Efficacy of hyperthermic isolated limb perfusion in the treatment of locally recurrent high-grade soft tissue sarcoma of the extremities.

BACKGROUND: This novel study compared the use of tumor necrosis factor (TNF)-alpha and melphalan-based isolated limb perfusion (TM-ILP) to the standard treatment of locally recurrent soft tissue extremity sarcoma. The aim was to assess whether TM-ILP positively influences the recurrence-free survival of locally recurrent high-grade soft tissue sarcoma (STS) of the extremities. METHODS: We retrospectively analyzed our clinical database for patients with STS. Variables were analyzed using chi-square test or Mann-Whitney rank-sum test. Furthermore, Kaplan-Meier survival plots were calculated and a proportional hazard regression model was developed. RESULTS: Out of 448 patients with extraabdominal STS treated between August 2012 and December 2015, 52 cases involving 47 patients had locally recurrent STS. Twenty-eight of these patients were treated with TM-ILP prior to surgical resection (TM-ILP-group), and 24 were treated with standard therapy (without TM-ILP). The 3-year recurrence-free survival for the TM-ILP-group was estimated at 75% (95% confidence interval (CI), 71.5-78.5). Local recurrence-free survival in the standard group was significantly lower (LRFS: 43.4%, 95% CI 38.7-48.1, p = 0.026). Multivariable analysis revealed resection with negative margins, lower number of previous recurrences, and TM-ILP as positive predictors for recurrence-free survival. CONCLUSIONS: TM-ILP and consecutive resection of residual tumor with negative resection margins significantly improves local recurrence-free survival for patients with a first local recurrence of high-grade STS in the extremities.

The pathologic response of resected synovial sarcomas to hyperthermic isolated limb perfusion with melphalan and TNF-α: a comparison with the whole group of resected soft tissue sarcomas.

BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-α and melphalan (TM-HILP) has been successfully used to treat limb soft tissue sarcomas (STSs) with high response rates. The data on the effectiveness of HILP-TM for the treatment of STSs are mainly based on various STS types. The aim of this study was to investigate the responses of synovial sarcomas (SS) to TM-HILP. METHODS: A total of 125 TM-HILP-treated tumors (STS all), including 14 SSs, were included in the study. The tumors were subdivided into proximal and distal limb localizations. Tumor typing (using the WHO classification), resection status (using the UICC classification), and response to therapy were assessed using light microscopy. The SSs were tested for the SYT-SSX translocation using RT-PCR. The following tests were applied: a chi-squared test, a t test, and the Mann-Whitney U test. RESULTS: The SSs were localized distally more often than were the STS cohort (STS(-SS)) (85.7% vs. 32.4%) and were smaller (5.8 cm vs. 10.7 cm). There were no differences in the responder/nonresponder ratios or the mean percentages of pathological regression between the SS and STS(-SS) cohorts (74.0% vs. 76.0%). A general localization-dependent difference in the tumor responses to TM-HILP could not be detected in the STS all cohort (distal, 72.0% vs. proximal, 78.0%); however, a UICC R0 status was more often observed in proximal tumors (distal, 50.0% vs. proximal, 71.4%). There was no association between the SYT-SSX type and SS responses to TM-HILP. CONCLUSIONS: Because of the high response rates, TM-HILP is recommended for the treatment of SSs. The distal limb localization of TM-HILP-treated STSs was generally (STS all cohort) associated with fewer R0 resections.

Size-based clinical response evaluation is insufficient to assess clinical response of sarcomas treated with isolated limb perfusion with TNF-α and melphalan.

BACKGROUND: The clinical assessment of the response of sarcomas to preoperative treatment is usually defined using size-based evaluation standards. For nonresectable sarcomas, hyperthermic isolated limb perfusion with TNF-α and melphalan (TM-ILP) yields high response rates. Based on our experience, we assume that anatomic radiological response criteria are insufficient to assess the degree of regression after TM-ILP. METHODS: The clinical response of 35 sarcomas to TM-ILP was assessed by unidimensional, bidimensional, and tridimensional size-based anatomical criteria, and responders were identified according to the established thresholds. The same tumors were investigated for pathological response according to the Salzer-Kuntschik regression scale (>90% devitalization) and reviewed for cystic degeneration, hemorrhage, and predominant necrotic or fibrosclerotic regression phenotype. RESULTS: None of the clinical response criteria were able to reliably identify the pathologic responders. The extent of size changes showed no association with the pathological degree of regression. The number of clinical responders was low compared with the number of pathological responders (RECIST N = 1, WHO N = 3, volumetry N = 3, pathology N = 19). The occurrence of hemorrhage and/or cystic degeneration was more frequently observed in predominant necrotic sarcomas and was associated with an increase in tumor size after TM-ILP. Furthermore, we identified the fibrosclerotic phenotype of regression to be more significantly strongly associated with posttherapeutic shrinkage than necrosis. CONCLUSIONS: Size-based clinical response evaluation is insufficient to assess clinical response in TM-ILP-treated sarcomas. The size changes of tumors after therapy reflect the type of regression rather than the extent of destruction.

Increased shedding of soluble TNF-receptor 1 during hyperthermic TNF-α-based isolated limb perfusion.

PURPOSE: Hyperthermic isolated limb perfusion (HILP) with TNF-α and melphalan has high response rates in patients with soft tissue sarcomas (STS) or melanomas of the limbs. Its effectiveness is based on the destructive effect of TNF-α on the blood supply of the tumours. Shedding of soluble TNF-receptor (sTNF-R) negatively modulates the effects of TNF-α, whereas hyperthermia (HT) induces shedding. Here, we investigated whether sTNF-R shedding in response to HT occurs during HILP. MATERIAL AND METHODS: The serum levels of sTNFR-1 were measured in 23 patients with HILP by obtaining serum from the extracorporeal and central circuits. The samples were taken from the patients under normothermic (37°C) and hyperthermic (39°C) conditions. Additionally, cell cultures of HUVEC, human fibrosarcoma cells and peripheral blood cells were used to confirm the effects of HT on sTNF-R1 shedding by ELISA and western blot. RESULTS: Under HT, levels of sTNF-R1 increased 23.5% in the extracorporeal circuit, but this increase was not observed in the systemic circuit. However, we could not confirm this effect using the cell culture model, where cellular TNF-R1 and sTNF-R1 of culture supernatants, respectively, were not significantly different between NT and HT conditions. CONCLUSIONS: HT is associated with an increase of sTNF-R1 in the extracorporeal circuit of perfused limbs. Interestingly, HT does not exhibit the same effect on cells cultured in vitro. Additional studies will be aimed at determining whether our findings have an impact in the clinic by analysing the relationship between TNF-R1 shedding and tumour response to HILP.