Combination of paclitaxel thermal gel depot with temozolomide and radiotherapy significantly prolongs survival in an experimental rodent glioma model

Abstract

OncoGel™ incorporates paclitaxel, a mitotic inhibitor, into ReGel™, 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. 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 and XRT given alone or in combination in a rodent intracranial gliosarcoma model.

Fig. 1

Intracranial efficacy of TMZ given IC or PO in combination with OncoGel 6.3 mg/ml with and without XRT for the treatment of experimental malignant gliosarcoma. F344 rats were intracranially implanted with 9L tumor. Controls (n = 7) received no further treatment (filled circle) and had a MS of 15 days. Animals receiving XRT (20 Gy) on Day 5 (n = 7) (filled circle) and animals that received oral TMZ on Days 5–9 (n = 7) (open diamond) had MS of 19 and 28 days, respectively. Animals receiving OncoGel 6.3 on Day 0 (n = 6) (filled triangle) had a MS of 33 days. Animals receiving a TMZ polymer on Day 5 (n = 8) (open circle) had a MS of 35 days. Animals that received OncoGel 6.3 and XRT (n = 7) (filled triangle) did not reach MS with 85 % long term survivors (LTS). Animals that received a TMZ polymer and XRT (n = 8) (emdashed line) reached MS on Day 70 with 50 % LTS. Animals that received OncoGel 6.3 and Oral TMZ (n = 7) (open triangle) did not reach MS with 57 % LTS. Animals receiving OncoGel 6.3, TMZ polymer and XRT (n = 8) (cross symbol) did not reach MS with 75 % LTS. Animals that received Oral TMZ and XRT (n = 8) (vertical line) had a MS of 35 days. Animals that received either OncoGel 6.3 and TMZ polymer (n = 8) (open square) or the triple combination of OncoGel 6.3, oral TMZ and XRT (n = 6) (filled circle) had no deaths with both groups having 100 % LTS

Fig. 2

a–b Tumor infiltration of untreated rat brain from control group (a macroscopic view) with mitotic figures (arrow) in neoplastic cells (b × 160 magnification); c–d rat brain from OncoGel + oral TMZ + XRT group with no tumor (c macroscopic view). 2D shows the area marked by the arrow in 2C, demonstrating hemosiderin-laden macrophages within the wound tract surrounded by reactive gliosis (left arrows) and dystrophic calcification (right arrow, ×160 magnification); e–f rat brain from OncoGel + 50 % TMZ + XRT group with no tumor (e macroscopic view) but showing inflammation, acellular debris, and residual polymer (arrow and f ×64 magnification)