Eight additional patients who were enrolled and treated on ated for their association with response using the Wilcoxon a previously conducted Phase I (n ϭ 6) or Phase II (n ϭ 2) study rank-sum test. Gender was compared with response using the ␹2 and who received IHP using the same treatment parameters as test. Logistic regression analysis was used to determine which the last 21 were included. Standard staging studies including factors were independently associated with response. computed tomography scan of the chest, abdomen, and pelvis, Survival was calculated from the on-study date until date of magnetic resonance imaging (MRI) of the liver, and as clinically death or last follow-up. The on-study date represented the day indicated, brain imaging or bone scan were performed. Eligibil- on which the patient signed informed consent and was registered ity criteria included Eastern Cooperative Oncology Group per- on the protocol, which was within 2 days of IHP. The proba- formance status of 0 or 1, a serum bilirubin Ͻ 2.0 mg/dl, a bility of survival was calculated using the Kaplan-Meier platelet count Ն 150,000/ml, and a serum creatinine Յ 1.5 method, and the significance of the difference between pairs of mg/dl. Kaplan-Meier curves was calculated using the Mantel-Haenszel Toxicity and Response. All patients were evaluated 6 procedure (20, 21). Initially, continuously measured parameters weeks after treatment and at 3–4 month intervals thereafter. were divided into quartiles to form groups for evaluation; sub-

Responses were scored by comparing gadolinium-enhanced T1- sequently, data were pooled when cutpoints in the data were or T2-weighted images on MRI scans or contrast-enhanced identified. The Cox proportional hazards model was used to computed tomography scans during follow-up with pretreatment identify which factors were jointly significant in association images. A complete response was defined as the disappearance with survival (22). of all radiographic evidence of disease based on computed All data are presented as mean and range unless otherwise tomography scan or MRI scan. A partial response was defined specified. A comparison with a two-tailed P Յ 0.05 was con- as a Ն50% decrease in the sum of the products of perpendicular sidered statistically significant, and the Ps have not been ad- diameters of all measurable lesions of 1 month’s duration with- justed for multiple comparisons. out progression (Ͼ25%) of any site; a minor response was defined as a 25–49% decrease in the sum of the products of the RESULTS perpendicular diameters of all measurable lesions. Any patient Demographics and tumor characteristics of the patient pop- Ͻ with less than a partial response or a response of 4 weeks ulation are shown in Table 1. There was an equal male to female duration was considered a nonresponder. Appearance of new distribution and the majority had not received prior therapy for Ͼ lesions or 25% increase in the products of the perpendicular of their condition. The time between initial diagnosis of the pri- known lesions after a partial response or a complete response mary melanoma and IHP treatment ranged from 4 months to 10 was scored as progressive disease. Because the therapy was years, which highlights the remarkable variability in the biology limited to liver and the entry criteria limited treatment to pa- of this malignancy as all patients were referred within a month tients with hepatic only disease, responses were assessed only on the measurable hepatic lesions. New lesions occurring out- side the liver were scored separately from new lesions occurring within the liver. The National Cancer Institute Common Toxicity Criteria 3 Internet address: http://ctep.info.nih.gov.

Table 1 Demographic and tumor characteristics of patients with metastatic lesions was counted at laparotomy, and the average hepatic metastases from ocular melanoma undergoing isolated number of 25 underestimates the true number because those hepatic perfusion (IHP) individuals who had Ͼ50 were scored as Ն50 nodules. The No. of patients 29 diameter of the largest lesion was based on trans-axial images of Age (yr, range) 49 (26–73) the T-1-weighted gadolinium-enhanced MRI, which usually Female:Male 15:14 Prior therapy for liver metastases provided the most discrimination in determining tumor margin None 22 from unaffected hepatic parenchyma. Similarly, the percent Interferon 7 hepatic replacement by tumor was estimated by viewing the Systemic chemotherapy 1 sequential axial views on the MRI scan. One-third of patients Prior surgery for liver metastasis None Ͼ Time between initial diagnosisa and IHP (mos) 4–125 had 25% hepatic replacement by tumor. Median 29 The mean total melphalan dose administered within the Mean 35 perfusion circuit was 105 mg based on a dosing schema of 1.5 Ͼ No. of metastatic lesions 25 (4– 50) mg/kg ideal body weight. However, the minimum and maxi- Diameter of the largest lesion (cm) 5.6 (2–14) % liver replaced by tumor mum total doses administered in the protocols were 90 and 120 Ͻ25% 20 (69%) mg, respectively. Mean flow rates during IHP were 750 ml/min 25–50% 8 (28%) and stable throughout the procedure consistent with our previ- Ͼ 50% 1 (3%) ous experience (23). The mean perfusion pressure of 138 mm a Diagnosis of primary tumor. Hg (range, 105–237 mm Hg) does not reflect the actual pressure within the hepatic artery proper but rather the pressure generated by flows through the 3-mm arterial inflow cannula positioned in or two of diagnosis of liver metastases. Of note, the number of the gastroduodenal artery. The hepatic artery pressure as esti- metastatic lesions in the liver was assessed at laparotomy, and mated by palpation at regular intervals during treatment was invariably, the number of metastatic lesions was greater what usually lower and estimated to be between 80 and 100 mm Hg. was imaged on contrast-enhanced computed tomography and The mean veno-veno bypass flow rate was 1600 ml/min, which T-1-weighted gadolinium-enhanced MRI scans. Many metasta- represented significant systemic venous return back to the heart ses Ͻ 5 mm in diameter and diffusely present in the hepatic during treatment and contributed to the stable hemodynamic parenchyma were frequently encountered, and in some circum- profile of the patients during treatment (23). Hepatic tempera- stances, the malignancy spread as a diffusely infiltrating process ture was assessed with two transhepatic temperature probes throughout the hepatic parenchyma (Fig. 1). The number of placed in the left and right lobes of the liver, as well as a flexible

Fig. 1 Intraoperative photo- graph taken from a patient with metastatic ocular melanoma to liver. The right lobe is reflected anteriorly as noted by the gall bladder (GB) inferiorly. Diffuse pigmented and nonpigmented metastases and larger infiltra- tive lesions (arrows)inthe right lobe and lateral to the fal- ciform ligament (FL) are present.

Fig. 2 T-2-weighted magnetic resonance imaging studies demonstrating a complete response in a patient with ocular melanoma metastatic to liver before (top panels) and 1 year after isolated hepatic perfusion (bottom panels).

thermister probe that was advanced into the portal venous sys- did not. Thus, baseline LDH appears to identify patients rea- tem during treatment. Prompt and uniform increase in hepatic sonably well who are likely to respond. parenchyma temperatures reflected uniform delivery of the per- The actuarial median hepatic progression-free survival in fusate through the entire hepatic parenchyma. Mobilization of 18 patients who initially had a response to treatment was 12 the liver and preparation of the vascular structures for hepatic months. Fig. 4 shows overall survival in the cohort of 29 perfusion accounted for the major portion of the operative time patients. The median time to disease progression at any site was (mean time, 8.3 h; range, 6–10 h). The perfusion itself lasted for 8 months, and the median overall survival was 12.1 months 60 min and the decannulation procedure was typically quite (range 3 to 39ϩ months). Twenty-five of 29 have had recur- short. However, we feel that the operative preparation of the rence; site of first recurrence was liver in 14, systemic in 8, and liver is important to ensure no leak of perfusate during treat- both in 3. ment. Consistent with our previous experience the mean hospi- Results of an exploratory univariate survival analysis iden- talization was ϳ10 days and 19 patients (65%) had reversible tified several factors that appeared to be associated with sur- grade 3 or greater hepatic toxicity. vival, including baseline LDH (100–160 versus 161ϩ), number All responses were assessed by standard radiographic cri- of metastases (1–20 versus 21–60), size of largest metastasis teria, and all 29 patients were assessable for response. There were three radiographic complete responses (10%; Fig. 2) and 15 partial responses (52%; Table 2, Fig. 3). Gender was not associated with response (p ϭ 0.32). Table 3 presents the Table 2 Results of treatment in patients undergoing isolated hepatic 2 perfusion for liver metastases from ocular melanoma results of analyses relating continuously measured parameters to response. As shown in the table, both lactate dehydrogenase n 29 (LDH) at baseline as well as the size of the largest metastasis Complete response 3 (10%) Duration (mos) 12, 14ϩ,15 were individually associated with response. Logistic regression Partial response 15 (52%) analysis was performed and was able to demonstrate that when Duration in months 10 (5–22) both factors were considered for evaluation, only baseline LDH Follow-up status a remained as significantly associated with response. Depending AWD 10 DOD 19 on the error probabilities one is willing to accept, the LDH Follow-up time (mos) cutpoint of ϳ275 could be used to classify patients into those Median 11 who were likely to respond (Ͻ275) versus those unlikely to Mean 13.5 respond. For example, of 27 patients with data, 16 of 20 (80%) Range 3–40 with LDH Ͻ 275 responded, whereas 7 of 7 with LDH Ͼ 275 a AWD, alive with disease; DOD, dead of disease.

Fig. 3 T-2-weighted magnetic resonance imaging studies demonstrating a partial response in a patient with ocular melanoma metastatic to liver before (top panels) and 4 months after isolated hepatic perfusion (bottom panels).

(1.5–7 versus 7.5ϩ cm), and percent hepatic replacement. Only the above factors were taken into consideration was baseline those factors that were associated with a marginal statistical LDH (0–160 versus Ͼ160, Fig. 4). Having a baseline LDH Ն significance in a univariate analysis (unadjusted P Ͻ 0.05) were 161 was associated with a hazard ratio of 17.1 with an associ- evaluated in a Cox model. Because trends in survival were not ated 95% confidence interval from 2.2 to 130.9 (P ϭ 0.0062). necessarily linear over the four quartiles used in the initial Thus, the magnitude of the baseline LDH is very useful to exploratory univariate survival analyses, for the Cox models, the identify the likely survival course of patients with ocular mel- data were dichotomized at the cutpoint that yielded the most anoma metastatic to the liver who are treated with IHP. significant results in the univariate analysis. As a result, the Cox model Ps may be biased because the cutpoints were selected based on an examination of the same data that went into the DISCUSSION model. However, the Cox models indicated clearly that the only These data show that IHP with hyperthermia and melpha- factor that was significantly associated with survival when all of lan can result in significant regression of metastatic ocular

Table 3 Relationship between response and continuously measured parameters in patients undergoing isolated hepatic perfusion (IHP)

Variable Category Mean n SE Min. Med. Max. P2 Baseline lactate dehydrogenasea Nonresp.b 548.0 11 167.2 154 335.0 1993 Resp. 173.0 16 10.9 101 159.5 275 0.0009 No. of metastases Nonresp. 28.7 11 5.8 4 25 55 Resp. 28.4 18 4.0 2 25 55 0.87 Size of largest metastases Nonresp. 8.3 11 0.7 4 9 12 Resp. 5.1 18 0.6 1.5 4.4 12 0.0048 Percentage of hepatic replacement Nonresp. 22.7 11 4.9 5 20 55 Resp. 15.5 18 2.2 5 15 40 0.25 Melphalan dose Nonresp. 98.2 11 3.4 81 95 120 Resp. 105.7 18 2.8 90 106.5 135 0.11 Age (yrs) Nonresp. 49.5 11 4.0 26 47 73 Resp. 47.1 18 2.2 27 46.5 64 0.65 Months from diagnosis to IHP Nonresp. 48.2 10 11.1 7 42.5 125 Resp. 28.2 18 4.2 4 23.5 70 0.13 a Upper limit of normal: 226 units per liter. b nonresp., nonresponders; resp., responders.

Fig. 4 Kaplan-Meier actuarial survival curves of 29 patients undergoing isolated hepatic (ء) perfusion for metastatic ocular melanoma to liver based on baseline lactate dehydrogenase (LDH) levels. Survival was significantly improved for 10 patients with baseline LDH Յ 160 (upper normal limit ϭ 226 units per liter) (G) compared to 17 patients with baseline LDH Ͼ 160 units per liter (ϫ).

melanoma to the liver in the majority of patients treated. How- patients, including two doses of melphalan (1.5 and 2 mg/kg), ever, the duration of response is variable and time to disease 1 mg of TNF in 11 patients, and perfusion via the hepatic artery progression at any site was relatively short (8 months). Of note, and portal vein in 5 patients. Outcomes from 6 patients in that hepatic recurrence was observed in two-thirds of patients who series are included in this study. did recur and tended to be at new sites of disease rather than IHP with melphalan alone appears to have comparable regrowth of established lesions. These data are consistent with outcome with respect to response and survival with other re- the observation that in individuals with in-transit extremity ported regional treatment strategies for patients with unresect- melanoma who have experienced a complete response to iso- able metastases from ocular melanoma. Mavligit et al. (13) lated limb perfusion using melphalan, with or without TNF, reported an objective response rate of 50% and an overall recurrences in the extremity are most commonly at new site of survival of 1 year using chemoembolization, and Leyvraz et al. disease (24). Taken together, these data suggest that micro- (14) reported a 40% response rate and 11-month overall survival scopic tumor deposits that do not have a well-established neo- using intra-arterial fotemustine (13, 14). Although all these vasculature may be somewhat resistant to isolation perfusion in strategies can result in regression of hepatic metastases, addi- general. tional treatment must be integrated to prolong duration of re- In this cohort, there was no treatment-related mortality, sponse and prevent progression of occult systemic disease. To although the toxicity associated with IHP can be substantial. that end, options are somewhat limited. Combination chemo- Overall the treatment related mortality in recently reported se- therapy with cytokine administration results in a 20% partial ries of patients undergoing IHP is Ͻ5% (15). We have previ- response rate for patients with this condition (12). ously shown that the use of TNF in IHP is associated with some Our data are consistent with others who have shown that additional regional and systemic toxicity compared with IHP baseline LDH is a significant independent prognostic factor with with melphalan alone, but the toxicities are transient and clini- respect to survival (14, 26). Our data confirm that observation cally straightforward to manage (25). The systemic toxicities and also demonstrate that baseline LDH is independently asso- may be because of the production of proinflammatory cytokines ciated with response. We noted that baseline LDH values Ͻ 275 such as interleukin 6 and interleukin 8 in the liver as a conse- were associated with an 80% response rate, whereas all 7 quence of high-dose TNF administration that result in a transient individuals with baseline LDH values Ͼ 275 did not have any hyperdynamic cardiovascular profile for the first 12–24 h after response to therapy. In the Cox proportional hazards model, we treatment. The greater question as to the role of TNF in isolated found that a baseline LDH of Յ160 was associated with a organ perfusion for in-transit extremity melanoma or unresect- significantly better survival than in individuals with baseline able hepatic metastases has not been defined in random assign- LDH values Ͼ 160. Therefore, baseline LDH appears to be a ment trials. We have reported initial results in 22 patients with very useful tool to identify the likely response or survival IHP using melphalan with or without TNF for patients with outcome for patients with ocular melanoma metastatic to liver metastatic ocular melanoma to the liver and observed an overall who are treated with IHP. response rate of 62% with a median duration of hepatic response In conclusion, IHP with melphalan appears to warrant of 9 months (18). However, various treatment parameters, as continued clinical evaluation for patients with hepatic metasta- dictated by the Phase I trial design, were used in that series of ses for ocular melanoma. The role of TNF in IHP for this

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H. Richard Alexander, Jr., Steven K. Libutti, James F. Pingpank, et al.

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