Isolated limb perfusion with tumor necrosis factor-alpha and melphalan for patients with unresectable soft tissue sarcoma of the extremities

BACKGROUND: Since 1992, isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNFalpha) and melphalan has been used for the treatment of patients with unresectable soft tissue sarcomas of the extremities. The authors retrospectively studied the results of limb salvage surgery using TNFalpha-ILP at their institution. METHODS: From 1992 to 2001, 49 patients (mean age, 51 years; range, 14-85 years) underwent ILP for unresectable soft tissue sarcomas of the extremities. All patients received melphalan and TNFalpha (four patients also received interferon-gamma). The median follow-up was 26 months (range, from 2 days to 103 months). RESULTS: In 1 patient (2%) who died 2 days after undergoing ILP, response and acute limb toxicity could not be assessed. One patient (2%) attained a clinical complete response (2%), 23 patients (47%) attained a clinical partial response, 17 patients (35%) demonstrated no change, and 7 patients (14%) had tumor progression. Thirty-one patients (63%) underwent tumor resection. Histologic material also was available from eight amputations and three punctures/biopsies. Pathologic response was complete in 4 patients (8%), partial in 14 patients (29%), and no change was observed in 24 patients (49%). Final response, based on both clinical and pathologic assessment in which pathology was decisive, was complete in 4 patients (8%) and partial in 27 patients (55%), resulting in a final overall response rate of 63%. Local control with preservation of the limb was attained in 28 patients (57%). Four of 32 patients (13%) who had been rendered tumor free by ILP with or without undergoing resection and radiation therapy, developed a local recurrence. The 5-year disease specific survival rate was 48% for the 49 patients. Acute limb toxicity after ILP was a mild Grade 1-2 reaction in 35 patients (71%) patients, a Grade 3 reaction in 12 patients (25%), and a Grade 4 reaction in 1 patient (2%). Three major ILP-related complications were encountered, including arterial thrombosis in two patients and a fulminant Clostridial infection leading to death in one patient. There were no severe cardiovascular reactions after ILP. CONCLUSIONS: In patients with unresectable soft tissue sarcomas of the limbs who underwent ILP with TNFalpha and melphalan followed by resection of the tumor remnant when possible, a 63% overall tumor response rate and a 57% local control rate with limb preservation was achieved.     

Isolated limb perfusion for melanoma patients--a review of its indications and the role of tumour necrosis factor-alpha.

AIMS: The treatment of melanoma in-transit metastases (IT-mets) can vary widely and is dependant on the size and the number of the lesions. When multiple, large lesions exist, isolated limb perfusion (ILP) has established itself as an attractive treatment option with high response rates. METHODS: Review on the various methods of treatment of melanoma in-transit metastases, with a focus on isolated limb perfusion. A Medline based literature search was performed for articles relating to this topic. Additional original papers were obtained from citations in those identified by the initial search. Indications and results are discussed and the extra value of tumour necrosis factor (TNF) is evaluated. RESULTS: ILP with Melphalan results in complete response rates of 40-82% and showed to be 54% in a large retrospective meta-analysis. The addition of TNF can improve these completes response rates (59-85%) and although no data from randomized controlled trials are available, it seems of particular value in large, bulky lesions or in patients with recurrent disease after previous ILP. CONCLUSIONS: TNF-based ILP has earned a permanent place in the treatment of patients with melanoma IT-mets. In patients with a high tumour burden, TNF-based ILP is the most efficacious procedure to obtain local control and achieve limb salvage.     

Isolated limb perfusion with tumour necrosis factor-alpha and melphalan with or without interferon-gamma for the treatment of in-transit melanoma metastases: a multicentre randomized phase II study

This open, multicentre, randomized phase II trial was conducted to determine the effect of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) in combination with melphalan with or without interferon-gamma (IFNgamma) in patients with in-transit metastases of melanoma of the limbs (MD Anderson stage IIIA or IIIAB, AJCC stage III). The 64 patients included were randomized to receive either a two- drug regimen consisting of TNFalpha and melphalan (TM-ILP) or a three-drug regimen consisting of TNFalpha, melphalan and INFgamma (TIM-ILP). Patients randomized to receive IFNgamma were pretreated for 2 days before the ILP with once daily 0.2 mg IFNgamma subcutaneously and also received the same amount of IFNgamma during ILP. A total of 47 complete responses (73%) were reported, 22 (69%) of which occurred in the TM-ILP group and 25 (78%) in the TIM-ILP group; the difference was not significant. The 14 partial responses (22%) were split evenly between the treatment groups. In the TM-ILP group, two cases of stable disease and one case of progressive disease were reported. The overall response rate (complete plus partial responses) was 100% in the TIM-ILP group and 91% in the TM-ILP group, yielding an overall response of 95% for this study. In the historical control data, where 103 patients had received melphalan alone (M-ILP), there were 54 records of complete responses (52%) and 80 of complete or partial responses (78%). The median survival time estimated by the Kaplan-Meier method was 819 days for the TM-ILP group, > 705 days for the TIM-ILP group and 873 days for the combined study population; estimates for time to local progression or recurrence were 327 days, in excess of 498 days and 405 days, respectively. The corresponding figure for the historical controls was 338 days. These data suggest that TNFalpha associated with melphalan may be superior to melphalan alone for ILP.     

Isolated limb perfusion for extremity sarcoma

Isolated limb perfusion has been used in patients with extremity sarcomas for over 40 years. In the majority of patients this approach has been employed as a limb-sparing alternative for patients with amputation as their only treatment option. Despite this long history of use in the treatment of patients with extremity sarcomas, many questions remain with respect to the appropriate drug or combination of drugs to be used in the perfusion circuit, the role of hyperthermia in isolated perfusion, and the use of hyperthermic perfusion in the neoadjuvant or adjuvant setting. Although many non-randomized studies have been performed, they suffer from a variety of problems, including small patient numbers, variety of chemotherapeutic agents employed, multiple levels of hyperthermia, and subjective evaluation of what constitutes amputation as a potential treatment option.     

Regional toxicity after isolated limb perfusion with melphalan and tumour necrosis factor- alpha versus toxicity after melphalan alone.

AIMS: To determine whether the addition of high-dose tumour necrosis factor-alpha (TNF alpha) to isolated limb perfusion (ILP) with melphalan increases acute regional tissue toxicity compared to ILP with melphalan alone. METHODS: A retrospective, multivariate analysis of toxicity after normothermic (37--38 degrees C) and 'mild' hyperthermic (38--40 degrees C) ILPs for melanoma was undertaken. Normothermic ILP with melphalan was performed in 294 patients (70.8%), 'mild' hyperthermic ILP with melphalan in 71 patients (17.1%) and 'mild' hyperthermic ILP with melphalan combined with TNF alpha in 50 patients (12.0%). Toxicity was nil or mild (grades I--II according to Wieberdink et al.) in 339 patients (81.7%), and more severe acute regional toxicity (grades III--V) developed in 76 patients (18.3%). A stepwise logistic regression procedure was performed for the multivariate analysis of prognostic factors for more severe toxicity. RESULTS: On univariate analysis, 'mild' hyperthermic ILP with melphalan plus TNF alpha significantly increased the incidence of more severe acute regional toxicity compared to normothermic and 'mild' hyperthermic ILP with melphalan alone (36% vs 16% and 17%; P=0.0038). However, after ILP using TNF alpha no grade IV (compartment compression syndrome) or grade V (toxicity necessitating amputation) reactions were seen. Significantly more severe toxicity was seen after ILPs performed between 1991 and 1994 compared with earlier ILPs (33%vs 14%P=0.0001). Also, women had a higher risk of more severe toxicity than men (22% vs 7%; P=0.0007). After multivariate analysis, prognostic factors which remained significant were: sex (P=0.0013) and either ILP schedule (P=0.013) or treatment period (P=0.0003). CONCLUSIONS: Regional toxicity after 'mild' hyperthermic ILP with melphalan and TNF alpha was significantly increased compared to ILP with melphalan alone. This may be caused by increased thermal enhancement of melphalan due to the higher tissue temperatures (39--40 degrees C) at which the melphalan in the TNF alpha-ILPs was administered or by an interaction between high-dose TNF alpha and melphalan. Copyright Harcourt Publishers Limited.     

Isolated hepatic perfusion with extracorporeal oxygenation using hyperthermia, tumour necrosis factor alpha and melphalan.

AIMS: To determine the toxicity and efficacy of isolated hepatic perfusion with tumour necrosis factor alpha (TNF-alpha) and melphalan (Alkeran) under mild hyperthermic conditions. METHODS: A phase I trial was performed. Eleven patients with unresectable metastatic malignancies in the liver were pre-treated with 3 x 10(6) U leukocyte IFN daily 2 days before the perfusion. The liver was isolated and inflow catheters inserted in the hepatic artery and the portal vein. The hepatic veins were drained via a catheter in the retrohepatic caval vein. The venous blood flow from the lower extremities and the splanchnic circulation was bypassed to the axillar vein. The liver circuit was perfused with oxygenated blood and 30-200 microg TNF-alpha was added. At 39 degrees C in the liver circuit 0.5 mg/kg melphalan was added and the perfusion was continued for 1 h. RESULTS: Six patients underwent re-operation due to post-operative bleeding. Two patients died of coagulopathy or multiple organ failure within the first post-operative month. Three of six patients with liver metastases from malignant melanoma or leiomyosarcoma showed a partial response while no patients with liver metastases from colorectal cancer showed any response. The mean survival time was 20 months, which is within the same range as seen in previous isolated hepatic perfusion (IHP) studies. CONCLUSIONS: IHP with this drug regimen is a method with a considerable toxicity, though it is hard to distinguish between toxicity from TNF-alpha and that from the perfusion procedure itself. The method was not effective in patients with colorectal liver metastasis, but the results in melanoma and leiomyosarcoma patients warrant further studies.     

Prerequisites for effective isolated limb perfusion using tumour necrosis factor alpha and melphalan in rats.

An isolated limb perfusion (ILP) model using soft tissue sarcoma-bearing rats was used to study prerequisites for an effective ILP, such as oxygenation of the perfusate, temperature of the limb, duration of the perfusion and concentration of tumour necrosis factor (TNF). Combination of 50 microg TNF and 40 microg melphalan demonstrated synergistic activity leading to a partial and complete response rate of 71%. In comparison to oxygenated ILP, hypoxia was shown to enhance anti-tumour activity of melphalan alone and TNF alone but not of their combined use. Shorter perfusion times decreased anti-tumour responses. At a temperature of 24-26 degrees C, anti-tumour effects were lost, whereas temperatures of 38-39 degrees C or 42-43 degrees C resulted in higher response rates. However, at 42-43 degrees C, local toxicity impaired limb function dramatically. Synergy between TNF and melphalan was lost at a dose of TNF below 10 microg in 5 ml perfusate. We conclude that the combination of TNF and melphalan has strong synergistic anti-tumour effects in our model, just as in the clinical setting. Hypoxia enhanced activity of melphalan and TNF alone but not the efficacy of their combined use. For an optimal ILP, minimal perfusion time of 30 min and minimal temperature of 38 degrees C was mandatory. Moreover, the dose of TNF could be lowered to 10 microg per 5 ml perfusate, which might allow the use of TNF in less leakage-free or less inert perfusion settings.     

Isolated limb perfusion with melphalan,tumour necrosis factor‐alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma

Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in‐transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer‐selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour‐targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor‐alpha (TNF‐α) and Lister strain vaccinia virus (GLV‐1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF‐α, melphalan and GLV‐1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV‐1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF‐α/GLV‐1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF‐α/melphalan‐based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted.     

Isolated limb perfusion for unresectable extremity sarcoma: results of 2 single-institution phase 2 trials

BACKGROUND:

Controversy has surrounded the role of isolated limb perfusion (ILP) for unresectable extremity sarcomas. However, there remains a group of sarcoma patients for whom amputation is the only potential treatment. Because systemic therapies are limited, the authors evaluated ILP in an effort to provide a limb‐salvage option.

METHODS:

Since 1995, patients with unresectable extremity sarcomas were entered in 2 prospective trials using ILP. Study 1 used tumor necrosis factor (TNF) and melphalan in the perfusion circuit at hyperthermic temperatures (39‐41°C). Study 2 used doxorubicin at normothermic temperatures. All ILPs were performed using the standard, previously described technique.

RESULTS:

Seventeen patients were entered into study 1; there were 10 (58%) partial responses, 1 (6%) near complete response (CR), 1 (6%) CR, and 5 (30%) no response/minor response. Fourteen patients died of their disease, with a median follow‐up of 17 months. Seven (41%) patients maintained their limb intact until the time of death. Twelve patients were entered into study 2; there were no partial or CRs and 2 (20%) minor responses. With a median follow‐up of 35 months, there are 3 patients alive (2 with their extremity intact and 1 with an amputation). Six patients developed myonecrosis with creatine phosphokinase levels up to 54,000 U/dL.

CONCLUSIONS:

Although doxorubicin is active systemically, TNF and melphalan appear to have greater activity and less toxicity during ILP. Future clinical trials are needed to clearly identify the role for ILP in patients with unresectable extremity sarcomas. Cancer 2011. © 2011 American Cancer Society.     

Isolated limb perfusion for extremity soft-tissue sarcomas, in-transit metastases, and other unresectable tumors: Credits, debits, and future perspectives

Isolated limb perfusion (ILP) with melphalan is effective against melanoma in-transit metastases but has failed in the treatment of limb-threatening extremity sarcomas. Tumor necrosis factor-α (TNF) has changed this situation completely. Now, ILP with TNF + melphalan is a very successful treatment to prevent amputation. In a multicenter European trial, ILP with TNF + melphalan resulted in a 76% response rate and a 71% limb salvage rate in patients with limb-threatening soft-tissue sarcomas, deemed unresectable by independent review committees, leading to approval of TNF in Europe. We have also reported on the success of this regimen against bulky melanomas, multifocal skin cancers, and drug-resistant bony sarcomas. High-dose TNF destructs tumor vasculature, and, most importantly, it enhances tumor-selective drug uptake (ie, melphalan and doxorubicin) by threefold to sixfold. Similar synergy is observed in well-vascularized liver metastases after isolated hepatic perfusion with TNF and melphalan. New (vasoactive) drugs and mechanisms of action and interaction with chemotherapy are in development. ILP is also a promising treatment modality for adenoviral vector-mediated gene therapy. Many clinical phase I/II evaluations in ILP are now underway.     

TNF-based isolated limb perfusion in unresectable extremity desmoid tumours.

BACKGROUND: Desmoid tumours are soft tissue sarcomas with local aggressive behaviour and a high rate of local recurrence after treatment. Although they do not tend to metastasise systemically, the local aggressiveness can lead to situations in which limb-preserving surgery cannot be performed without severe disability. As isolated limb perfusion (ILP) with TNF and melphalan has proven to be extremely effective in the treatment of soft tissue sarcoma, we studied its potential in locally advanced extremity desmoid tumours. METHODS: Prospectively maintained database in a tertiary referral centre. Between 1991 and 2003, 12 ILP procedures were performed in 11 patients for locally advanced desmoid tumours. Local surgical therapy with preservation of limb function was impossible in all patients due to large or multifocal tumours, multiple recurrences or extensive previous treatment. Perfusions were performed with 4-3mg TNF and 10-13 mg/l limb volume melphalan form leg and arm perfusions, respectively. RESULTS: Overall response rate was 75%: Two complete responses were recorded (17%) and seven patients had a partial response (58%). Amputation could be avoided in all cases. Local control was obtained after 10/12 ILPs and in the other two patients through repeat ILP and systemic chemotherapy, thus leading to an overall local control rate of 100%. Local toxicity was mild and systemic toxicity was absent in all patients. CONCLUSION: ILP is a very effective treatment option in the multimodality treatment of limb desmoid tumours. It should be considered in patients with aggressive and disabling disease where resection without important functional sacrifice is impossible.     

Tumour necrosis factor alpha increases melphalan concentration in tumour tissue after isolated limb perfusion

Several possible mechanisms for the synergistic anti-tumour effects between tumour necrosis factor alpha (TNF-alpha) and melphalan after isolated limb perfusion (ILP) have been presented. We found a significant sixfold increase in melphalan tumour tissue concentration after ILP when TNF-alpha was added to the perfusate, which provides a straightforward explanation for the observed synergism between melphalan and TNF-alpha in ILP.     

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in patients with locally advanced soft tissue sarcomas: treatment response and clinical outcome related to changes in proliferation and apoptosis.

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan (HILP-TM) with or without IFN-gamma is a promising local treatment in patients with locally advanced extremity soft tissue sarcomas (STSs), with response rates of up to 84%. The mechanisms of the treatment response are poorly understood. Here, we determined the HILP-TM-induced changes in mitotic activity, proliferation, and apoptosis in 37 STSs; the additional effect of IFN-gamma; and the association of HILP-TM with treatment response and clinical outcome. On archival material, obtained before and 6-8 weeks after HILP-TM with (n = 15) or without (n = 22) IFN-gamma, the number of mitoses was counted, and the proliferation fraction was determined by immunohistological staining for the proliferation associated Ki-67 antigen (MIB1). Apoptosis was visualized by enzymatic detection of DNA fragmentation (terminal deoxynucleotidyl transferase-mediated nick end labeling method). Clinical and histological response, follow-up status, and survival were recorded. The number of mitoses dropped 57% and proliferation rate decreased with 40% after HILP-TM, whereas the amount of apoptosis after HILP-TM more than doubled as before HILP-TM. The addition of IFN-gamma to HILP-TM did not influence the changes in tumor parameters and did not affect treatment response. A better clinical response to HILP-TM was correlated with high mitotic activity and low amount of apoptosis in tumor samples before HILP-TM. Patients with highly proliferative STS before and after HILP-TM had a relatively poor prognosis. Furthermore, patients who developed distant metastases after HILP-TM had a relatively high number of dividing cells in the tumor remnants after treatment.     

Isolated limb perfusion with melphalan for femoral metastases of breast cancer: case report

BACKGROUND AND OBJECTIVES: Complications of bone destruction occur in 10-29% of breast cancer patients with skeletal metastases. Palliative treatment consists of systemic chemotherapy, hormonal treatment, radiotherapy, and/or surgery in the case of (impending) fracture. A case is presented where isolated limb perfusion was applied for this indication. METHODS: A 43-year-old woman with extensive femoral metastases of breast cancer with impending fracture was treated with isolated limb perfusion (ILP) with melphalan. Radiotherapy had resulted only in pain reduction, and intramedullary fixation was opted against because stable fixation was considered not feasible due to the location of the metastases. ILP with high-dose melphalan (10-20 times the amount that can be administered systemically) under normothermic (37-38 degrees C) conditions, resulted in partial remission and reossification. RESULTS: One year after ILP, until her death 2 years later, due to progressive metastases at other sites, the patient was able to bear weight again on her left leg. CONCLUSIONS: In selected patients with symptomatic large bone metastases from breast cancer, and no other treatment options, ILP with melphalan may be used for successful palliation.     

Repeat isolated limb perfusion with TNFalpha and melphalan for recurrent limb melanoma after failure of previous perfusion.

AIM: To assess the effectiveness of isolated limb perfusion (ILP) with tumour necrosis factor-alpha (TNFalpha) and melphalan for recurrent or persistent melanoma lesions after previous ILP. METHODS: Between 1978 and 2001, 21 patients (mean age 65, range 29-83 years) underwent repeat ILP for recurrent or persistent melanoma after a previous ILP. First ILPs had been performed with melphalan alone in 13 patients and with addition of TNFalpha in eight, for a median of nine lesions (interquartile (IQ) range 2-23 lesions). Repeat ILP was performed with TNFalpha and melphalan in all 21 patients for a median of nine lesions (IQ range 5-25 lesions). Median follow-up after repeat ILP was 18 months (IQ range 6-36 months). RESULTS: Thirteen patients attained a complete response (CR) after repeat ILP compared to 11 of 17 with measurable lesions after the first ILP. Nine patients relapsed after CR. Median limb recurrence-free survival was 13 months. Fourteen patients had mild acute regional toxicity after repeat ILP compared to 18 after the first ILP (n.s.). One patient underwent amputation for critical limb ischemia 10 months following repeat ILP. The limb salvage rate was 95%. Overall median survival was 62 months after CR compared to 13 months for those without CR (P=0.05). CONCLUSION: Repeat ILP with TNFalpha and melphalan is feasible after previous ILP with mild regional toxicity. The CR rate is relatively high and comparable to the first procedure with good limb recurrence-free survival and high limb salvage rate.     

Expression of P-glycoprotein, multidrug resistance-associated protein 1, and lung resistance-related protein in human soft tissue sarcomas before and after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan

BACKGROUND: Multidrug resistance (MDR) is associated with expression of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and lung resistance-related protein (LRP). Tumor necrosis factor (TNF-alpha) is able to modify the expression of these three proteins in different cell types. The effect of TNF-alpha in the clinical situation on patients with soft tissue sarcomas (STS) is indeterminate. METHODS: Thirty-seven patients with a locally advanced extremity STS underwent hyperthermic isolated limb perfusion (HILP) with TNF-alpha and melphalan; 15 patients received additional interferon gamma. Clinical and histologic responses were documented and used to define the overall response. Samples before and after HILP were analyzed immunohistochemically for P-gp, MRP1, and LRP. Samples were scored as negative or positive (< or = 5% or > 5% positive tumor cells). RESULTS: Six patients had an overall complete response, 25 patients had a partial response, and 4 patients with STS revealed no change; in 2 patients, the response remained unclear. The percentage STS samples that were positive for all three proteins dropped from 92% before HILP to 85% after HILP. P-gp positive samples were encountered more often than MRP1 positive samples (P < 0.05). The percentage of samples that were negative for all three MDR proteins increased after HILP from 6% to 16%. MDR status had no significant correlation with tumor response. CONCLUSIONS: HILP with TNF-alpha and melphalan results in excellent overall tumor response in patients with locally advanced STS. STS more often are positive for P-gp than for MRP1. MDR status in patients with STS is not predictive for tumor response after HILP. Data from the current study suggest that the combination of TNF-alpha and melphalan does not induce MDR positive STS: a result with clinical importance when consecutive, adjuvant, doxorubicin-containing chemotherapy is considered.     

Isolated limb perfusion with cisplatin and doxorubicin for locally advanced soft tissue sarcoma of an extremity.

AIMS: To identify independent adverse clinico-pathological factors for disease-free and overall survival in patients undergoing isolated limb perfusion (ILP) with cisplatin and doxorubicin for locally advanced soft tissue sarcoma (STS) of an extremity. METHODS: A retrospective analysis was carried out, using a univariate method and a multivariate analysis, to look at the patient, tumour and treatment associated with prognostic factors in 37 patients with locally advanced STSs of the limbs who underwent ILP with cisplatin and doxorubicin. Patient's age, gender, presenting status, tumour location, tumour grade, tumour stage according to TNM classification, tumour size and radiotherapy (RT) were analysed. Survival curves were calculated according to the Kaplan-Meier method. A Cox proportional hazard model was used to indicate which factors related to overall survival and the recurrence-free interval after ILP. RESULTS: No major systemic toxicity was seen. Regional toxicity was limited. Limb salvage was achieved in 94.6% of the patients. The estimated 5-year overall and disease-free survival rates were 62% and 54%, respectively. It was found that tumour stage, tumour grade, presenting status, RT and tumour size were associated with cumulative overall survival when the Kaplan-Meier method was applied (P<0.05). By Cox proportional hazards model, only tumour grade (P=0. 0254) was found to have significant influence on overall survival; however, tumour stage (P=0.0157) and RT (P=0.0014) were related to disease-free survival. CONCLUSIONS: ILP and delayed excision followed by RT achieves good limb salvage rates and may improve survival.