Is there synergy between carbon ions and minibeam radiation therapy to trigger tumor control in a radioresistant model of osteosarcoma?
Although radiotherapy plays a key role in cancer treatment, it remains inefficient for radioresistant tumors, including osteosarcoma. Minibeam radiation therapy (MBRT) has emerged as a promising strategy, minimizing normal tissue toxicity while boosting immune responses. MBRT is a spatially fractionated radiotherapy (SFRT) technique that uses highly modulated dose distributions, at the class of submillimetric beams (0.5–1.0 mm wide) spaced by approximately 1.0 to 4.0 mm. Preliminary evidence thus far suggests that combination of X-rays and proton MBRT improves the therapeutic index for aggressive tumor models. However, long-term follow-up, statistically significant data, tumor efficacy studies, and dose-escalation trials with clinical beams are required to validate its clinical potential. Bertho et al. in a recent manuscript published in the journal Scientific Reports, went on to investigate the efficacy of carbon minibeam radiation therapy (C-MBRT) in an osteosarcoma murine model.
Following ethical approval, the study involved 8-week-old male C3H/He mice. LM8 osteosarcoma cells were injected into one of the mice’s posterior limbs, which a week later was either irradiated using conventional carbon ion therapy (CT, n = 9) or carbon minibeam radiation therapy (C-MBRT, n=10), or were not irradiated at all (n=8). C-MBRT was delivered using a pencil beam scanning system, with the beam split into six vertical slits. Dosimetry was performed with ionization chambers, microdiamond detectors, and radiochromic films. After irradiation, mice were monitored for 28 days, for tumor growth, lung metastasis and overall health. Tumor volume and metastasis in lungs were quantified using ImageJ. At the end of the study mouse osteosarcoma tumors and lungs were collected for histopathological analyses. Antibodies against Ki67 and CD8 were used as proliferation and T cell markers, respectively. Statistical analyses were performed using ANOVA and Tukey’s test.
Irradiated mice showed slight alopecia in the treated region, but no skin toxicities. Both C-MBRT and CT delayed tumor growth significantly compared to non-irradiated controls, with tumor control similar in both treatments despite C-MBRT delivering lower doses to most of the tumor. Histopathological analysis revealed no significant differences in Ki67-positive cells, but CD8-positive T-cell infiltration was higher in CT. Both irradiated groups reduced lung metastasis, with CT showing greater efficacy than C-MBRT.
This work was the first to assess the tumor control efficacy of an unconventional radiation therapy like C-MBRT, which combines mini-beam spatial fractionation and carbon ions in a radioresistant osteosarcoma murine model. Results showed that C-MBRT achieves tumor control similar to conventional CT, with only a small portion receiving high doses, suggesting activation of distinct mechanisms beyond direct tumor cell death from radiation. Immune responses on the other hand, were stronger in the conventional CT irradiation. Authors concluded that C-MBRT shows potential for effective tumor control with reduced healthy tissue damage, warranting further optimization and combination with immune therapies.