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10.1245/ASO.2006.02.005
Annals of Surgical Oncology 13:518-524 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Isolated Limb Perfusion With Tumor Necrosis Factor {alpha} and Melphalan for Locally Advanced Soft Tissue Sarcoma: The Value of Adjuvant Radiotherapy

Katja M. J. Thijssens, MD1, Robert J. van Ginkel, MD, PhD1, Elisabeth Pras, MD, PhD2, Albert J. H. Suurmeijer, MD, PhD3 and Harald J. Hoekstra, MD, PhD1

1 Department of Surgical Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
2 Department of Radiation Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
3 Department of Pathology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands

Correspondence: Address correspondence and reprint requests to: Harald J. Hoekstra, MD, PhD; E-mail: h.j.hoekstra{at}chir.umcg.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: The aim was to investigate the value of adjuvant radiotherapy for locally advanced soft tissue sarcoma after hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor {alpha} and melphalan followed by limb-saving surgery.

Methods: From 1991 to 2003, 73 patients (median age, 54 years; range, 14–80 years) underwent 77 ILPs, followed by resection in 68 patients (93%). Radiotherapy was administered in case of marginally or microscopically positive resection margins. Local recurrences were scored and calculated according to the Kaplan-Meier method and log-rank test.

Results: After residual tumor mass resection, 58% received radiotherapy (external beam radiotherapy [EBRT]+ group), and 42% did not (EBRT– group). The median follow-up was 28 months (range, 2–159 months). A significantly better local control rate was observed in the EBRT+ compared with the EBRT– group (P < .0001). When only R0 resections in patients without metastasis were considered, the significance remained between groups (P = .0003). In the EBRT– group, an R1 or R2 resection resulted in earlier relapse of local disease compared with R0 resections (P = .0475).

Conclusions: Adjuvant EBRT reduces the risk for local recurrence after delayed resection in soft tissue sarcoma patients treated with ILP and tumor necrosis factor and is indicated when resection margins are close or microscopically positive. It also seems beneficial after an R0 resection.

Key Words: Sarcoma • Isolated limb perfusion • Radiotherapy • Tumor necrosis factor • Melphalan • Long-term results


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Soft tissue sarcomas (STS) comprise a heterogeneous group of malignant mesenchymal tumors and are generally classified according to their resemblance to healthy tissue. Currently 19 histological types and >50 different subtypes can be recognized. Many histological types reveal different biological behavior, but even within a single histological group, considerable divergence in the malignant potential has been noticed. During the last decade, it has become evident that the studies in STS provide more insight into tumor behavior when they are specified for histological type and grade.1

Major difficulties in the management of STS are their low incidence and insidious presentation. During the last two decades, there have been improvements in the radiodiagnostic evaluation of these tumors. The development of magnetic resonance imaging with or without angiography and spiral computed tomography (CT) helps the surgeon plan the surgical procedure and helps the radiation oncologist plan the preoperative or postoperative radiation treatment. More extensive surgical procedures became possible with the reconstructive surgical techniques that use implants and/or tissue transfer with the ultimate goal of improving the outcome: e.g., performing limb-saving operations, decreasing the local failure rate, and increasing the disease-free and overall survival without increasing long-term morbidity. The role of (neo)adjuvant chemotherapy in the treatment of STS is limited with the exception of the Ewing sarcomas, primitive neuroectodermal tumors, and rhabdomyosarcomas.1

Although limb-saving surgical procedures are feasible in most patients with STS of the limb, a small proportion of patients can be treated only with an amputation. Since the early 1990s, these patients have been candidates for hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor (TNF)-{alpha} and melphalan followed by delayed resection. Eggermont et al.2 investigated this new treatment approach and documented in a large European study an objective response rate of 76% and a limb-salvage rate of 71% with a minimal treatment-related morbidity. This treatment approach has also been applied at the University Medical Center Groningen since 1991. We recently investigated the overall limb salvage rate of these patients and described long-term morbidity that resulted in late amputations years after therapy. The role of adjuvant radiotherapy in this late observed morbidity was discussed as a possible contributing factor.3 The goal of this study was to investigate the primary role of the radiotherapy as an adjunct to prevent local recurrence after ILP with TNF-{alpha} and melphalan.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
From July 1991 to December 2003, 73 patients—36 males (49%) and 37 females (51%) with a median age of 54 years (range, 14–80 years) with locally advanced primary or recurrent STS—were eligible for an ILP with TNF-{alpha} and melphalan, followed by delayed resection and adjuvant external beam radiotherapy (EBRT). The sarcomas were graded according to the French grading system, and the histological diagnosis was based on the most recent World Health Organization’s classification of tumors (Table 1Go).4,5 All patients had the same preoperative work-up to stage the disease locally and to detect possible distant metastases: magnetic resonance imaging of the affected limb and CT scans of the lungs.6 Patients without metastatic disease were treated with curative intent, whereas patients with metastatic disease were eligible for a so-called palliative perfusion when they had a minimum lifetime expectancy of 6 months and when the intention of the treatment was limb salvage. According to the American Joint Committee on Cancer staging system, there were 10 stage I, 1 stage II, 50 stage III, and 12 stage IV tumors.7 All patients were treated after informed consent was obtained according to the institutional guidelines.


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  		TABLE 1. Classification of the locally advanced soft tissue sarcomas (STS) in this study: primary/recurrent tumor, grade, and histological diagnosis
 
Perfusion Technique
ILP was performed with patients under general anesthesia. The major artery and vein of the limb were clamped after heparinization with heparin 3.3 mg/kg (Thrombolique; Organon BV, Oss, The Netherlands). Collateral vessels were ligated, and a tourniquet was applied to compress the remaining minor vessels. The perfused limb was wrapped in a thermal blanket to reduce heat loss. The perfusion technique of the axillary, iliac, and popliteal vessels was previously extensively described.8,9 Leakage of the perfusion circuit to the systemic circulation was measured with radiolabeled iodide and technetium.10 The extremities were perfused for 90 minutes under mild hyperthermia (39°C–40°C) with TNF-{alpha} (Beromun; Boehringer, Ingelheim, Austria) and melphalan (L-phenylalanine mustard; GlaxoSmithKline, Parma, Italy). The following doses were used: 3 mg of TNF-{alpha} (arm), 4 mg of TNF-{alpha} (leg), or 3 mg of TNF-{alpha} (popliteal perfusion) and 10 mg/L of melphalan (limb volume, leg) to 13 mg/L of melphalan (limb volume, arm). In the beginning of the study, 18 patients also received .2 mg of interferon (Boehringer) subcutaneously 1 and 2 days before perfusion, followed by .2 mg of interferon {gamma} injected into the arterial line at the start of perfusion. At the end of the perfusion, the heparin was antagonized with prothrombin, and a fasciotomy was performed. Patients received subcutaneous low-dose molecular heparin until full mobilization.

Clinical and Pathologic Response
Complete clinical response was defined as disappearance of all measurable disease in the limb for >4 weeks; partial response, as regression of the tumor size by >50% for >4 weeks; and no change, as regression of <50% of the tumor in the limb or progression of <25% for >4 weeks. After resection, the tumor remnants were measured in three dimensions, and, on the basis of an integration of gross and microscopic findings, the percentage of necrosis was estimated. The histopathologic response of ILP was standardized and scored according to the World Health Organization criteria.11 The resection margins of the tumor were classified as radical when the resection margins were free of tumor cells (complete resection; R0), as R1 when resection margins were microscopically involved, or as R2 when resection margins were macroscopically involved. Resection margins were perioperatively marked with clips to facilitate adjuvant radiotherapy when indicated.

Radiation Treatment
Postoperative radiotherapy (60–70 Gy) was considered indicated in case of <95% necrosis on pathologic examination of the tumor or with marginal or microscopically positive resection margins. EBRT was given with a daily dose of 2 Gy (25 x 2 Gy) and an additional boost dose of 10 Gy (after R0 resection) or 20 Gy (after R1 or R2 resection; 2 Gy/day). Radiotherapy started within 5 to 6 weeks after tumor resection. Radiation treatment was delivered through a multiple-field technique with CT treatment planning. Radiotherapy was given on a linear accelerator, 6 to 15 MV. When indicated, patients received rehabilitation services and physiotherapy.

Follow-Up
All patients were clinically followed up after treatment according to a standardized protocol at 3-month intervals during the first year, 4-month intervals during the second year, and then every 5 months; after 5 years, they were followed up once a year. A chest radiograph was performed after each visit. The primary end point in this study was local recurrence. Disease-free and overall survival and regional and distant metastases were also scored. Analyses of end points were calculated according to the Kaplan-Meier method and log-rank test.12 Values of P < .05 were considered statistically significant. GraphPad Prism for Windows statistical software (GraphPad Software, Inc., San Diego, CA) was used.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Ten perfusions (14%) were performed for a sarcoma tumor grade I; 24 perfusions (32%), for grade II; and 43 perfusions (54%), for grade III. Sixty perfusions (88%) were performed for primary and 17 perfusions (12%) for recurrent sarcomas; 61 curative perfusions and 12 palliative perfusions were performed. Sixty-two sarcomas (85%) were located in the lower limb, and 11 sarcomas (15%) were located in the upper limb. Perfusion was performed at the iliac level in 32 patients (42%), at the popliteal level in 23 patients (30%), at the femoral level in 11 patients (14%), and at the axillary level in 11 patients (14%). Four patients underwent a second perfusion: in two of these patients, there was an insufficient response after the first perfusion. In two other patients, a complete response was achieved; however, the tumor recurred, for which a second perfusion was performed.

The median tumor size before an ILP was performed was 16.2 cm (range, 8.3–23 cm). Resection of the residual tumor was performed after a median postperfusion time of 8 weeks (range, 2–15 weeks) in 68 patients (93%). After ILP, a complete clinical response was observed in 19 patients (25%); a partial response, in 53 patients (69%); and no response, in 5 patients (6%). Resection of the remnant tumor was performed in 68 patients. In four patients, no resection was performed because of progression of distant metastasis, and one patient with a complete response refused further surgical treatment. The median follow-up of the patients treated with ILP was 28 months (range, 2–159 months), and a flowchart of the 73 ILPs is presented in Fig. 1Go.


Figure 1
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  		FIG. 1. A flowchart of the patients from entry all the way to the final group. EBRT, external beam radiotherapy; ILP, isolated limb perfusion.

 
Local Control Rate
From the 68 patients, another 4 could not complete the combined-modality treatment schedule because they underwent amputation shortly after resection of the STS. This amputation was performed because of vascular disturbances or wound-healing disturbances or because the tumor did not respond after the perfusion treatment. After residual tumor mass resection, 37 (58%) of the 64 patients received EBRT (EBRT+ group), and 27 patients (42%) did not (EBRT– group). The 5-year local control rate was 96.5% ± 3.5% in the EBRT+ group and 52% ± 23% in the EBRT– group (P < .0001; Fig. 2Go).


Figure 2
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  		FIG. 2. Local tumor control rate in all patients: the 5-year local control rate in the external beam radiotherapy (EBRT)+ group (n = 37) was 96.5% ± 3.5% vs. 52% ± 23% in the EBRT– group (n = 20; P < .0001).

 
When only patients with curative intention—i.e., without distant metastases at the time of perfusion—were selected, the local tumor control rate was 96.5% ± 3.5% in the EBRT+ group (n = 35) and was 56% ± 25% in the EBRT– group (n = 20; P < .0001; Fig. 3Go). When R0 resections were considered in the curative treatment group, the local tumor control rate was 100% in the EBRT+ group (n = 29) and was 55% ± 31% in the EBRT– group (n = 15; P = .0003; Fig. 4Go).


Figure 3
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  		FIG. 3. Local control rate in patients treated with curative intent: the 5-year local control rate in the external beam radiotherapy (EBRT)+ group (n = 35) was 96.5% ± 3.5% vs. 56% ± 25% in the EBRT– group (n = 20; P < .0001).

 

Figure 4
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  		FIG. 4. Local control rate in patients treated with curative intent and R0 resections: the 5-year local control rate for the external beam radiotherapy (EBRT)+ R0 group (n = 29) was 100% vs. 55% ± 31% in the EBRT– R0 group (n = 15; P = .0003).

 
In the EBRT– group of patients treated with curative intent, an R1 or R2 resection (n = 3) resulted in an earlier relapse of local disease compared with R0 resections (n = 15; P = .0475), with, at 2 years, a difference of 57% ± 28% vs. 33% ± 33% (Fig. 5Go). In the EBRT+ group of patients treated with curative intent, an R0 resection (n = 29) resulted after 5 years in a 100% local tumor control rate, versus 75% ± 25% for R1 resection (n = 6; P = .01; Fig. 6Go).


Figure 5
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  		FIG. 5. Local control rate in patients treated with curative intention without adjuvant radiotherapy: for external beam radiotherapy (EBRT)– R0 (n = 15) versus R1 or 2 resections (n = 3), the 2-year local control rate was 57% ± 28% vs. 33% ± 33%, respectively (P = .0475).

 

Figure 6
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  		FIG. 6. In patients treated with curative intent, for external beam radiotherapy (EBRT)+ R0 (n = 29) versus EBRT+ R1 resections (n = 6), the 5-year local control rate was 100% vs. 75% ± 25%, respectively (P = .01).

 
Metastasis and Overall Survival
Twelve patients (16%) presented with distant metastasis (stage IV) at the time of ILP. There was a significant difference in survival between the group of patients with and without distant metastases at the time of ILP (P < .001). During follow-up, 25 patients (36%) developed distant metastasis at a median interval of 9 months (range, 2–100 months). A total of 21 amputations (28%) had to be performed in the entire series. The overall 1-, 5-, and 10-year survival was 83.1% ± 4.4%, 61.4% ± 6.4%, and 47.5% ± 7.5%, respectively (Fig. 7Go).


Figure 7
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  		FIG. 7. Overall survival in all isolated limb perfusion patients: the overall 1-, 5-, and 10-year survival was 83.1% ± 4.4%, 61.4% ± 6.4%, and 47.5% ± 7.5%, respectively.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
The goal of adjuvant radiotherapy in this combined limb-saving treatment modality was to decrease the local recurrence rate. From previous studies, we know that survival figures in extremity sarcoma patients are not influenced by limb-saving procedures.13–15 Adjuvant radiation treatment improves local tumor control in limb-saving treatment of STS.16,17 The first goal of the applied combined-modality treatment of ILP was to increase the limb salvage rate in patients with extremity sarcomas whose disease was locally irresectable by standard surgical treatment. Indeed, we were able to achieve a limb salvage rate of 72%. Tumors with microscopically or macroscopically involved margins received adjuvant radiation, as did marginal resected tumors with <95% necrosis on pathologic examination. From an earlier study, we knew that adjuvant radiation after ILP and delayed tumor resection of locally advanced extremity STS were feasible.18 In this study, we demonstrated unequivocally that adjuvant radiation treatment should be used in this combined-modality treatment, even after radical resections. Radiation can improve local control after marginal resection (R1 or R2). Trovik et al.19 showed a local failure rate in R1 and R2 resection of 39% without irradiation, compared with 24% with irradiation. There is also a relationship between the delivered radiation doses and local tumor control in sarcoma treatment. Fein et al.17 demonstrated that boost therapy with a total dose of >62.5 Gy resulted in a 5-year local control rate of 95%, compared with 78% for patients who received <62.5 Gy (P = .008).

The value of adjuvant radiotherapy in limb-saving sarcoma surgery was first demonstrated by Rosenberg et al.15 in the early 1980s. Yang et al.16 updated their initial experience and described, after a median follow-up of 9.6 years, a highly significant decrease in the probability of local recurrence after irradiation (P = .0028), without differences in overall survival. Adjuvant irradiation resulted in significantly worse limb strength, edema, and range of motion. However, these deficits were often transient and had few measurable effects on activities of daily life or on global quality of life.

Despite the advantage of decreasing the local recurrence rate, the clinical importance of acute and late morbidity after radiotherapy may not be underestimated. Two patients in our series developed late radiation-induced complications after ILP and adjuvant radiotherapy. A pathologic fracture of the femur occurred at 78 and 129 months, and in both patients this resulted in pseudarthrosis. Treatment of these fractures might be difficult.20 Therefore, a study was designed by Sullivan et al.21 in the 1990s to overcome the postoperative radiation morbidity. Postoperative radiotherapy was compared with preoperative radiotherapy, and a disadvantage of preoperative radiotherapy, with an increased risk of wound complications, was shown. Recently, Lans et al.22 demonstrated that ILP can also be safely applied in preirradiated limbs. There is often a discussion with respect to the "unresectability" of these kinds of extensive sarcomas and the type of treatment to be performed. Instead of ILP, preoperative radiotherapy might be an option to reduce tumor volume and tumor aggressiveness and to render disease resectable for cure. A disadvantage of this treatment option is the increased risk for wound complications.21 Another point of discussion might be whether ILP patients with a good clinical/pathologic response (>95% necrosis) and "good" surgical margins need adjuvant radiation. We showed that, indeed, these patients need adjuvant radiation, because the local control rate in this group was only 56% without adjuvant radiation. Our positron emission tomography studies in sarcomas after ILP often showed in these tumors an active rim on the outside of the tumor.23 This was the rim with viable tumor: inside, full necrosis; outside, viable tumor cells. It is well known that a "good" surgical margin in sarcoma surgery is often an inadequate margin for local tumor control.15,16

Therefore, wide local tumor resections are advocated, but these wide local resections were impossible in these perfused patients. The results of this study emphasize the key role of adjuvant radiation in reducing the risk of local recurrences in the combined-modality treatment of ILP for locally advanced STS of the extremities. Although we observed in an earlier study the risks of late morbidity of radiation in a perfused limb, the contributing effect of radiotherapy should outweigh this risk, because patients with locally advanced STS are at a high risk of dying of distant metastases.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
ILP followed by delayed surgical resection is an effective limb salvage treatment regimen for locally advanced extremity STS. Adjuvant EBRT reduces the risk for local recurrence significantly and is indicated when resection margins are close or microscopically positive and also seems beneficial after an R0 resection.

Received for publication February 7, 2005. Accepted for publication October 21, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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  10. Daryanani D, Komdeur R, Ter Veen J, Nijhuis PH, Piers DA, Hoekstra HJ. Continuous leakage measurement during hyperthermic isolated limb perfusion. Ann Surg Oncol 2001; 8:564–5.[Free Full Text]
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  15. Rosenberg SA, Tepper J, Glatstein E, et al. The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 1982; 196:305–15.[Medline]
  16. Yang JC, Chang AE, Baker AR, et al. Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 1998; 16:197–203.[Abstract/Free Full Text]
  17. Fein DA, Lee WR, Lanciano RM, et al. Management of extremity soft tissue sarcomas with limb-sparing surgery and postoperative irradiation: do total dose, overall treatment time, and the surgery-radiotherapy interval impact on local control? Int J Radiat Oncol Biol Phys 1995; 32:969–76.[Medline]
  18. Olieman AF, Pras E, van Ginkel RJ, Molenaar WM, Schraffordt Koops H, Hoekstra HJ. Feasibility and efficacy of external beam radiotherapy after hyperthermic isolated limb perfusion with TNF-alpha and melphalan for limb-saving treatment in locally advanced extremity soft-tissue sarcoma. Int J Radiat Oncol Biol Phys 1998; 40:807–14.[CrossRef][Medline]
  19. Trovik CS, Bauer HC, Berlin O, et al. Local recurrence of deep-seated, high-grade, soft tissue sarcoma: 459 patients from the Scandinavian Sarcoma Group Register. Acta Orthop Scand 2001; 72:160–6.[Medline]
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