Isolated limb perfusion with tumour necrosis factor-α and melphalan for unresectable bone sarcomas of the lower extremity (original) (raw)
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Journal of surgical …, 2008
Background: The aim of this study was to investigate the long-term limb salvage rate and overall survival after isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan for locally advanced soft tissue sarcoma (STS). Methods: From 1991 to 2003, 73 patients (36 men, 37 women, median age 54 [range 14-80] years) with biopsy-proven STS underwent 77 perfusions followed by delayed surgical resection, with or without adjuvant radiation. Limb salvage and overall survival curves were calculated by the Kaplan-Meier method. Results: A total of 21 amputations (28%) were performed. Overall 1, 5, and 10 yearsÕ limb salvage was 80.1% ± 4.8%, 68.2% ± 6.5%, and 60.6% ± 9.2%, respectively. We found that the risk of amputation was linked to three time periods. The first was within a year after perfusion, mainly as a result of massive necrosis of the tumor and overlying skin, resulting in soft tissue deficit or recurrent disease (n = 17). The second was within 5 years, with two amputations performed for late local recurrence. The third occurred 10 years after perfusion, with two amputations performed for critical leg ischemia. Another two patients developed a pathological fracture of the femur due to radiation osteonecrosis. These four patients received adjuvant radiotherapy. Overall, 1, 5, and 10 yearsÕ survival was 82.9% ± 9.2%, 58.7% ± 13.1%, and 42.5% ± 18.2%, respectively. Conclusions: ILP treatment with tumor necrosis factor alpha and melphalan followed by delayed surgical resection and adjuvant radiation treatment is an effective limb salvage treatment regimen for locally advanced STS. However, we observed late morbidity, with two amputations performed for critical leg ischemia and two pathological fractures of the femur in patients receiving adjuvant radiotherapy.
European Journal of Surgical Oncology, 2000
Aims: Patients with non-resectable soft tissue sarcomas of the extremities do not live longer if they are treated by amputation or disarticulation. In order to avoid major amputations, we tested isolated limb perfusion (ILP) with tumour necrosis factor (TNF)+melphalan+/−interferon-(IFN) as a pre-operative, neoadjuvant limb salvage treatment. Methods: Twenty-two patients were included (six men and 16 women; three upper limb and 19 lower limb tumours). The AJCC stage was IIA in four patients, III in seven and IV in 11. Thirteen cases were recurrent or progressive after previous therapy; five tumours had a diameter [20 cm, and four were multiple or regionally metastatic. There were six malignant fibrous histiocytomas, five liposarcomas, four malignant peripheral nerve sheath tumours, three rhabdomyosarcomas, two leiomyosarcomas, one recurrent extraskeletal osteosarcoma and one angiosarcoma. Results: Twenty-four ILPs were performed in the 22 patients, and 18 (82%) experienced an objective response: this was complete in four (18%) and partial in 14 (64%). Three patients had a minimal or no response and the tumour progressed in one case. All patients had fever for 24 hours but only one developed a reversible grade 3 distributive shock syndrome with no sequelae. There was no grade 4 toxicity. Seventeen patients (77%) underwent limb-sparing resection of the tumour remnants after a median time of 3.4 months: 10 resections were intracompartmental and seven extracompartmental. Surgery included flaps or skin grafts in five patients, arterial replacement in two and knee arthrodesis in one. Adjuvant chemotherapy was given to eight patients and radiotherapy to six. In one patient amputation was necessary after a second ILP. Secondary amputations were performed for recurrence in two patients, resulting in an overall limb salvage rate of 19/22 (86%). After a median follow-up of 18.7 months, 10 recurrences were recorded: seven were both local and systemic and three were only local. The median disease free and overall survival times have been >12.5 and 18.7 months respectively: this is similar to the outcome after primary amputations for similar cases. Conclusion: ILP with TNF and chemotherapy is an efficient limb sparing neoadjuvant therapy for a priori nonresectable limb soft tissue sarcomas.
Isolated limb perfusion with melphalan and TNF-alpha in the treatment of extremity sarcoma
2007
Isolated limb perfusion (ILP) with chemotherapy alone has uniformly failed in the treatment of irresectable extremity soft tissue sarcomas. The addition of tumor necrosis factor-alpha (TNF-a) to this treatment approach contributed to a major step forward in the treatment of locally advanced extremity soft tissue sarcoma (STS). High response rates and limb salvage rates have been reported in multicenter trials, which combined ILP with TNF-a plus melphalan, which resulted in the approval of TNF-a for this indication in Europe in 1998. Subsequently a series of confirmatory single institution reports on the efficacy of the procedure have now been published. TNF-a has an early and a late effect; it enhances tumor-selective drug uptake during the perfusion and plays an essential role in the subsequent selective destruction of the tumor vasculature. These effects result in a high response rate in high-grade soft tissue sarcomas. This induction therapy thus allows for resection of tumor remnants some 3 months after ILP and thus avoidance of limb amputation. TNF-a-based ILP is a well-established treatment to avoid amputations. It represents an important example of tumor vasculatory-modulating combination therapy and should be offered in large volume tertiary referral centers. may require extensive and mutilating surgery followed by radiotherapy. Several studies suggested that amputation of the limb did not result in an improved
Efficacy of high vs low dose TNF-isolated limb perfusion for locally advanced soft tissue sarcoma
European Journal of Surgical Oncology (EJSO), 2009
Aims: The administration of a high dose of rTNF-a (3e4 mg) and Melphalan via isolated limb perfusion (ILP) for patients with locally advanced limb STS was shown to be effective. Reports that a low dose of TNF (1 mg) is as effective, led to the adoption of the low dose regimen as the treatment of choice. The purpose of this study was to compare two groups of patients with locally advanced limb STS, that was treated with high and low dose TNF-ILP, in terms of limb preservation. Methods: Retrospective study of 41 patients who underwent ILP, with ''high dose'' (HD) and ''low dose'' (LD) TNF. ILP/TNF was performed on candidates to either amputation or significantly mutilating surgery without this treatment. In both groups, all patients, with the exception of three in each group, underwent resection of the residual tumor or tumor bed or limb 8e12 weeks after the procedure. Results: In the HD group, marked tumor softening occurred within 48 h, and in tumors protruding through the skin, hemorrhagic necrosis was evident within 24 h. The overall response rate was 65.2%. Five patients achieved a CR and 10 had a PR; in five of these patients >90% necrosis of the tumor occurred. In eight patients, only minimal regression was observed (stabilization of disease). The rate of limb sparing was 69.5%. In the LD group, the overall response rate was 30.7%. CR was achieved in one patient. PR was observed in two. Two patients were lost to follow up. Of the remaining 15 patients, limb preservation was achieved in 53.3%. Conclusion: Despite the retrospective comparison and possible selection bias, it is possible to raise the concern that at least some patients may benefit from a higher TNF dose perfusion in ILP for advanced limb STS.
Annals of Surgical Oncology, 2003
Background: Isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan is highly effective in treating limb-threatening soft tissue sarcoma (STS) and other bulky tumors. Because of fear of TNF-associated toxicity, ILP with TNF is not offered to older patients in some cancer centers, although especially in older patients, every attempt to avoid an amputation that may end their independence must be considered. Methods: Out of 306 TNF-based ILPs, 50 ILPs were performed for limb salvage in 43 patients Ͼ75 years old (range, 75-91 years): 29 STS and 14 melanoma patients. Results: In the STS patients, a response rate of 76% and a limb-salvage rate of 76% were achieved; in the melanoma patients, a 100% response rate and a 93% limb-salvage rate were achieved. Local toxicity was mild. The three postoperative deaths that occurred in the total series of 306 TNF-based ILPs in Rotterdam (Ͻ1%) occurred in patients Ͼ75 years old after leakage-free perfusions and were not related to TNF but to extremely high-risk profiles in these three patients. Conclusions: Older patients should not be withheld a TNF-based ILP for limb salvage, because the procedure is safe and highly effective in these patients.
Tumori Journal, 1996
Background 24-60% of patients with soft tissue sarcoma shows local recurrences after treatment of the primary tumor. The event is associated with a high incidence of macroscopic or microscopic metastases and a poor survival. Our goal is to preserve a patient's functional limb by treating such cases with isolated limb perfusion (ILP) with recombinant human tumor necrosis factor alpha (rHu TNF-α) and melphalan, which have demonstrated a potent antitumor activity in vivo and in vitro studies. Methods During the period November 1991 to November 1995, 10 patients with unresectable recurrent soft tissue sarcoma of the limb were treated by ILP at intermediate hyperthermia (40-40.5 °C) with rHu TNF-α and melphalan. Two patients also received recombinant interferon gamma (rIFN-γ) before and during ILP. We used a range of 2-4 mg for rHu TNF-α and 50-100 mg of melphalan. rIFN-γ was administered on days -2 and -1 (15x106 IU) subcutaneously and the same dose was injected in the arterial line...
Limb salvage with isolated perfusion for soft tissue sarcoma: could less TNF- be better?
Annals of Oncology, 2005
Background: The optimal dose of TNF-a delivered by isolated limb perfusion (ILP) in patients with locally advanced soft tissue sarcoma is still unknown. Patients and methods: Randomised phase II trial comparing hyperthermic ILP (38 -408) with melphalan and one of the four assigned doses of TNF-a: 0.5 mg, 1 mg, 2 mg, and 3/4 mg upper/lower limb. The main end point was objective tumour response on MRI. Secondary end points were histological response, rate of amputation and toxicity. Resection of the remnant tumour was performed 2 -3 months after ILP. The sample size was calculated assuming a linear increase of 10% in the objective response rates between each dose level group. Results: One hundred patients (25 per arm) were included. Thirteen per cent of patients had a systemic leakage with a cardiac toxicity in six patients correlated with high doses of TNF-a. Objective tumour responses were: 68%, 56%, 72% and 64% in the 0.5 mg, 1 mg, 2 mg and 3 or 4 mg arms, respectively (NS). Sixteen per cent of patients were not operated, 71% had a conservative surgery and 13% were amputated with no difference between the groups. With a median follow-up of 24 months, the 2 year overall and disease-free survival rates (95% CI) were 82% (73% to 89%) and 49% (39% to 59%), respectively. Conclusion: At the range of TNF-a doses tested, there was no dose effect detected for the objective tumour response, but systemic toxicity was significantly correlated with higher TNF-a doses. Efficacy and safety of low-dose TNF-a could greatly facilitate ILP procedures in the near future.