melphalan and Sarcoma--Synovial

The objective of the study was to achieve limb salvage in patients with locally advanced soft tissue sarcomas that can only be treated by amputation or functionally mutilating surgery by performing an isolated limb perfusion (ILP) with tumor necrosis factor (TNF) + melphalan (M) as induction biochemotherapy to obtain local control and make limb-sparing surgery possible.. To increase the number of limb-sparing resections in the treatment of locally advanced extremity soft tissue sarcoma, preoperative radiation therapy or chemotherapy or a combination of the two often are applied. The ILP with cytostatic agents alone is another option but rarely is used because of rather poor results. The efficacy of the application of TNF in ILP markedly has changed this situation.. In 8 cancer centers, 186 patients were treated over a period of almost 4.5 years. There were 107 (57%) primary and 79 (43%) recurrent sarcomas, mostly high grade (110 grade III; 51 grade II; and 25 very large, recurrent, or multiple grade I sarcomas). The composition of this series of patients is unusual: 42 patients (23%) had multifocal primary or multiple recurrent tumors; median tumor size was very large (16 cm); 25 patients (13%) had known systemic metastases at the time of the ILP. Patients underwent a 90-minute ILP at 39 to 40 C with TNF + melphalan. The first 55 patients also received interferon-tau. A delayed marginal resection of the tumor remnant was done 2 to 4 months after ILP.. A major tumor response was seen in 82% of the patients rendering these large sarcomas resectable in most cases. Clinical response rates were: 33 complete response (CR) (18%), 106 partial response (PR) (57%), 42 no change (NC) (22%), and 5 progressive disease (PD) (3%). Final outcome was defined by clinical and pathologic response: 54 CR (29%), 99 PR (53%), 29 NC (16%), and 4 PD (2%). At a median follow-up of almost 2 years (22 months; range, 6-58 months), limb salvage was achieved in 82%. Regional toxicity was limited and systemic toxicity minimal to moderate, easily managed, with no toxic deaths.. In the setting of isolated limb perfusion, TNF is an active anticancer drug in patients. The ILP with TNF + melphalan can be performed safely in many centers and is an effective induction treatment with a high response rate that can achieve limb salvage in patients with locally advanced extremity soft tissue sarcoma.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Histiocytoma, Benign Fibrous; Humans; Liposarcoma; Male; Melphalan; Middle Aged; Sarcoma; Sarcoma, Synovial; Soft Tissue Neoplasms; Treatment Outcome; Tumor Necrosis Factor-alpha

Curative treatments for patients with metastatic synovial sarcoma (SS) do not exist, and such patients have a poor prognosis. We explored combinations of molecularly-targeted and cytotoxic agents to identify synergistic treatment combinations in SS cells.. Two SS cell lines (HS-SY-II and SYO-I) were treated with single agents or combinations of molecularly targeted therapies (HDAC inhibitor, vorinostat; mTOR inhibitor, ridaforolimus) and cytotoxic agents. After 72 hours, cell viability was measured using the MTS cell proliferation assay. Combination Indices (CI) were calculated to determine whether each combination was synergistic, additive, or antagonistic. Western Blot analysis assessed alterations in total and phospho-AKT protein levels in response to drug treatment.. We determined the single-agent IC50 for ridaforolimus, vorinostat, doxorubicin, and melphalan in HS-SY-II and SYO-I. Synergism was apparent in cells co-treated with ridaforolimus and vorinostat: CI was 0.28 and 0.63 in HS-SY-II and SYO-I, respectively. Ridaforolimus/doxorubicin and ridaforolimus/melphalan exhibited synergism in both cell lines. An additive effect was observed with combination of vorinostat/doxorubicin in both cell lines. Vorinostat/melphalan was synergistic in HS-SY-II and additive in SYO-I. Western blot analysis demonstrated that ridaforolimus increased pAKT-ser473 levels; this effect was abrogated by vorinostat co-treatment.. The combination of ridaforolimus and vorinostat demonstrates in vitro synergism in SS. Addition of vorinostat abrogated ridaforolimus-induced AKT activation. Since AKT activation is a possible mechanism of resistance to mTOR inhibitors, adding vorinostat (or another HDAC inhibitor) may be a route to circumvent AKT-mediated resistance to mTOR inhibitors.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Enzyme Activation; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Inhibitory Concentration 50; Melphalan; Molecular Targeted Therapy; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Sarcoma, Synovial; Sirolimus; TOR Serine-Threonine Kinases; Vorinostat

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.. 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.. 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.. 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.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Chemotherapy, Cancer, Regional Perfusion; Child; Cohort Studies; Combined Modality Therapy; Extremities; Female; Follow-Up Studies; Humans; Hyperthermia, Induced; Male; Melphalan; Middle Aged; Neoplasm Staging; Perfusion; Prognosis; Sarcoma; Sarcoma, Synovial; Tumor Necrosis Factor-alpha; Young Adult

The use of isolated, hyperthermic limb perfusion (ILP) for locally recurrent synovial sarcoma in two children is reported. In both cases recurrence was biopsy-proven after multiple surgical excisions followed by adjuvant chemo- and radiotherapy while no systemic metastases could be detected. ILP was performed using high-dose recombinant tumor necrosis factor alpha (rhTNF alpha) combined with melphalan via an extracorporeal circulation. Six weeks later, the former tumor bed and irradiation field was excised together with myocutaneous flap reconstruction for soft tissue coverage. The resection specimen revealed extensive necrosis of the tumor in both cases. Six months after completion of treatment, near-perfect limb function was determined by general clinical assessment and validated scoring systems. ILP, an accepted technique in treating adult extremity sarcoma, might also be of value in children as a means of limb-saving therapy.

Topics: Adolescent; Chemotherapy, Cancer, Regional Perfusion; Child; Female; Humans; Leg; Male; Melphalan; Neoplasm Recurrence, Local; Recombinant Proteins; Sarcoma, Synovial; Tumor Necrosis Factor-alpha

High-dose chemotherapy with autologous peripheral blood stem cell transplantation was administered to 10 patients with refractory bone and soft tissue sarcoma (2 patients with primitive neuroectodermal tumor, 4 patients with Ewing's sarcoma, 3 patients with synovial sarcoma and one patient with osteosarcoma). Busulfan 4 mg/kg x 4, melphalan 140 mg/m2 and thiotepa 200 mg/m2 x 3 were used in the high-dose chemotherapy. Complications related to the treatment were limited to one patient who developed hepatic veno-occlusive disease, no serious complications were seen in the other patients. Four patients died of their disease, one patient was alive with the disease and 5 patients were alive with no evidence of disease. The prognosis for non-resectable primitive neuroectodermal tumor and Ewing's sarcoma is said to be very poor. However, there are some patients in whom the disease is kept in remission by high-dose chemotherapy with autologous peripheral blood stem cell transplantation, so this therapy may be a possible substitute for radical operation. With spindle cell sarcomas, the efficacy of this treatment was temporary, so it will be necessary to investigate frequent high-dose chemotherapy and to change the high-dose chemotherapy regimen.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Busulfan; Child; Combined Modality Therapy; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Sarcoma; Sarcoma, Ewing; Sarcoma, Synovial; Soft Tissue Neoplasms; Thiotepa; Transplantation, Autologous

Topics: Adult; Antibiotics, Antineoplastic; Antineoplastic Agents; Cyclophosphamide; Drug Therapy, Combination; Fibrosarcoma; Hemangiosarcoma; Humans; Leiomyosarcoma; Liposarcoma; Male; Melphalan; Neoplasm Metastasis; Neurilemmoma; Nitrogen Mustard Compounds; Sarcoma; Sarcoma, Synovial; Thiotepa