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10.1245/ASO.2005.03.093
Annals of Surgical Oncology 12:406-411 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Isolated Limb Perfusions With Tumor Necrosis Factor and Melphalan for Locally Recurrent Soft Tissue Sarcoma in Previously Irradiated Limbs

T. E. Lans, MD, PhD, D. J. Grünhagen, MD, J. H. W. de Wilt, MD, PhD, A. N. van Geel, MD, PhD and A. M. M. Eggermont, MD, PhD

Department of Surgical Oncology, Erasmus MC–Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: A. M. M. Eggermont, MD, PhD; E-mail: a.m.m.eggermont{at}erasmusmc.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Recurrent extremity soft tissue sarcoma (STS) in a previously operated and irradiated area can usually be managed only by amputation. Tumor necrosis factor (TNF)-{alpha}based isolated limb perfusion (ILP) is an established alternative to achieve limb salvage but is assumed to require sufficient vasculature. Because radiotherapy is known to destroy vasculature, we wanted to evaluate retrospectively whether the outcome of ILP in patients with radiotherapy for their primary tumor nonetheless showed a benefit from TNF treatment.

Methods: We consulted a prospective database of TNF-based ILPs at the Erasmus MC–Daniel den Hoed Cancer Center in Rotterdam. Out of 342 TNF-based ILPs between 1991 and 2003, 30 ILPs were performed in 26 patients with recurrent STS in the irradiated field after prior surgery and radiotherapy. Eleven patients (42%) had multiple tumors (n = 2–20). All patients were candidates for amputation.

Results: We observed 6 complete responses (20%), 15 partial responses (50%), no change in 8 patients (27%), and progressive disease in 1 patient (3%). The median duration of response was 16 months (range, 3–56 months) at a median follow-up of 22 months (range, 3–67 months). The local recurrence rate was 45% in patients with multiple tumors and 27% in patients with single tumors. Ten patients (35%) died of systemic metastases. Limb salvage was achieved in 17 patients (65%). Regional toxicity was limited and systemic toxicity minimal.

Conclusions: TNF-based ILP can avoid amputations in most patients with recurrent extremity STS in a prior operated and irradiated field.

Key Words: Isolated limb perfusion • Soft tissue sarcoma • Limb salvage • TNF • Radiotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The approval by the European Medicine Evaluation Agency of tumor necrosis factor (TNF)-{alpha} in combination with melphalan in the setting of isolated limb perfusion (ILP) for the treatment of locally advanced extremity soft tissue sarcomas (STS), on the basis of the excellent limb salvage results of multi-center trials in Europe, has added an important treatment modality to avoid limb amputations.1–4 Patients with local recurrences in the limb after prior surgery and high dose radiotherapy and patients with multiple sarcomas are usually all candidates for amputation of the extremity.

In the early experience with the TNF-based ILP program for irresectable extremity STS, much attention was given to the post-ILP necrosis of the foot of a particular patient treated with TNF-based ILP after prior resections, high dose radiotherapy, and prior ILP with cisplatin.5 It was then speculated that the high dose radiotherapy might have resulted in damage to the vasculature of the foot. This might have rendered it susceptible to the toxic effects of the combination of high-dose TNF and melphalan, thus leading to complete necrosis of the healthy tissues, in contrast to the usually selective toxic effects on the tumor vasculature only. This observation led to hesitation to offer TNF-based ILP to patients when a local recurrence presented in a high-dose-irradiated area. In an attempt to avoid amputation, we decided to offer TNF-based ILP in all cases in which amputation was the only option, regardless of prior treatments. We performed 30 ILPs 26 in patients with tumor recurrences in irradiated limbs. Here we report on this unique experience.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Between 1992 and 2003, 26 patients with recurrent STS initially treated with surgery and radiotherapy were treated with ILP with melphalan and TNF. All patients were considered candidates for amputation at the time of referral because of extensive and/or irresectable disease. Irresectability was defined as the impossibility of performing an oncologically justified surgical resection without substantial functional loss of the limb or complete loss of the limb.

The technique of ILP with recombinant TNF and melphalan is described in detail elsewhere.2 Briefly, recombinant human TNF (Boehringer Ingelheim GmbH, Ingelheim/Rhein, Germany) and the cytostatic drug melphalan, obtained as a sterile powder (100 mg), were dissolved aseptically by using solvent and diluents (Burroughs Welcome, London, UK). ILPs were performed with patients under general anesthesia and normally took 2.5 to 4 hours. Isolation of the blood circuit of a limb was achieved by clamping the major artery and vein and by applying a tourniquet to compress the remaining collateral vessels. Perfusion was performed at the axillary, brachial, iliac, femoral, or popliteal level. ILP consisted of a 90-minute perfusion with 1.5 to 3 mg (arm) or 2 to 4 mg (leg) of TNF and a 10 mg/L (leg) or 13 mg/L (arm) volume of melphalan at mild hyperthermia. Maximum tissue temperatures were 39.5° C in the leg and 38.5° C in the arm. The composition of the perfusate was as follows: the priming volume of 700 to 850 mL consisted of 400 to 500 mL of blood (50% RBCs and 50% plasma), 200 to 400 mL of 5% dextran 40 in glucose 5% (Isodex; Pharmacia, Uppsala, Sweden), 10 to 30 mL of 8.4% sodium bicarbonate, and .5 mL of 2500 to 5000 IU of heparin. TNF was injected as a bolus into the arterial line provided that the limb tissue temperature was greater than 38° C. Melphalan was administered 30 minutes later at limb temperatures between 38° C and 39.5° C. At the end of the ILP, the limb was washed with 1 L (axillary) to 4 L (iliac perfusion) of physiologic saline solution and 6% dextran 70 (Macrodex; Pharmacia).

Evaluation of Response and Toxicity
Tumor response was assessed at least twice between 4 and 12 weeks after perfusion. Complete response was defined as the disappearance of all measurable disease in the limb for more than 4 weeks, partial response was defined as tumor size regression by greater than 50% for more than 4 weeks, no change was defined as regression of less than 50% or progression of less than 25% for longer than 4 weeks, and progressive disease was defined as more than 25% disease progression. In patients in whom a resection of residual tumor, necrotic tissue mass, or both was performed after the ILP, a histological response rate was assessed by determining the percentage of necrosis. Clinical responses were standardized according to World Health Organization criteria.

Regional toxicity was graded according to Wieberdink et al.6: grade 1, no toxicity; grade 2, redness and slight edema; grade 3, considerable edema or erythema with some blistering; grade 4, extensive epidermolysis or obvious damage to the deep tissues causing definite functional disturbances, or threatening or manifest compartmental syndrome; and grade 5, reaction requiring amputation. Systemic toxicity was graded according to Eastern Cooperative Oncology Group/World Health Organization criteria.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Over the past 10 years, more than 340 patients with advanced melanoma or sarcoma were treated by using ILP with melphalan in combination with TNF in the department of surgical oncology at the Erasmus MC–Daniel den Hoed Cancer Center. Twenty-six of these patients were previously treated with surgery and high dose radiotherapy (50–70 Gy) for their primary sarcoma and developed one or more irresectable local recurrences. One patient had known distant metastases at the time of treatment. Patient and tumor characteristics are listed in Tables 1Go and 2Go. The group consisted of 15 men and 11 women, with a median age of 50 years (range, 21–84 years; mean, 52 years). The median interval between treatment of the primary tumor and recurrence of disease was 19 months and ranged from 0 to 156 months.


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  		TABLE 1. Characteristics of 26 recurrent sarcoma patients treated with ILP (n = 30) after radiotherapy treatment
 

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  		TABLE 2. Additional characteristics of 26 recurrent sarcoma patients treated with ILP (n = 30) after radiotherapy treatment
 
In all patients, systemic toxicity after ILP was mild to moderate and was easily manageable. More than 10% leakage was measured in five patients during perfusion, but this was without significant toxicity. When postoperative hypotension occurred, it responded immediately to fluid administration, and none of the patients required circulatory support with vasopressors. One patient experienced a fever higher than 40° C after the ILP; this, however, was reversible within 24 hours. No patients endured neurotoxicity after the ILP.

A major tumor response was seen after 21 (70%) of 30 perfusions, with a partial response in 15 patients (50%) and a complete response in 6 patients (20%). Nine perfusions (30%) were not followed by any objective tumor response; four of these patients (patients 3, 4, 22, and 24) underwent an amputation of the limb. Two patients died of systemic disease with tumor present in the limb (patients 1 and 12). Patient 8 had a mixed response to the first perfusion, with four of six tumors showing a complete response but two tumors not responding at all, thus resulting in a no change score. The two remaining tumors responded well to the repeated perfusion scheduled 13 months after the first ILP. However, the patient relapsed within 3 months after the second perfusion and eventually underwent amputation. Patient 10 responded insufficiently on the first perfusion but showed a partial response after a second ILP, 7 months later. Because of a local recurrence, an amputation had to be performed after 10 months. In patient 20, the clinical response was insufficient for a partial response score. However, the tumor had shrunk enough to allow resection. Histological responses could be established in 11 patients who were treated with an additional tumor resection. In three patients, these responses showed much more necrosis in the tumor remnant than was clinically expected (patients 11, 16, and 26).

In 17 (65%) of 26 patients, limb salvage could be achieved. The duration of response was confined to the time from ILP until the first evidence of local recurrent disease and varied from 2 to 57 months (and ongoing), with a median of 12 months (mean, 17 months). The median follow-up of patients was 22 months (range, 3 to >61 months; mean, 29 months).

In 9 patients (11 perfusions), the tumor recurred locally after ILP: in 4 patients (4 ILPs) with a single tumor (24%) and in 5 patients (7 ILPs) with multiple tumors (54%). An amputation had to be performed to achieve local control in five patients, whereas in three patients no amputation was performed because of the poor short-term prognosis due to systemic metastases. In one patient (patient 5), a local recurrence occurred 43 months after the perfusion, and it could primarily be resected. This patient died 1 year later as a result of lung carcinoma. Nine patients developed systemic metastases, of which they died, after ILP. Overall survival is shown in Fig. 1Go. There was no significant difference in response between low-grade and high-grade tumors. There was no correlation between tumor size and subsequent tumor response.


Figure 1
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  		FIG. 1. Overall survival of 26 patients after isolated limb perfusion for previously irradiated recurrent sarcoma (x-axis, time in months; y-axis, cumulative percentage of surviving patients).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our experience with 30 TNF-based ILPs in 26 patients with irresectable extremity STS recurrences in limbs previously treated with surgery in combination with high dose radiotherapy shows that even in this patient population, limb salvage can be achieved in most patients. Moreover, limb salvage was achieved in 65% of the patients even though multiple recurrences were present in 42% of the patients. Furthermore, we have shown that TNF-based ILP in previously highly irradiated limbs is not associated with an increased local toxicity or complication rate.

In general, the management of extremity sarcomas has moved away from ablative surgical procedures and toward function-preserving surgery, which is often being combined with radiotherapy. As a result, more patients now incur locally recurrent sarcoma arising in previously irradiated areas. Amputation might be the most effective treatment option in this selected group of patients with local recurrences, but although this will improve local disease control, it does not affect overall survival rates.7–11 Because amputation implies a significant decrease in quality of life, treatment modalities that guarantee preservation of the extremity and good limb function have become more important. Surgical resection of recurrent tumor in a previously irradiated field is often impossible because it usually requires the resection of all tissue exposed to a high radiation dose of 60 to 70 Gy. This can sometimes be handled by free transfer of vascularized tissue, but in most cases it will require amputation.

Comparing our experience with data from the literature is difficult because comparable series of patients with recurrent STS in an irradiated field are not at hand. Moreover, 42% of patients in our series had multiple tumors, and these cases are usually not present in series that discuss the application of single uses or combinations of reoperation and/or reirradiation of the recurrent sarcoma. Thus, comparison with data from the literature is limited to cases with single tumor recurrences after prior surgery in combination with radiotherapy.

Results after reirradiation are reported by Essner et al.12 in a group of 32 patients who received a second course of radiation for STS. In this group, 84% of patients showed benefit from preoperative radiotherapy in combination with subsequent surgery. Local excision of recurrent tumors followed by a second course of postoperative radiation resulted in local treatment failure in 8 (57%) of 14 patients and could not be recommended as a valuable therapy.

The use of external beam therapy is restricted to patients with large tumors lying at least partially outside the previous treatment volume. When STS recur in a previously irradiated area, further external beam radiation is often not possible. Here brachytherapy allows a radiotherapeutic alternative in an attempt to reduce the risk of further local recurrence.13 Pearlstone et al.14 reported on 26 patients who underwent resection and perioperative brachytherapy in conjunction for recurrent STS. At a median follow-up of 16 months, they reported a 5-year local recurrence–free survival rate of 52% and a 33% disease-free survival. This experience shows that in a series with single tumor recurrences, the local control rate is still far from optimal. In addition, 15% of all patients experienced major wound complications that warranted reoperation. Another study by Nori et al.15 describes 40 patients treated with brachytherapy, with a 5-year local control rate of 68 % and a 12.5% severe wound complication rate. Catton et al.16 advocate combined conservative surgery with reirradiation as the primary salvage therapy for patients who experience treatment failure with combined therapy and who are suitable for conservative re-excision. In this highly selective patient population, local control for patients treated with conservative excision without radiation was only 36%, compared with 100% for conservative surgery with reirradiation. A very high proportion of patients (60%) experienced postradiation complications. Obviously, this patient population eligible for conservative surgery does not even resemble the patient population with single tumor recurrences that we have treated with TNF-based ILP, let alone patients with multiple tumors.

Until now, trials with systemic neoadjuvant chemotherapy have failed to achieve any significant improvement in the survival of patients with primary or recurrent STS.17 According to our findings, there are no data available in the literature up to now that describe the use of chemotherapy alone or in combination with the previously mentioned therapies for recurrent sarcoma in previously irradiated areas.

Regarding locoregional toxicity, no enhanced toxicity was observed as compared with TNF-based ILP in patients without prior surgery in combination with radiotherapy. In essence, TNF-based ILP has no increased regional toxicity over ILP with melphalan alone.18 Regarding systemic toxicity, no toxicity of importance was observed in this patient population. This was the case in patients without significant leakage as well in the few patients with significant leakage during perfusion and is in line with earlier reports on our experiences with these patients.19,20 This underscores our opinion that TNF-based ILP is safe and should be considered in all patients with limb-threatening tumors, irrespective of age, number of tumors, or prior therapies.4,21–23

In conclusion, our experience clearly demonstrates that extremities should not be amputated without consideration of TNF-based ILP for limb salvage. In the described patient population with the extremely unfavorable characteristics of (multiple) limb-threatening sarcoma recurrences in an irradiated field after prior surgery and radiotherapy, the achievement of a 65% limb salvage rate clearly shows the efficacy of the TNF-based ILP approach to avoid amputations in what are often considered to be lost cases.

Received for publication March 23, 2004. Accepted for publication December 19, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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  18. Vrouenraets BC, Eggermont AMM, Hart AA, et al. Regional toxicity after isolated limb perfusion with melphalan and tumour necrosis factor-alpha versus toxicity after melphalan alone. Eur J Surg Oncol 2001;27:390–19.[CrossRef][Medline]
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