“Sequential” Boron Neutron Capture Therapy (BNCT): A Novel Approach to BNCT for the Treatment of Oral Cancer in the Hamster Cheek Pouch Model

Abstract

In the present study the therapeutic effect and potential toxicity of the novel "Sequential" boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster cheek pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with "Sequential" BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the "Sequential" BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in the dose-limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47 ± 12% and 60 ± 22% of the animals, respectively. No normal tissue toxicity was associated with tumor response for any of the protocols. "Sequential" BNCT enhanced tumor response without an increase in mucositis in dose-limiting precancerous tissue.

Therapeutic efficacy of boron neutron capture therapy mediated by boron-rich liposomes for oral cancer in the hamster cheek pouch model

“…As described earlier, the posttreatment follow-up period for tumor control studies in the hamster cheek pouch oral cancer model was previously established as 4 wk after one treatment of BNCT or after the second treatment in the case of two-treatment protocols (12,40). For the first time to our awareness, it was possible to extend the follow-up period to 16 wk in the case of two-treatment protocols, mainly as a result of good therapeutic outcome, i.e., good tumor control, and reduced mucositis.…”

“…In terms of therapeutic efficacy, lengthening overall treatment time in conventional (i.e., low-LET) radiotherapy is known to reduce toxicity at the expense of reducing tumor control probability (43). However, in the case of BNCT that involves a combination of low and high LET radiation components, a repeat treatment would allow for boron retargeting of cell populations originated in tumor cells that were refractory to the first application and subsequently proliferated (3,40). Within the time frame evaluated (intervals of 4, 6, and 8 wk between applications), the present data do not reveal statistically significant differences in tumor response attributable to differences in the interval.…”

“…To evaluate toxicity, the clinical signs and bw of all animals were monitored twice per week. The tumor and precancerous tissue responses were assessed by visual inspection and tumor volume assay before treatment and at 1, 7, 14, 21, and 28 d posttreatment in keeping with the previously established follow-up period for tumor control studies in this model (12,32,40,49). When possible, the animals were followed for longer periods of time (up to 16 wk from the first treatment).…”

Boron delivery with liposomes for boron neutron capture therapy (BNCT): biodistribution studies in an experimental model of oral cancer demonstrating therapeutic potential

“…Based on previous BNCT radiobiological studies in the hamster cheek pouch oral cancer model with other boron compounds (e.g., Kreimann et al 2001b;Trivillin et al 2006;Molinari et al 2011), we previously defined the following guidelines to establish the potential therapeutic value of the boron carriers, the administration protocols, and timepoints post-administration • No manifest toxicity • Absolute boron concentration in tumor [20 ppm • Boron concentration ratio tumor/normal tissue [1 • Boron concentration ratio tumor/blood [1 Although the actual usefulness of a particular boron carrier and protocol can only be determined by in vivo radiobiological BNCT studies, our previous studies in the hamster cheek pouch oral cancer model with other boron compounds suggest that the protocols that meet the above requirements are potentially therapeutic and warrant radiobiological assessment.…”

“…MAC was administered at a dose of 6 mg B/kg bw (approximately 0.69 ml/100 g bw), and MAC-TAC was administered at a dose of 18 mg B/kg bw (approximately 1.39 ml/100 g bw). In view of the fact that MAC-TAC proved to be the compound with the best therapeutic potential (see ''Results'' section), an additional group of 3 tumor-bearing hamsters were injected with MAC-TAC and followed for 28 days [the traditional follow-up period employed in tumor control studies in the hamster cheek pouch oral cancer model (e.g., Kreimann et al 2001b;Trivillin et al 2006;Pozzi et al 2009;Molinari et al 2011)] to assess potential signs of toxicity in terms of clinical status and body weight.…”