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10.1245/ASO.2005.03.059
Annals of Surgical Oncology 12:473-479 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Isolated Limb Perfusion With Tumor Necrosis Factor and Melphalan Prevents Amputation in Patients With Multiple Sarcomas in Arm or Leg

Dirk J. Grünhagen, MD1, Flavia Brunstein, MD1, Wilfried J. Graveland, MSc2, Albertus N. van Geel, MD, PhD1, Johannes H. W. de Wilt, MD, PhD1 and Alexander M. M. Eggermont, MD, PhD1

1 Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, 301 Groene Hilledijk, 3075 EA Rotterdam, The Netherlands
2 Department of Statistics, Erasmus MC-Daniel den Hoed Cancer Center, 301 Groene Hilledijk, 3075 EA Rotterdam, The Netherlands

Correspondence: Address correspondence and reprint requests to: Alexander 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: Treatment for extremity soft tissue sarcoma (STS) has shifted in recent years from amputation to local wide excision combined with irradiation. For multiple sarcomas, this limb-sparing approach is often not possible. To avoid amputations, isolated limb perfusion (ILP) with tumor necrosis factor and melphalan is an attractive treatment option for patients with multiple extremity sarcomas.

Methods: We investigated a prospective database at a tertiary referral institute. From July 1991 to July 2003, out of 217 ILPs, 64 ILPs were performed for either multifocal primary sarcomas or multiple sarcoma recurrences in 53 patients. All ILPs were performed under mild hyperthermic conditions by using 1 to 4 mg of tumor necrosis factor and 10 to 13 mg/L of limb volume for leg and arm perfusions, respectively.

Results: The overall response was 88%, with 42% complete response, 45% partial response, 11% no change, and 2% progressive disease. This response rate is significantly better than our experience in 153 locally advanced single-STS cases (88% vs. 69%). The toxicity of the procedure was mild to moderate in almost all cases; no treatment-related amputation had to be performed. The time to local recurrence was 29 months and differed significantly between multiple primary and multiple recurrent STS. The 5-year survival rate was 39%. Limb salvage was achieved in 45 (82%) of 55 treated limbs.

Conclusions: In a group of patients who are uniformly candidates for amputation, ILP can achieve limb salvage in approximately four out of five patients. Because this treatment option provides excellent local control, it should be considered before an amputation is planned.

Key Words: Isolated limb perfusion • Soft tissue sarcoma • Extremity • TNF


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Of the 7800 new cases of soft tissue sarcoma (STS) diagnosed in the United States each year, approximately 4700 occur in the extremities.1 Tumors are often large at the time of diagnosis. Treatment options for locally advanced extremity STS may consist of amputation or an extensive limb-sparing surgical procedure followed by radiotherapy. This combination may mutilate and compromise limb function considerably. Since the application of tumor necrosis factor (TNF)-{alpha} in combination with melphalan in the isolated limb perfusion (ILP) setting, a new limb-salvage strategy has emerged. Multicenter trials in Europe have established high response rates and limb-salvage rates in the management of limb-threatening STS, which led to the approval of TNF for this indication in Europe.2,3 Subsequent single-center reports on TNF/melphalan-based (TM) ILP have reported response rates varying from 63% to 92% and limb-salvage rates ranging from 58% to 85%4–8; this is very much in line with the 76% response rate and 71% limb-salvage rate achieved in the multicenter pivotal trials setting.9

Multiple sarcomas in the extremities are very rare and are usually uniformly treated by amputation of the limb.10,11 Reports on the surgical management of these patients are scarce because surgical options are usually limited to amputation of the limb. Limb salvage has come to the forefront in the management of all patients with extremity STS in light of the data that have shown that this approach has not influenced survival outcome adversely.12–14 Because amputations are very rarely performed for patients with melanoma in-transit metastases, we have adopted a limb-salvage approach in patients with multiple sarcomas by using TM-ILP. In this report, we describe our unique experience with 64 TM-ILPs in the management of 53 patients with multiple limb sarcomas.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Out of 217 TM-ILPs for STS performed in the Daniel den Hoed Cancer Center between 1991 and July 2003, 64 ILPs were performed on 53 patients with multifocal sarcoma. Two patients, one patient with Kaposi sarcoma and one patient with Stewart-Treves lymphangiosarcoma, underwent ILPs on both legs, thus making the total number of limbs 55. There were 29 women and 24 men with a median age of 61 years (range, 20–88 years). Nine ILPs (14%) were performed in patients with stage III disease (systemic metastases were present). Histological subtyping of the tumors and classification of tumor grade according to Trojani et al.15 are listed in Table 1Go. In total, 28 ILPs were performed on patients with multifocal primary STS, and 36 ILPs were performed for multiple recurrent STS. A patient was regarded as having multifocal primary STS when presenting with multifocal disease without previous surgical resection of STS in the limb. Multiple recurrent STS was defined as the occurrence of multifocal recurrences of STS after previous surgery (with or without irradiation) for the primary tumor. Recurrences of Kaposi sarcoma and Stewart-Treves lymphangiosarcoma were also considered multifocal primary tumors when they "recurred" after ILP, because the nature of the disease dictated that no complete surgical resections had preceded ILP. Twenty-six patients had undergone other previous treatments for their STS. These treatments consisted of irradiation (n = 11), systemic chemotherapy (n = 4), ILP (n = 8 [7 in our institution and 1 elsewhere]), a combination of irradiation and systemic chemotherapy (n = 1), and a combination of ILP and irradiation (n = 2). All patients were candidates for amputation because primary surgical resection was impossible because of the multifocality of the tumors.


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  		TABLE 1. Tumor characteristics of 64 TM-ILPs for multiple STS
 
Treatment
Patients underwent an ILP via the axillary (n = 13), brachial (n = 4), iliac (n = 28), femoral (n = 14), or popliteal (n = 5) approach. The ILP technique has been described previously.2,3 Briefly, recombinant human TNF (Boehringer Ingelheim GmbH, Ingelheim/Rhein, Germany) and the cyto-static drug melphalan (Alkeran; Burroughs Wellcome Ltd., London, UK), obtained as a sterile powder, were dissolved aseptically with solvent and diluents (Burroughs Wellcome Ltd.). 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 and cannulation of the major artery and vein, connection to an oxygenated extracorporeal circuit, and application of a tourniquet to compress the remaining collateral vessels. ILP consisted of a 90-minute perfusion with 1 to 3 mg (arm) or 3 to 4 mg (leg) of TNF and a 10 mg/L (leg) or 13 mg/L (arm) volume of melphalan at mild hyperthermia (maximal tissue temperatures of 39.5°C in the leg and 38.5°C in the arm).

The median dose of melphalan was 60 mg (mean, 68.7 mg; range, 14–140 mg); the median dose of TNF was 4 mg (mean, 3.3 mg; range, 1–4 mg). TNF was injected as a bolus into the arterial line provided that the limb tissue temperature had reached 38°C. Melphalan was administered after 30 minutes at limb temperatures between 38°C and 39.5°C. During the procedure, continuous leakage monitoring was performed by using a precordial scintillation probe to detect leakage of radiolabeled albumen injected into the perfusion circuit. At the end of the ILP, the limb was washed out with 1 L (arm) to 4 L (iliac perfusion) of physiologic saline solution and 6% dextran 70 (Macrodex; Pharmacia, Uppsala, Sweden).

Response Evaluation and Toxicity
Clinical response evaluation was performed 2, 4, 8, and 12 weeks after ILP and thereafter every 3 months for the first year both by clinical examination and by magnetic resonance imaging (4–6 and 8–12 weeks after ILP and thereafter every 3–6 months)16,17 and was reported according to World Health Organization criteria. Histological response could be assessed in 22 cases after a median interval of 3 months (range, 1–17 months) and was obtained in 14 cases by a biopsy of responding lesions and in 8 cases by evaluation of the resection specimen of tumor remnants that had become resectable. In these patients, the final outcome was adjusted if the pathologic response (necrosis percentage: complete response [CR] if 100% necrosis, partial response [PR] if 50%–99% necrosis, and no change [NC] if <50% necrosis) differed from the clinical response. Of the eight patients with completely resected disease, seven received adjuvant radiotherapy after resection because of a high tumor grade or narrow resection margins. Other post-ILP treatment consisted of radiotherapy (n = 2) or chemotherapy (n = 4).

Acute local toxicity of the ILP procedure was classified according to Wieberdink et al.18: grade I, no reaction; grade II, slight erythema or edema; grade III, considerable erythema or edema with some blistering, slightly disturbed motility permissible; grade IV, extensive epidermolysis or obvious damage to the deep tissues, causing definite functional disturbance and threatening or manifest compartmental syndrome; and grade V, reaction that may necessitate amputation. Systemic toxicity was reported according to World Health Organization criteria.

Statistical Evaluation
Estimates of overall survival (OS) and time to local or systemic progression (TTLP and TTSP, respectively) were made according to the method of Kaplan and Meier. The 64 multiple ILPs were compared with the group of single-sarcoma ILPs in our ILP database, and multifocal primary sarcomas were compared with multiple recurrences of STS because of the expected difference in behavior, both by using the log-rank test. Because desmoid tumors and aggressive fibromatosis are tumor types known to be locally aggressive but to have benign systemic behavior, survival and progression were separately calculated with exclusion of these tumor types. Comparison between two groups was tested with Fisher’s exact test or the Wilcoxon trend test if appropriate. P values < .05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Response
A clinical CR after ILP in 64 patients with multiple sarcomas was observed in 38%. PR occurred in 47%, NC in 14%, and progressive disease in 2%. In eight patients with a limited number of tumors (n = 2–5), the post-ILP response was nearly complete, and this made the tumor remnants resectable. In five patients, no more vital tumor cells were found in the resected tumor remnants. In another 14 responding patients, a biopsy of (some of) the lesions was performed for response assessment, mainly to distinguish between PR and CR. Of these 14, 9 had >50% to 100% necrosis. The final outcome, therefore, was 42% CR, 45% PR, 11% NC, and 2% progressive disease. Compared with our ILP experience in single STS, the outcome of TM-ILP in multiple sarcomas was significantly better (total response rate, 88% vs. 69%; P = .005). There was no statistically significant difference in overall response among high-, intermediate-, and low-grade tumors (trend test; P = 0.402). Response rates of multiple STS were analyzed separately for multifocal primary sarcoma and multiple recurrences and were shown to be 96% in multiple primary tumors and 81% in multiple recurrences (P = 0.070). Response rates for each group are listed in Table 2Go.


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  		TABLE 2. Response rates
 
Progression and Survival
The local recurrence rate was 45% (29 local recurrences in 64 ILPs); the median TTLP was 29 months. This was significantly lower than TTLP after ILP for single sarcomas (median TTLP, >129 months; P < .001; Fig. 1Go). For the patients who developed a local recurrence, the median time to this event was 8 months (vs. 13 months in single-sarcoma patients; P = .074). No significant difference in TTLP could be detected between multifocal primary (20 months) and multiple recurrent (39 months) STS (P = .605). Systemic progression occurred in 28 patients; the median TTSP was 67 months. There was no statistically significant difference in TTSP for multiple versus single STS (P = .711) or for multifocal primary versus multiple recurrent STS (P = .105). Actuarial 5-year OS after ILP for multiple STS was 39% (Fig. 2Go), which is lower than but not significantly different from the 53% 5-year survival rate for single STS (P = .152). No significant difference in OS could be detected for multifocal primary versus multiple recurrent STS (P = .164). However, analysis excluding aggressive fibromatosis/desmoid tumors (all seven multiple recurrent STS) revealed a significant difference in both TTSP (P = .021) and OS (P = .030) between multifocal primary and multiple recurrent STS. The median follow-up of the patients in this study was 22.2 months (range, .2–129 months).


Figure 1
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  		FIG. 1. Time to local progression for single versus multiple sarcomas. x-axis, time (months); y-axis, cumulative percentage.

 

Figure 2
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  		FIG. 2. Overall survival. x-axis, time (months); y-axis, cumulative percentage.

 
Toxicity and Limb Function
Local toxicity was mild (grade 1–2) to moderate (grade 3) in all ILPs. Systemic toxicity was absent or mild: only one patient had a fever >40°C for >24 hours (Table 3Go). Limb function of the 55 limbs was available in 53 cases and was perfect in 38 limbs, mildly disturbed in 4 cases, and moderately disturbed, leading to the use of crutches, in 1 patient. An amputation could not be avoided in 10 perfused limbs, thus leading to a limb-salvage percentage of 82%.


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  		TABLE 3. Local and systemic toxicity
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our experience with TM-ILP for limb salvage in the treatment of multiple STS of the extremities is the largest experience reported to date and demonstrates the efficacy of this approach. In patients with multi-focal limb-threatening STS, ILP with TNF and melphalan can prevent amputation in the vast majority of the perfused limbs. Response rates are excellent, and local control is obtained for a median of 29 months.

The overall response rate of 88% of multiple sarcomas in this study compares to previously reported response rates in the literature of 63% to 91% with TNF and melphalan2,4,6,8 and is considerably better than that reported in ILP with only chemotherapeutics.19–22 The overall response rate is in line with the results obtained by TM-ILP in a small series of 13 patients reported by Lev-Chelouche et al.23

Compared with our own experience in 153 single-STS ILPs, the overall response rate was significantly better. This can be attributed mainly to the high CR rate in multifocal primary STS of 61%. Because the nature of multifocal primary STS such as Kaposi sarcoma and Stewart-Treves lymphangiosarcoma is comparable to melanoma in terms of the number of lesions and the approach of post-ILP resection, we compared the response rates of multiple primary STS with our experience in 100 TNF-ILPs for melanoma.24 The CR rate in melanoma (69%) was markedly higher than can be achieved in all STS patients (single and multiple tumors combined), but the CR rate of 61% in our series of multifocal primary STS was virtually the same as the high CR rate in melanoma. Also, the overall response rates in melanoma (95%) and in multifocal primary STS (96%) were practically identical. Moreover, the relatively short TTLP in multifocal primary STS of 20 months also compares to our melanoma experience (median TTLP, 16 months). The behavior of the tumors and the response on ILP of multifocal primary STS therefore matches more with melanoma than with single sarcomas, and this is further supported by the previously reported excellent response rates after ILP of 100% for Kaposi sarcoma25 and 87% for Stewart-Treves lymphangiosarcoma.26

Desmoid tumors and aggressive fibromatosis in this study all presented as multiple recurrences of STS after previous surgical resections. Recurrent STS is a known adverse prognostic factor for both systemic recurrence and disease-specific survival.14 However, in desmoid tumors, systemic metastases do not occur.27 Excluding these tumor types in progression and survival analysis in this study indeed revealed a worse outcome for multiple recurrent STS compared with multifocal primary tumors.

The local recurrence rate of 45% is very high in comparison to previously reported data in single STS, both after surgery28 (19%) and after ILP2,3 (22%). Because a large proportion of the presently studied patient population presented with recurrent disease, which is known to be an independent adverse prognostic factor for local recurrence,14 this high local recurrence rate is to be expected. Still, local control of disease could be achieved for a significant period (median TTLP, 29 months), and amputation could be avoided in 82% of the perfused limbs.

Local toxicity of the procedure was mild to moderate in all cases and did not seem to be influenced by repeated ILPs or by previous radiotherapy. This is in accordance with previous observations in our institute in 26 patients treated with ILP after previous irradiation29.

In this series of patients with difficult-to-treat tumors, these observations show that TM-ILP can provide limb salvage in approximately four out of five patients. Because no treatment other than surgical excision has proven to be effective in extremity STS and because this option is not applicable in patients with multiple STS, TM-ILP has to be considered before a patient is scheduled for amputation.

Received for publication March 19, 2004. Accepted for publication January 19, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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