Outcome and prognostic factor analysis of 217 consecutive isolated limb perfusions with tumor necrosis factor-alpha and melphalan for limb-threatening soft tissue sarcoma.
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BACKGROUND: Extensive and mutilating surgery is often required for locally advanced soft tissue sarcoma (STS) of the limb. As it has become apparent that amputation for STS does not improve survival rates, the interest in limb-preserving approaches has increased. Isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF) and melphalan is successful in providing local tumor control and enables limb-preserving surgery in a majority of cases. A mature, large, single-institution experience with 217 consecutive ILPs for STS of the extremity is reported. METHODS: At a prospectively maintained database at a tertiary referral center, 217 ILPs were performed from July 1991 to July 2003 in 197 patients with locally advanced STS of the extremity. ILPs were performed at mild hyperthermic conditions with 1-4 mg of TNF and 10-13 mg/L limb-volume melphalan (M) for leg and arm perfusions, respectively. RESULTS: The overall response rate was 75%. Limb salvage was achieved in 87% of the perfused limbs. Median survival post-ILP was 57 months and prognostic factors for survival were Trojani grade of the tumor and ILP for single versus multiple STS. The procedure could be performed safely, with a perioperative mortality of 0.5% in all patients with no age limit (median age, 54 yrs; range, 12-91). Systemic and locoregional toxicity were modest and easily manageable. CONCLUSION: TNF+M-based ILP can provide limb salvage in a significant percentage of patients with locally advanced STS and has therefore gained a permanent place in the multimodality treatment of STS. (+info)
Modulation of chemotherapy resistance in regional therapy: a novel therapeutic approach to advanced extremity melanoma using intra-arterial temozolomide in combination with systemic O6-benzylguanine.
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This study investigated whether the therapeutic index of regional melanoma therapy using parenteral temozolomide could be improved by chemomodulation with O6-benzylguanine (O6BG), an inhibitor of the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase (AGT). Using a nude rat s.c. human melanoma xenograft model of the extremity, tumors were analyzed for AGT level 2 to 3 hours after the i.p. injection of 3.5 to 70.0 mg/kg O6BG to inhibit AGT activity. Survival studies were conducted using animals that were treated with a 15-minute isolated limb infusion with 10% DMSO in PBS (control), temozolomide alone, or temozolomide in conjunction with single or multiple doses of i.p. O6BG. Tumor volume and toxicity level were monitored every other day. Administration of 3.5 mg/kg O6BG depleted tumor AGT activity by 93.5% (P < 0.01). Groups treated with regional temozolomide alone (350 mg/kg), systemic temozolomide with O6BG, or vehicle combined with O6BG showed no significant tumor responses compared with controls. Whereas use of regional temozolomide alone at a higher dose (750 mg/kg) showed some degree of tumor response, regional temozolomide given in conjunction with multiple dosages of O6BG showed a marked (P < 0.01) reduction in tumor growth with minimal toxicity. Our findings suggest that AGT modulation by the administration of O6BG in combination with temozolomide regional chemotherapy leads to a significant improvement in melanoma antitumor responses. Clinical trials using chemotherapy modulation may improve response rates in future regional infusion and perfusion drug trials. (+info)
Efficiency of recombinant human TNF in human cancer therapy.
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Recombinant human tumour necrosis factor (TNF) has a selective effect on angiogenic vessels in tumours. Given that it induces vasoplegia, its clinical use has been limited to administration through isolated limb perfusion (ILP) for regionally advanced melanomas and soft tissue sarcomas of the limbs. When combined with the alkylating agent melphalan, a single ILP produces a very high objective response rate. In melanoma, the complete response (CR) rate is around 80% and the overall objective response rate greater than 90%. In soft tissue sarcomas that are inextirpable, ILP is a neoadjuvant treatment resulting in limb salvage in 80% of the cases. The CR rate averages 20% and the objective response rate is around 80%. The mode of action of TNF-based ILP involves two distinct and successive effects on the tumour-associated vasculature: first, an increase in endothelium permeability leading to improved chemotherapy penetration within the tumour tissue, and second, a selective killing of angiogenic endothelial cells resulting in tumour vessel destruction. The mechanism whereby these events occur involves rapid (of the order of minutes) perturbation of cell-cell adhesive junctions and inhibition of alphavbeta3 integrin signalling in tumour-associated vessels, followed by massive death of endothelial cells and tumour vascular collapse 24 hours later. New, promising approaches for the systemic use of TNF in cancer therapy include TNF targeting by means of single chain antibodies or endothelial cell ligands, or combined administration with drugs perturbing integrin-dependent signalling and sensitizing angiogenic endothelial cells to TNF-induced death. (+info)
Surgical treatment of giant cell tumour of long bone with anhydrous alcohol adjuvant.
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This study was designed to evaluate the feasibility and effectiveness of the use of anhydrous alcohol as an adjuvant treatment for giant cell tumours (GCTs) of long bone. Between October 1989 and January 2004, 42 GCT patients were treated and followed up for an average of 4.1 years (range 1-13 years). Mean patient age was 34 years (range 17-67 years). After curettage and additional burring, anhydrous alcohol was used as an adjuvant therapy in all patients before the bone defect was filled with bone graft or cement. Four patients (9.5%) experienced local recurrence. There were no alcohol-related complications. Recurrence-free probability was 87.6% at final follow-up (13 years) after index surgery by Kaplan-Meyer analysis. Our data suggest that anhydrous alcohol can be used as an effective safe adjuvant for the treatment of GCT of long bone. (+info)
Histological response of peritoneal carcinomatosis after hyperthermic intraperitoneal chemoperfusion (HIPEC) in experimental investigations.
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BACKGROUND: In selected patients with peritoneal carcinomatosis from colorectal cancer prognosis can be improved by hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery. The aim of this study was to evaluate the tumor response of peritoneal carcinomatosis in tumor-bearing rats treated with HIPEC. METHODS: CC531 colon carcinoma (2,5 x 106 cells), implanted intraperitoneally in Wag/Rija rats, was treated by hyperthermic intraperitoneal chemotherapy. After 10 days of tumor growth the animals were randomized into five groups of six animals each: group I: control (n = 6), group II: sham operated animals (n = 6), group III: hyperthermic intraperitoneal perfusion (HIP) without cytostatic drugs, group IV: HIPEC with mitomycin C in a concentration of 15 mg/m2 (n = 6), group V: mitomycin C i.p. alone in a concentration of 10 mg/m2 (n = 6). After 10 days the extent of tumor spread and histological outcome were analysed by autopsy. RESULTS: All control animals developed extensive intraperitoneal tumor growth. Histological tumor load was significantly reduced in group III and group V and was lowest in group IV. In group II tumor load was significantly higher than in group I. Implanted metastases were significantly decreased in group IV compared with group I and group II. CONCLUSION: These findings indicate that HIPEC is an effective treatment for peritoneal carcinomatosis in this animal model. HIPEC reduced macroscopic and microscopic intraperitoneal tumor spread. (+info)
Randomized multicenter trial of hyperthermic isolated limb perfusion with melphalan alone compared with melphalan plus tumor necrosis factor: American College of Surgeons Oncology Group Trial Z0020.
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PURPOSE: To determine in a randomized prospective multi-institutional trial whether the addition of tumor necrosis factor alpha (TNF-alpha) to a melphalan-based hyperthermic isolated limb perfusion (HILP) treatment would improve the complete response rate for locally advanced extremity melanoma. PATIENTS AND METHODS: Patients with locally advanced extremity melanoma were randomly assigned to receive melphalan or melphalan plus TNF-alpha during standard HILP. Patient randomization was stratified according to disease/treatment status and regional nodal disease status. RESULTS: The intervention was completed in 124 patients of the 133 enrolled. Grade 4 adverse events were observed in 14 (12%) of 129 patients, with three (4%) of 64 in the melphalan-alone arm and 11 (16%) of 65 in the melphalan-plus-TNF-alpha arm (P = .0436). There were two toxicity-related lower extremity amputations in the melphalan-plus-TNF-alpha arm, and one disease progression-related upper extremity amputation in the melphalan-alone arm. There was no treatment-related mortality in either arm of the study. One hundred sixteen patients were assessable at 3 months postoperatively. Sixty-four percent of patients (36 of 58) in the melphalan-alone arm and 69% of patients (40 of 58) in the melphalan-plus-TNF-alpha arm showed a response to treatment at 3 months, with a complete response rate of 25% (14 of 58 patients) in the melphalan-alone arm and 26% (15 of 58 patients) in the melphalan-plus-TNF-alpha arm (P = .435 and P = .890, respectively). CONCLUSION: In locally advanced extremity melanoma treated with HILP, the addition of TNF-alpha to melphalan did not demonstrate a significant enhancement of short-term response rates over melphalan alone by the 3-month follow-up, and TNF-alpha plus melphalan was associated with a higher complication rate. (+info)
Histamine, a vasoactive agent with vascular disrupting potential, improves tumour response by enhancing local drug delivery.
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Tumour necrosis factor (TNF)-based isolated limb perfusion (ILP) is an approved and registered treatment for sarcomas confined to the limbs in Europe since 1998, with limb salvage indexes of 76%. TNF improves drug distribution in solid tumours and secondarily destroys the tumour-associated vasculature (TAV). Here we explore the synergistic antitumour effect of another vasoactive agent, histamine (Hi), in doxorubicin (DXR)-based ILP and evaluate its antivascular effects on TAV. We used our well-established rat ILP model for in vivo studies looking at tumour response, drug distribution and effects on tumour vessels. In vitro studies explored drug interactions at cellular level on tumour cells (BN-175) and Human umbilical vein endothelial cells (HUVEC). There was a 17% partial response and a 50% arrest in tumour growth when Hi was combined to DXR, without important side effects, against 100% progressive disease with DXR alone and 29% arrest in tumour growth for Hi alone. Histology documented an increased DXR leakage in tumour tissue combined to a destruction of the TAV, when Hi was added to the ILP. In vitro no synergy between the drugs was observed. In conclusion, Hi is a vasoactive drug, targeting primarily the TAV and synergises with different chemotherapeutic agents. (+info)
Liposarcoma in adult limbs treated by limb-sparing surgery and adjuvant radiotherapy.
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Between December 1995 and March 2003, 38 adult patients with intermediate or high-grade liposarcoma in a limb were treated by limb-sparing surgery and post-operative radiotherapy. The ten-year local recurrence-free survival was 83%, the ten-year metastasis-free survival 61%, the ten-year disease-free survival 51% and the ten-year overall survival 67%. Analysis of failure and success showed no association with the age of the patients, gender, the location of the primary tumour, the type of liposarcoma and the quality of resection. Our results indicate that liposarcoma may recur even ten years after the end of definitive therapy and may spread to unexpected sites as for soft-tissue sarcoma. (+info)