Variation in response rates to isolated limb perfusion in different soft-tissue tumour subtypes: an international multi-centre study.

OBJECTIVE: The aim of this study was to investigate the response rates of different extremity soft-tissue sarcoma subtypes (eSTS) after isolated limb perfusion (ILP), based on an international multi-centre study. MATERIALS AND METHODS: The retrospective cohort comprised eSTS patients from 17 specialised ILP centres that underwent melphalan-based ILP, with or without recombinant human tumour necrosis factor (rhTNFα) (TM-ILP and M-ILP, respectively). Response was measured on imaging (magnetic resonance imaging) and/or clinical response, for which M-ILPs were excluded. RESULTS: A total of 1109 eSTS patients were included. The three most common histological subtypes were undifferentiated pleomorphic sarcoma (17%, n = 184), synovial sarcoma (16%, n = 175) and myxofibrosarcoma (8%, n = 87). rhTNFα was used in 93% (TM-ILP) and resulted in a significantly better overall response rate (ORR, p = 0.031) and complete responses (CR, p < 0.001) in comparison to M-ILP, without significant differences among histological subgroups. The ORR of TM-ILP was 68%, including 17% CR. Also, 80% showed progressive disease. Significantly higher response rates were shown for Kaposi sarcoma (KS) with 42% CR and 96% ORR (both p < 0.001), and significantly higher CR rates for angiosarcoma (AS, 45%, p < 0.001) and clear cell sarcoma (CCS, 31%, p = 0.049). ILP was followed by resection ≤ 6 months in 80% of the patients. The overall limb salvage rate was 88%, without significant differences among histological subgroups, but was significantly higher for ILP responders compared to non-responders (93% versus 76%, p < 0.001). CONCLUSION: ILP resulted in high response and LRS among all eSTS subtypes, however, with significant differences between subtypes with most promising results for KS, AS and CCS.

Isolated limb perfusion for unresectable extremity cutaneous squamous cell carcinoma; an effective limb saving strategy.

BACKGROUND: A small minority of patients present with locally advanced cutaneous Squamous Cell Carcinoma (cSCC). The aim of this study was to evaluate the effectiveness of Tumour necrosis factor α (TNF) and melphalan based isolated limb perfusion (TM-ILP) as a limb saving strategy for locally advanced extremity cSCC. METHODS: A retrospective search from prospectively maintained databases, at two tertiary referral centers, was performed to identify patients treated with TM-ILP for locally advanced cSSC of an extremity between 2000 and 2015. RESULTS: A total of 30 patients treated with TM-ILP for cSCC were identified, with a median age of 71 years (36-92) and 50% female. Response could not be evaluated in 3 patients. After a median follow up of 25 months, the overall response rate was 81% (n = 22), with 16 patients having a complete response (CR, 59%). A total of 7 patients developed local recurrence, with a median time to recurrence of 9 months (Interquartile Range 7-10). Progressive disease was observed in 5 patients (19%). Limb salvage rate was 80%. The overall 2-year survival was 67%. CONCLUSIONS: TM-ILP should be considered as an option in patients with locally advanced cSCC in specialised centers, resulting in a high limb salvage rate.

Repeated isolated limb perfusion in melanoma patients with recurrent in-transit metastases.

In-transit metastases of melanoma occur in 5-8% of all melanoma patients. In case of extensive locoregional disease, Tumor necrosis factor-α and melphalan-based isolated limb perfusion (TM-ILP) had proven to yield excellent local control. Here, we report on repeat TM-ILP for locoregional recurrence after isolated limb perfusion. Between 1991 and 2013, 37 consecutive repeat TM-ILPs were analyzed in 32 different patients. Three patients underwent a third TM-ILP. During a median follow-up of 20 months after repeat TM-ILP, the overall response rate was 86%. Complete response (CR) was recorded after 24 TM-ILPs (65%). CR after first TM-ILP was a strong predictor for successful repeat TM-ILP in terms of clinical response and local recurrence. Local toxicity was mild (70% Wieberdink I-II). The local recurrence rate was 59%. Five-year overall survival was 35%. Repeat TM-ILP is a safe treatment modality in melanoma patients with recurrent in-transit metastases of melanoma. Those with a CR after first TM-ILP benefit the most from repeat TM-ILP.

Treatment modifications in tumour necrosis factor-α (TNF)-based isolated limb perfusion in patients with advanced extremity soft tissue sarcomas.

BACKGROUND: Tumour necrosis factor-α (TNF) and melphalan based isolated limb perfusion (TM-ILP) is an attractive treatment option for advanced extremity soft tissue sarcomas (STS). This study reports on a 20-year single centre experience and discusses the evolution and changes in methodology since the introduction of TNF in ILP. PATIENTS AND METHODS: We performed 306 TM-ILPs in 275 patients with extremity STS. All patients were candidates for amputation or mutilating surgery in order to achieve local control. Clinical response evaluation consisted of clinical examination and magnetic resonance imaging. To evaluate the importance of TNF-dose, treatment results of two periods (1991-2003 high dose (3-4 mg) TNF; 2003-2012 reduced dose (1-2mg) TNF) were compared. RESULTS: During the study period, more femoral perfusions were done instead of iliac perfusions. Reduction of TNF dose and reduction of total ILP time did not lead to different clinical response rates (70% and 69% for periods 1 and 2 respectively) or different local recurrence rates, but was associated with less local toxicity (23% and 14% for periods 1 and 2 respectively). Hospital stay was significantly reduced during the study period. There was an improved pathological response in the high dose TNF group without consequences for clinical outcome. CONCLUSION: TM-ILP remains a very effective treatment modality for limb threatening extremity STS. Moreover, reduction of dose and the growing experience in ILP led to less local toxicity and shorter hospital stay.

20 years experience of TNF-based isolated limb perfusion for in-transit melanoma metastases: TNF dose matters.

BACKGROUND: Approximately 5-8% of melanoma patients will develop in-transit metastases (IT-mets). Tumor necrosis factor-α (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is an attractive treatment modality in melanoma patients with multiple IT-mets. This study reports on a 20 years experience and outlines the evolution and major changes since the introduction of TNF in ILP. METHODS: A total of 167 TM-ILPs were performed in 148 patients, between 1991 and 2009. TM-ILPs were performed at high doses of TNF (3-4 mg) from 1991 to 2004 (n = 99) and at low doses of TNF (1-2 mg) from 2004 to 2009 (n = 68) under mild hyperthermic conditions (38°C-39.5°C.). Melphalan doses were unchanged at 10-13 mg/l (leg and arm, respectively). Characteristics for the 167 ILPs were: 81 stage IIIB, 65 stage IIIC, and 21 stage IV disease. RESULTS: The overall response rate was 89% (n = 148). (Complete response [CR] = 61%; partial response [PR] = 28%). CR rates correlated with stage (P = .001) and with high-dose vs. low-dose TNF (70% vs. 49%; P < .006). High-dose TNF prolonged local control (median 16 months vs. 11 months; P = .076). Survival was not influenced by TNF dose. CR after ILP and number of lesions also correlated with local progression-free interval. Overall survival did correlate with stage of disease (P < .001), size of the lesions (P = .001), and a CR (P < .001). CONCLUSIONS: This 2-decade single-center experience demonstrates that TM-ILP is a safe and effective treatment modality for melanoma patients with multiple IT-mets. Higher dose of TNF was associated with significantly higher CR rates and prolonged local control without an effect on overall survival.

Isolated limb perfusion with TNF-alpha and melphalan for distal parts of the limb in soft tissue sarcoma patients.

BACKGROUND: Approximately 10% of soft tissue sarcomas (STS) occur in the most distal parts of the extremities. The standard therapy is local excision with adjuvant radiotherapy, but achieving wide resection margins might be difficult in the distal parts of the limb. Tumor necrosis factor-alpha (TNF) and melphalan-based isolated limb perfusion (TM-ILP) is effective in locally advanced STS of the extremities. We report the results of TM-ILP for STS in the most distal parts of the limb. METHODS: Between 1991 and 2009, 34 ILPs were performed in patients with irresectable STS of the wrist, hand, ankle, or foot. Disease was unifocal in 21 (62%) patients. RESULTS: Overall response rate was 71% (n = 24). After a median follow-up of 34 (range 1-143) months the local recurrence rate was 32%. Amputation was unavoidable in four patients (13%), four other patients (13%) underwent a partial amputation of the hand or foot. CONCLUSION: With a limb salvage rate of 87%, TM-ILP is an effective treatment modality in patients with distal STS. In all patients with an indication for amputation surgery due to an STS in the distal part of the limb, TM-ILP should be considered.

Long-term results of tumor necrosis factor alpha- and melphalan-based isolated limb perfusion in locally advanced extremity soft tissue sarcomas.

PURPOSE: Because there is no survival benefit of amputation for extremity soft tissue sarcomas (STSs), limb-sparing surgery has become the gold standard. Tumor size reduction by induction therapy to render nonresectable tumors resectable or facilitate function-preserving surgery can be achieved by tumor necrosis factor α (TNF) -based and melphalan-based isolated limb perfusion (TM-ILP). This study reports the long-term results of 231 TM-ILPs for locally advanced extremity STS. PATIENTS AND METHODS: We analyzed 231 TM-ILPs in 208 consecutive patients (1991 to 2005), who were all candidates for functional or anatomic amputation for locally advanced extremity STS. All patients had a potential follow-up of up to 5 years. TM-ILP was performed under mild hyperthermic conditions with 1 to 4 mg of TNF and 10 to 13 mg/L of limb-volume melphalan. Almost all patients (85%) had intermediate- or high-grade tumors. RESULTS: The overall response rate (ORR) was 71% (complete response, 18%; partial response, 53%). Multifocal sarcomas had a significantly better ORR of 83% (P = .008). The local recurrence rate was 30% (n = 70); local recurrence rates were highest for multifocal tumors (54%; P = .001) and after previous radiotherapy (54%; P < .001). Five-year overall survival rate was 42%. Survival was poorest in patients with large tumors (P = .01) and with leiomyosarcomas (P < .001). Limb salvage rate was 81%. CONCLUSION: We demonstrated that TM-ILP results in a limb salvage rate of 81% in patients with locally advanced extremity STS who would otherwise have undergone amputation. Whenever an amputation is deemed necessary to obtain local control of an extremity STS, TM-ILP should be considered.

Local and intralesional therapy of in-transit melanoma metastases.

Regional relapse of melanoma may occur as satellite or in-transit metastases proximal to the primary tumor in the direction of the lymph flow. The management of in-transit metastases is challenging because the efficacy of treatment is largely dictated by the biological behavior of the patient's melanoma. This review examines local treatment modalities.

Hepatic steatosis is not always a contraindication for cadaveric liver transplantation.

BACKGROUND: Macrovesicular steatosis is assumed to be an important risk factor for early allograft dysfunction (EAD) after orthotopic liver transplantation (OLT). AIM: To evaluate the impact of steatosis in combination with other risk factors on the outcome of OLT. METHODS: The degree of steatosis was analysed in 165 consecutive OLTs and was classified by histological examination as non (M0), mild (<30%, M1), moderate (30-60%, M2) or severe steatosis (>60%, M3). Recipients were analysed for EAD. RESULTS: EAD was observed in 28% of patients with M0, 26% with M1, 53% with M2 and 73% with M3 (P < 0.001). Patients with EAD had a significantly shorter graft survival after liver transplantation (P = 0.005) but did not correlate with survival. In multivariate regression analysis, the grade of steatosis, donating after cardiocirculatory death (DCD) grafts and duration of cold ischaemia time were significantly associated with EAD (P < 0.001, P = 0.01 and P = 0.001, respectively). CONCLUSION: Livers with severe (M3) steatosis from DCD donors, combined with a prolonged CIT have a high risk for developing EAD which is correlated with shorter graft survival. Therefore M3 livers should only be considered for OLT in selected recipients without the presence of additional risk factors.

Isolated limb perfusion for melanoma in-transit metastases: developments in recent years and the role of tumor necrosis factor alpha.

PURPOSE OF REVIEW: The treatment of in-transit metastasis of melanoma remains challenging and is essentially dictated by the biological behavior of melanoma. When lesions are large or numerous, isolated limb perfusion (ILP) is an attractive treatment modality. In this review an overview of literature on treatment options of melanoma in-transit metastases will be discussed. RECENT FINDINGS: Most recent studies report on tumor necrosis factor (TNF) and melphalan based ILP (TM-ILP) series or mixed series of TM-ILP and melphalan only based ILP (M-ILP). After TM-ILP complete response rates of 70% (range 44-90%) have been reported, while for M-ILP this is lower with complete response rates of 54% (range 40-76%). The only randomized trial comparing TM-ILP and M-ILP revealed no clear benefit of TNF at 3 months, but improved outcome at 6 months and in patients with bulky disease. Reports on isolated limb infusion (ILI) with melphalan and actinimycin D indicate lower response rates, but similar local control rates as M-ILP at lower cost. SUMMARY: ILP is an attractive treatment option in melanoma patients with multiple in-transit metastases. In our opinion TM-ILP is superior to M-ILP as it achieves higher response rates, especially in patients with bulky disease. When lesions are small and in the distal two-thirds of the leg only, ILI is a valuable alternative.

Radiotherapy for soft tissue sarcomas after isolated limb perfusion and surgical resection: essential for local control in all patients?

BACKGROUND: Standard treatment for localized soft tissue sarcoma (STS) is resection plus adjuvant radiotherapy (RTx). In approximately 10% of cases, resection would cause severe loss of function or even require amputation because of the extent of disease. Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-α) and melphalan can achieve regression of the tumor, facilitating limb-saving resection. RTx improves local control but may lead to increased morbidity. METHODS: In our database of over 500 ILPs, 122 patients with unifocal STS were treated by ILP followed by limb-sparing surgery. All included patients were candidates for amputation. RESULTS: Surgery resulted in 69 R0 resections (57%), and in 53 specimens (43%) resection margins contained microscopic evidence of tumor (R1). Histopathological examination revealed >50% ILP-induced tumor necrosis in 59 cases (48%). RTx was administered in 73 patients (60%). Local recurrence rate was 21% after median follow-up of 31 months (2-182 months). Recurrence was significantly less in patients with >50% ILP-induced necrosis versus ≤50% necrosis (7% vs. 33%, P = 0.001). A similar significant correlation was observed for R0 versus R1 resections (15% vs. 28%, P = 0.04). In 36 patients with R0 resection and >50% necrosis, of whom 21 were spared RTx, no recurrences were observed during follow-up. CONCLUSIONS: In patients with locally advanced primary STS, treated with ILP followed by R0 resection, and with >50% ILP-induced necrosis in the resected specimen, RTx is of no further benefit.