Combination of pegylated-liposomal doxorubicin (PLD) and bevacizumab (B) (PLD-B) in sarcoma (SAR)

Abstract

20506 Background: Vascular endothelial growth factor (VEGF) plays an important role in many tumors including SAR. Because of the known efficacy of PLD in SAR and the presumed importance of VEGF in SAR, we have treated SAR patients with PLD-B. It is possible that the addition of B to PLD might alter the toxicity profile. The toxicities of this combination are not well described. Methods: To better define the toxicity of the combination of PLD-B in SAR, we reviewed our experience with PLD-B in patients treated between 2004 and 2006. Results: We identified 20 patients with SAR treated with PLD-B at our institution. There were 9 men and 11 women, with a median age of 47.5 years (range 23–77). Ten patients initiated therapy with PLD q28 days at a median dose of 45 mg/m2 (range 45–50), and 10 q14 days at a median dose of 21.2 mg/m2 (range 20–25), in combination with B at 5 mg/kg q14 days. A median of 5 cycles was given (range 1–15). Dose delay was required in 3 patients for the second cycle, and dose reduction was required in 9 patients by cycle 3. Of the 10 patients starting with monthly PLD, 7 were changed to q14 day PLD by cycle 4. Mucositis and skin toxicity were the dose limiting toxicities (DLT) in 14/20 patients, and myelosuppression was the DLT in 1/20 patients. Nine patients were felt to have clinical benefit; 3 had a PR and 6 had SD. Notably, 2/4 recurrent Ewing sarcoma patients had symptomatic improvement and at least SD for 10 and 11 months, respectively, with minor toxicity allowing a good quality of life. Conclusions: This report describes the toxicity profile of PLD-B in 20 patients with SAR. The toxicities observed were similar to those seen with PLD alone, however, these toxicities appeared more pronounced with the addition of B. Since VEGF is important for wound healing, the known effects of B on this process may contribute to more skin and mucosal toxicity of PLD at a given dose. Future studies of PLD-B should consider the potential of increased mucosal and skin toxicity. The use of q14 day PLD to allow more control over toxicity is suggested; a maximal starting dose of 20 mg/m2 is reasonable, although dose reduction will be common due to skin or mucosal toxicity. This combination can be given with limited toxicity, and meaningful responses were observed in recurrent sarcomas, including 2/4 Ewing sarcomas. No significant financial relationships to disclose.

Interpatient Pharmacokinetic and Pharmacodynamic Variability of Carrier-Mediated Anticancer Agents

“…once every 14 days in combination with Doxil once every 14 or 28 days. Doxil toxicities appeared to be more pronounced in these patients, with mucositis and skin toxicity being the dose‐limiting toxicities in 14 of 20 patients 62 . The suggested mechanisms underlying this synergistic toxicity include (i) direct pharmacologic interaction between Doxil and bevacizumab; (ii) effects of bevacizumab on the vasculature of soles, palms, and possibly the oral mucosa, resulting in increased accumulation of Doxil in these areas; and (iii) impairment of wound healing of dermal and mucosal injuries by bevacizumab 61 …”

Angiogenesis and vascular targeting in Ewing sarcoma

“…Cancer February 1, 2010 Another study treated 4 patients with Ewing sarcoma with bevacizumab and liposomal doxorubicin. 40 Two of those patients had stable disease for at least 10 months. These results, although not definitive, suggest that bevacizumab may have a clinical role in inhibiting the growth of Ewing sarcoma.…”

Bone Sarcomas in Pediatrics: Progress in Our Understanding of Tumor Biology and Implications for Therapy

“…Preclinical efficacy of VEGF-based therapeutics, including anti-VEGF antibodies and small-molecule inhibitors against VEGFR, has been confirmed in pediatric bone sarcomas [ 27 , 175 ]. The anti-VEGF mAb bevacizumab demonstrated some clinical benefit as monotherapy or in combination with doxorubicin in patients with recurrent ES [ 176 , 177 ]. Three phase II trials of bevacizumab in combination with chemotherapy for patients with OS and ES are currently underway.…”