Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an exp
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LABORATORY INVESTIGATION
Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model Ananth K. Vellimana • Violette Renard Recinos • Lee Hwang • Kirk D. Fowers • Khan W. Li • Yonggang Zhang • Saint Okonma Charles G. Eberhart • Henry Brem • Betty M. Tyler
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Received: 30 July 2012 / Accepted: 22 November 2012 / Published online: 7 December 2012 Ó Springer Science+Business Media New York 2012
Abstract OncoGelTM incorporates paclitaxel, a mitotic inhibitor, into ReGelTM, a thermosensitive gel depot system to provide local delivery, enhance efficacy and limit systemic toxicity. In previous studies the alkylating agent temozolomide (TMZ) incorporated into a polymer, pCPP:SA, also for local delivery, and OncoGel were individually shown to increase efficacy in a rat glioma model. We investigated the effects of OncoGel with oral TMZ or locally delivered TMZ polymer, with and without radiotherapy (XRT) in rats with intracranial gliosarcoma. Eighty-nine animals were intracranially implanted with a 9L gliosarcoma tumor and divided into 12 groups that received various combinations of 4 treatment options; OncoGel 6.3 mg/ml (Day 0), 20 Gy XRT (Day 5), 50 % TMZ–pCPP:SA (Day 5), or oral TMZ (50 mg/kg, qd, Days 5–9). Animals were followed for survival for 120 days.
A. K. Vellimana V. R. Recinos L. Hwang K. W. Li S. Okonma H. Brem B. M. Tyler (&) Department of Neurosurgery, Johns Hopkins University School of Medicine, 1550 Orleans Street CRB2 2M41, Baltimore, MD 21231, USA e-mail: [email protected] K. D. Fowers Protherics Salt Lake City Inc., Salt Lake City, UT, USA Y. Zhang Radiation Oncology and Molecular Radiation Services, Baltimore, MD 21231, USA C. G. Eberhart H. Brem Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA H. Brem Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
Median survival for untreated controls, XRT alone or oral TMZ alone was 15, 19 and 28 days, respectively. OncoGel 6.3 or TMZ polymer alone extended median survival to 33 and 35 days, respectively (p = 0.0005; p \ 0.0001, vs. untreated controls) with 50 % living greater than 120 days (LTS) in both groups. Oral TMZ/XRT extended median survival to 36 days (p = 0.0002), with no LTS. The group that received OncoGel and Oral TMZ did not reach median survival with 57 % LTS (p = 0.0002). All other combination groups [OncoGel/XRT], [TMZ polymer/XRT], [OncoGel/TMZ polymer], [OncoGel/TMZ polymer/XRT], and [OncoGel/oral TMZ/XRT] yielded greater than 50 % LTS (p \ 0.0001 for each combination as compared to controls), therefore median survival was not reached. OncoGel/TMZ polymer and OncoGel/oral TMZ/XRT had 100 % LTS (p \ 0.0001 and p = 0.0001 vs. oral TMZ/ XRT, respectively). These results indicate that OncoGel given locally with oral or locally delivered TMZ and/or XRT significantly increased the number of LTS and improved median survival compared to oral TMZ
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