Radiation synergizes with antitumor activity of CD13-targeted tissue factor in a HT1080 xenograft model of human soft tissue sarcoma

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 during ILP. Results No perioperative surgical complication was observed. Local toxicity was moderate (grade I or II); general toxicity was observed in 6 patients (2 grade I and 4 grade III). Complete response was obtained in 7 cases; 2 patients had a partial response and finally 1 was a nonresponder and showed local progression, which required surgical amputation. Tumor necrosis (observed in 5 cases) was maximal in 4 patients (80-100%) and absent in the patient who had local progression. Conclusions The results we obtained with the treatment of soft tissue sarcoma confirm the efficacy of ILP as a limb-sparing methodology for unresectable recurrences. Furthermore, rHu TNF-α and melphalan confirmed their antitumor activity when associated with hyperthermia. Amputation or disarticulation may be reliable as a second-choice treatment for these patients.

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A phase I trial of doxorubicin and flavopiridol in soft tissue sarcoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.9523 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 9523-9523 ◽

Cited By ~ 1

Author(s):

D. R. D’Adamo ◽

K. Scheu ◽

S. Singer ◽

G. K. Schwartz ◽

R. G. Maki

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Phase I ◽

Stable Disease ◽

Kinase Inhibitor ◽

Single Agent ◽

Xenograft Model ◽

Fixed Dose ◽

Preclinical Model ◽

Combination Methods

9523 Background: Flavopiridol, a potent cyclin dependent kinase inhibitor, has been shown in vitro to enhance doxorubicin induced apoptosis. Using the BWH dediffentiated liposarcoma xenograft model we have shown that sequential therapy with doxorubicin (D) followed 1 hour later by flavopiridol (F) is superior to doxorubicin alone (p=0.006). Single agent flavopiridol was also active in this xenograft model, but less so than the combination. Methods: We have commenced an ongoing phase I study of the combination of D and F on the basis of this preclinical data in soft tissue sarcoma with fixed dose D (60 mg/m2), followed 1 hour later by escalating doses of F (40–70 mg/m2) administered over one hour, every 3 weeks. Standard phase I eligibility criteria apply. No prior anthracycline therapy is allowed. At 300 mg/m2 D, dexrazoxane is added to D F. Patients with responsive or stable disease after cumulative D dose of 600mg/m2 can receive single agent flavopiridol. Results: Median characteristics of 7 evaluable patients: age 52 (31–65), KPS 80% (70–90), 3 males / 4 females, 0 prior regimens (range 0–2). The combination has been well-tolerated, with no dose limiting toxicity (DLT) yet. There has been 1 grade 3 bleed in the setting of progressive disease and 1 grade 4 neutropenia without fever. Grade 1 and 2 diarrhea, related to flavopiridol have been observed. Pharmacokinetic (PK) studies are ongoing. We have observed no partial responses (PR). Prolonged stable disease (SD) has been seen in 3 patients for 6, 6 and 11 months. Two patients with SD have liposarcoma. One patient with liposarcoma continues on single agent flavopiridol with stable disease after having reached the prescribed limit of D of 600 mg/m2. Conclusions: The combination of doxorubicin and flavopiridol is safe, with no unexpected toxicities. Disease stabilization in STS has been observed. This appears to be an encouraging combination in liposarcoma and is consistent with our preclinical model. Flavopiridol dose escalation is continuing. No significant financial relationships to disclose.

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