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10.1245/ASO.2005.12.038
Annals of Surgical Oncology 12:398-405 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Hyperthermic Isolated Perfusion With Low-Dose Tumor Necrosis Factor {alpha} and Doxorubicin for the Treatment of Limb-Threatening Soft Tissue Sarcomas

Carlo Riccardo Rossi, MD1, Simone Mocellin, MD1, Pierluigi Pilati, MD1, Mirto Foletto, MD1, Luca Campana, MD1, Luigi Quintieri, PhD2, Gian Luca De Salvo, MD3 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 Pharmacology and Anesthesiology, University of Padova, Largo Meneghetti, 2, 35131 Padova, Italy
3 Clinical Epidemiology Unit, Regional Oncology Centre, Via Gattamelata, 6, 4 35128 Padova, Italy

Correspondence: Address correspondence and reprint requests to: Carlo Riccardo Rossi, MD; E-mail: carlor.rossi{at}unipd.it.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Tumor necrosis factor (TNF)-{alpha}–based hyperthermic isolated limb perfusion (HILP) is one of the most active available approaches for locally advanced soft tissue sarcomas (STS) of the limbs. The aim of this study was to investigate the anticancer activity of a novel drug regimen including doxorubicin (DXR) and low-dose TNF-{alpha}.

Methods: HILP with low-dose TNF-{alpha} (1 mg) and DXR (8.5 mg/L of limb volume) was given to 21 patients with limb-threatening STS: 14 had primary and 7 had recurrent STS, most of which were high grade (grade 1, n = 3; grade 2, n = 6; grade 3, n = 12). Resection of the tumor remnant was performed 6 to 8 weeks after HILP. TNF-{alpha} concentrations in plasma and perfusate were measured throughout perfusion.

Results: A major tumor response was observed at histology and clinical evaluation in 90% and 62% of patients, respectively. After a median follow-up of 30 months, limb salvage and local disease control were achieved in 71% and 81% of cases, respectively. Fourteen patients had moderate regional toxicity, which was resolved in all cases. One patient had severe limb toxicity, which did not require amputation. Systemic side effects were minimal, and there were no postoperative deaths. The perfusate/plasma area under the curve ratio for TNF-{alpha} was 56.

Conclusions: HILP with low-dose TNF-{alpha} and DXR seems to be an active neoadjuvant drug regimen against limb-threatening STS. This therapeutic approach can achieve high limb-sparing surgery rates with acceptable local and negligible systemic toxicity.

Key Words: Limb-threatening soft tissue sarcoma • Isolated limb perfusion • TNF-{alpha} • Doxorubicin


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Soft tissue sarcomas (STS), a heterogeneous group of malignant tumors that originate in mesenchymal tissue and account for approximately 1% of all malignancies, mainly affect the limbs. Surgical resection combined with high-dose adjuvant external beam radiotherapy is the treatment of choice.1,2 However, limb-sparing surgery is not always feasible because of the size and extent of the tumor or the proximity of vital structures; mutilating surgical procedures or amputation is occasionally necessary.1,3–6 Currently, one of the most promising limb-saving procedures is hyperthermic isolated limb perfusion (HILP) combined with delayed tumor excision.7,8 The main advantages of HILP are as follows: (1) it allows cytostatic concentrations 15- to 20-fold greater than those achieved with systemic administration,9,10 and (2) hyperthermia, under which HILP is performed, can enhance the cytotoxic effect of some antiblastic agents, such as melphalan and doxorubicin (DXR).11,12

The encouraging results reported in 1992 by Lienard et al.,13 who used HILP to administer high-dose (3–4 mg) human recombinant tumor necrosis factor (TNF)-{alpha} in combination with melphalan, prompted others to perform HILP with melphalan and high-dose TNF-{alpha} administration in the treatment of locally advanced limb STS; tumor response and limb-sparing rates of up to 84% and 82%, respectively, have been reported.13–17

One concern regarding the use of TNF-{alpha} in humans is systemic toxicity, which can be severe if important perfusate-to-plasma leakage occurs,13,18–20 because TNF-{alpha} can cause a shocklike syndrome. Accurate real-time monitoring of leakage is therefore of crucial importance in minimizing the risk of systemic toxicity.21

Because DXR is one of the most active antiblastic drugs for STS single-drug systemic chemotherapy,22 we conducted a phase I/II study to determine its maximum tolerated dose (MTD) when administered via HILP in combination with TNF-{alpha}23,24 and found that the administration of low-dose (1 mg) TNF-{alpha} combined with DXR was followed by complete or partial tumor response in some cases. We therefore conducted a formal phase II study to assess the activity of HILP with low-dose TNF-{alpha} and DXR in the treatment of limb-threatening STS. In this article, we report on the clinical outcome of 21 patients enrolled in this phase II study and discuss the pharmacokinetic findings that support the use of low-dose TNF-{alpha}.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between January 1998 and April 2002, 21 patients were enrolled in the study, which was conducted in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. The protocol received written unconditional approval by the local ethics committee. Criteria for inclusion in the study were (1) a histological diagnosis of limb STS; (2) locally advanced disease (multicompartmental/multi-focal; bone or neurovascular infiltration) requiring amputation or major mutilating surgery; and (3) patients’ fully informed consent. All patients underwent preoperative computed tomography (CT) or magnetic resonance imaging (MRI) scans. In all cases, HILP lasted for 90 minutes; 1 mg of TNF-{alpha} (Beromun; Boehringer, Ingelheim, Germany) was injected at the beginning of perfusion, and DXR 8.5 mg/L of limb volume (Adriblastina; Pharmacia, Milan, Italy) was added after 30 minutes. The DXR MTD in combination with TNF-{alpha} was previously determined in a phase I study conducted by our group,24 in which DXR dosage was expressed as milligrams per kilogram of body weight. Because after that trial unexpected grade 4 locoregional toxicity occurred in some patients (3 of 12), in this study the DXR dosage was calculated per liter of limb volume (8.5 mg/L). Toxicity occurred only with DXR doses of 9 mg/L or higher. This finding might be explained by the fact that there is probably little correspondence between body weight and limb volume, particularly in patients with android obesity. Moreover, our decision was supported by the fact that the dose of antineoplastic drugs calculated per liter of limb volume is widely used in HILP.15,16

The surgical technique for HILP adopted in this study is described in detail elsewhere.23,25 Briefly, the main artery and vein of the affected limb (axillary or femoral/iliac vessels for the upper or lower extremity, respectively) were exposed and encircled with tourniquets. After systemic heparinization, the tourniquets were tightened, and arterial and venous cannulas were inserted in the vessels by means of a transverse incision. For the upper limb, an Esmarch tourniquet was placed proximal to the upper deltoid, whereas for the lower limb, it was placed around the root of the thigh, at the inguinal crease.

Cannulas were connected to the extracorporeal circuit, and circulation was restored via a roller pump. Arterial flow rates of 40 to 60 mL/min/kg of limb weight were used. The perfusate was oxygenated and heated to 42°C in a water bath. Limb temperature was monitored by thermometric probes inserted in the tumor, the subcutaneous tissue, and the muscles proximal and distal to the tumor. Once the temperature had stabilized, 99mTc-albumin (.5 MBq/kg) was injected into the circuit to measure perfusate/plasma leakage by means of a gamma probe placed over the heart and connected to the gamma counter for continuous monitoring and recording.26 At the end of perfusion, the limb was rinsed with 3000 mL of .9% saline solution and refilled with 1000 mL of low-molecular-weight dextran solution. On post-HILP days 0, 1, and 2, 18% mannitol solution (500 mL/day) was administered to increase diuresis and minimize the risk of renal failure from myoglobin precipitation. No additional treatment was given in the interval between HILP and delayed tumor resection.

Before tumor excision, patients underwent CT or MRI scans to evaluate tumor necrosis/shrinkage, as well as the relation of the tumor to surrounding structures, to plan the surgical approach. Post-HILP surgery, performed 6 to 8 weeks after perfusion, consisted of marginal resection, wide resection, or amputation. External beam radiotherapy (55–70 Gy), with the shrinking field technique, was administered only after marginal resection. All patients underwent postoperative physical examination, CT scans of the chest and upper abdomen, and CT/MRI of the perfused limb every 4 months for the first 2 years and every 6 months thereafter for 3 years.

The clinical response was evaluated according to National Cancer Institute criteria: complete response indicates the disappearance of all measurable disease; partial response indicates tumor shrinkage more than 50%; no change indicates tumor shrinkage less than 50%, stable disease, or tumor progression less than 25%; and progressive disease indicates tumor progression greater than 25%.

For histology, the surgical specimen was sectioned along the longitudinal and transverse planes to calculate the mean percentage of tumor necrosis by (1) macroscopic evaluation of necrotized tissue and (2) histological examination of the tumor tissue surrounding the necrotic area. Tissue without identifiable nuclei was considered necrotic; response was ranked as follows: very good response indicated more than 90% necrosis; partial response indicated 50% to 90 % necrosis; and no response indicated less than 50% necrosis.

Locoregional toxicity was evaluated according to Wieberdink and colleagues’ criteria27 (Table 1Go), and systemic toxicity was classified according to the World Health Organization system.


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  		TABLE 1. Wieberdink’s criteria for the classification of locoregional toxicity after hyperthermic antiblastic isolated limb perfusion
 
Two patients (9%) with disease-free resection margins measuring less than 1 cm underwent adjuvant radiotherapy.

Throughout HILP, the TNF-{alpha} concentration was determined in plasma and perfusate by means of enzyme-linked immunosorbent assay by using the Quantikine TNF-{alpha} kit (R&D Systems, Minneapolis, MN), by following the manufacturer’s instructions. Recombinant TNF-{alpha} was used as a standard. The assay range was from 15.6 to 1000 pg/mL of TNF-{alpha}. At 0, 5, 15, 30, 60, and 90 minutes, perfusate and plasma samples were obtained for pharmacokinetic analysis.

The one-sample multiple testing procedure for phase II clinical trials28 was used to test the hypothesis that the anticancer activity of HILP with TNF-{alpha} and DXR would be between a minimum very good response rate (histologically evaluated; null probability [P0] = 30%), below which further investigation was not required, and a very good response rate (alternative probability [P1] = 60%), implying an acceptable level of activity. The total number of assessable patients required was 20, with a two-sided test sized at 5% and a power of accepting P1, if true, of 80%. The HILP procedure was to be declared promising if 11 or more complete responses were observed. The proportion of responses and 95% confidence intervals (CIs) were determined.

The Kaplan-Meier method was used to analyze overall and local disease–free survival. The time course of TNF-{alpha} concentrations was best described by a monoexponential decay with an offset in the perfusate and by a biexponential association in the plasma. The best fit procedure was performed by using GraphPad Prism (version 2.0; GraphPad Software, San Diego, CA) software. The area under the concentration/time curves from 0 to 90 minutes in perfusate and plasma were calculated with the trapezoidal rule.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The median age of patients (11 men and 10 women) at the time of diagnosis was 40 years (range, 25–71 years). Tumors were located in the upper and in the lower limb in 3 (14%) and 18 (86%) patients, respectively. At the time of HILP, three patients (14%) had distant metastases.

The histological tumor types were liposarcoma (n = 4; 19%), malignant peripheral nerve sheath tumor (n = 4; 19%), malignant fibrous histiocytoma (n = 3; 14%), synovial sarcoma (n = 5; 24%), leiomyosarcoma (n = 2; 9%), extraosseous myxoid chondrosarcoma (n = 1; 5%), rhabdomyosarcoma (n = 1; 5%), and angiosarcoma (n = 1; 5%). Tumor grade distribution was as follows: grade 1, n = 3; grade 2, n = 6; and grade 3, n = 12. All the tumors were deeply situated and large (median diameter, 11 cm; range, 4–30 cm).

Seven patients (33%) were referred to our institution for recurrent disease; on average 6 months previously, they had undergone marginal excision for the primary tumor, combined with radiotherapy in one case. The other 14 patients had primary STS, diagnosed by means of core or incisional biopsy. The mean time between tumor biopsy and HILP was 18 days (range, 10–34 days). Tumor characteristics are listed in Table 2Go.


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  		TABLE 2. Characteristics of tumors in 21 patients affected with locally advanced soft tissue sarcoma and treated with hyperthermic isolated limb perfusion with low-dose TNF-{alpha} and doxorubicin
 
HILP Procedure
The duration of HILP was 90 minutes for all patients. The mean muscle temperature was 41.2°C (range, 39.4°C–41.6°C), and the mean DXR dose was 9.6 mg (range, 8.4–10.8 mg) and 3 mg (range, 2.4–3.6 mg) for the upper and lower limb, respectively. Mean perfusate/plasma leakage, measured by scintigraphy, was 3% (range, 1%–7%).

Morbidity and Mortality
There were no postoperative deaths. Wound infection occurred in four patients (19%). In the postoperative period, there were no cases of deep venous thrombosis or arterial occlusion to the treated limb.

Grade 1, 2, or 3 locoregional toxicity was observed in six (29%), eight (38%), and six (29%) patients, respectively. None of these patients had any permanent sequelae. One patient (4%) had grade 4 locoregional toxicity, which was characterized by compartmental syndrome requiring fasciotomy (to prevent leg ischemia), after which the patient developed external and internal popliteal nerve palsy. This patient had been previously treated with radiotherapy and had undergone two surgical procedures (at the tumor site) before undergoing HILP.

In six patients, chronic but reversible regional neuralgia occurred that required antalgic therapy of 4 to 8 months’ duration. Systemic toxicity, consisting of grade 1 nausea/vomiting, was reported in three cases (14%).

Tumor Response
Histological response was evaluated in 20 of 21 cases because the patient who had a complete clinical response refused to undergo surgery after HILP. Histological response rates were as follows: 11 very good responses (55%; 95% CI, 32%–77%), 7 partial responses (35%), and 2 no change (10%). Out of the 11 very good responses, 4 were complete. A major histological response (complete plus very good plus partial responses) was recorded in 90% of patients (95% CI, 70%–97%). Clinical response was complete in 1 case (5%) and partial in 12 cases (57%), whereas no change was observed in 8 patients (38%; Fig. 1Go).


Figure 1
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  		FIG. 1. Computed tomographic scan evaluation of a recurrent liposarcoma of the thigh before (a) and 5 weeks after (b) hyperthermic isolated limb perfusion (HILP) with low-dose tumor necrosis factor {alpha} and doxorubicin. Massive tumor necrosis (>90%) was found at histology examination after HILP.

 
Clinical Outcome
Limb-sparing surgery after neoadjuvant HILP was performed in 17 (85%) of 20 patients, who underwent delayed tumor exeresis. After a median follow-up of more than 2 years (30 months; range, 8–59 months), local recurrence was observed in three patients (14%), who were treated with delayed limb amputation. Therefore, the overall limb salvage rate at the time of writing was 71% (15 of 21).

To date, 12 patients (57%) are alive without disease, 4 (19%) are alive with disease (lung metastases, n = 3; local recurrence, n = 1), 4 (19%) died of disease, and 1 died of other causes (suicide). Data on local disease–free survival are shown in Fig. 2Go.


Figure 2
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  		FIG. 2. Kaplan-Meier local disease–free survival analysis of 21 patients with locally advanced soft tissue sarcoma of the extremities treated with hyperthermic isolated limb perfusion with low-dose tumor necrosis factor {alpha} and doxorubicin. After a median follow-up of 30 months, the median local disease-free time was not reached.

 
TNF-{alpha} Pharmacokinetics
Pharmacokinetic findings confirmed that perfusate-to-plasma leakage was minimal during HILP. At analysis of the time course of TNF-{alpha} concentrations in perfusate and plasma, the perfusate/plasma area under the concentration/time curves from 0 to 90 minutes ratio was 56. TNF-{alpha} concentrations in the perfusate decreased during the first 20 minutes in a monoexponential fashion (half-life, 5.4 minutes), after which stable values were reached and maintained until the end of HILP (Fig. 3Go). Initially, there was a rapid increase in TNF-{alpha} plasma concentrations (half-life, 3.1 minutes) followed by a very gradual increase (half-life, 1.6 hours). Overall, these observations confirmed that, as observed at real-time monitoring during HILP, TNF-{alpha} leakage in the systemic circulation was minimal.


Figure 3
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  		FIG. 3. Time courses of tumor necrosis factor (TNF)-{alpha} concentrations (ng/mL; mean ± SD) in perfusate and plasma during hyperthermic isolated limb perfusion performed in 21 patients with locally advanced soft tissue sarcomas. The perfusate/plasma area under the curve ratio was 56.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In Europe, after the registration of TNF-{alpha} by the European Agency for the Evaluation of Medicinal Products, TNF-{alpha}–based HILP has become one of the most widely used treatments for limb-threatening STS.13–16,29–33 The main advantages of this therapeutic strategy are that it allows a high rate of limb salvage and local disease control, whereas its two main disadvantages are the potential systemic toxicity and the high costs. As for the latter issue, recombinant human TNF-{alpha} is available on the market at the price of {euro}2300/mg. Costs therefore range from {euro}6900 to {euro}9200 per procedure if investigators use 3 to 4 mg of TNF-{alpha}.

Some investigators have suggested that low-dose TNF-{alpha}–based HILP may be as active as HILP with higher doses of this cytokine.34 The results of our phase I/II study of HILP with TNF-{alpha} combined with DXR showed no improvement in tumor response with cytokine doses greater than 1.6 mg, but the observed locoregional toxicity rate increased.23,24 In this phase I/II study, DXR was chosen rather than melphalan: first, because it is considered to be the most active single antiblastic drug available for the treatment of STS22; second, because a previous phase II study from our institution demonstrated that HILP-administered DXR is active and well tolerated25; and third, because in vitro experiments demonstrated that both DXR35,36 and heat37,38 have a synergistic antitumoral effect when combined with TNF-{alpha}. Finally, it has recently been demonstrated that TNF-{alpha} increases DXR uptake by the tumor.39

In the 2 years after the previously described study, we treated 12 patients with DXR MTD (DXR .7–1.4 mg/kg of body weight plus 1 mg of TNF), but we also measured the limb volume of each patient undergoing HILP. In fact, one criticism made of our phase I/II study was that the DXR dose had not been calculated on the basis of limb volume (as is routine with melphalan). Three of these 12 patients had grade 4 locoregional toxicity. On analyzing the data from this group of patients, we observed that, if we expressed DXR dosage per liter of limb volume (total dose of administered DXR divided by liters of limb volume), grade 4 toxicity occurred in patients who received dosages of 9 mg/L or more. We therefore decided to perform a formal phase II study to assess the tumor response rate and locoregional toxicity after HILP by using the novel drug regimen (1 mg of TNF plus 8.5 mg/L of limb volume).

In the present series of patients who underwent HILP, the administration of low-dose TNF-{alpha} (1 mg) plus DXR led to tumor response, limb salvage, and local disease control rates of 90%, 71%, and 86%, respectively, at a follow-up of more than 2 years. These results are comparable with those reported by several authors who used 3 to 4 mg of TNF-{alpha} combined with melphalan.15,16,30,31,40,41 Furthermore, systemic toxicity was minimal, and severe locoregional toxicity occurred in only one patient, who had undergone repeated surgical procedures and radio-therapy to the diseased limb before HILP.

These encouraging results obtained with low-dose TNF-{alpha} might be related to a TNF-{alpha} receptor saturation mechanism, as suggested by in vitro cytotoxicity experiments.42 Our pharmacokinetic study showed that the TNF-{alpha} perfusate concentration is roughly 20-fold that of in vitro cytotoxic TNF-{alpha} dosages.43 Moreover, we found that TNF-{alpha} perfusate levels, after a short initial decay (20 minutes), remain quite constant during HILP, thus supporting the hypothesis that tissue uptake is fast and systemic leakage minimal.

Overall, these observations suggest that TNF-{alpha} might be administered in doses lower than those used so far by most investigators. However, a randomized study comparing different TNF-{alpha} dosages is warranted to define the optimal HILP drug schedule for the treatment of limb STS. Moreover, because the number of patients enrolled in this phase II trial was small, the actual rate of DXR-related toxicity might have been underestimated. Therefore, further studies on larger series are probably required to define the optimal DXR dosage for HILP.

Received for publication December 16, 2003. Accepted for publication December 22, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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