Joint Optimization of Photon–Carbon Ion Treatments for Glioblastoma

Abstract

Carbon ions are radiobiologically more effective than photons and are beneficial for treating radioresistant gross tumor volumes (GTV). However, owing to a reduced fractionation effect, they may be disadvantageous for treating infiltrative tumors, in which healthy tissue inside the clinical target volume (CTV) must be protected through fractionation. This work addresses the question: What is the ideal combined photon−carbon ion fluence distribution for treating infiltrative tumors given a specific fraction allocation between photons and carbon ions? Methods and Materials: We present a method to simultaneously optimize sequentially delivered intensity modulated photon (IMRT) and carbon ion (CIRT) treatments based on cumulative biological effect, incorporating both the variable relative biological effect of carbon ions and the fractionation effect within the linear quadratic model. The method is demonstrated for 6 glioblastoma patients in comparison with the current clinical standard of independently optimized CIRT−IMRT plans. Results: Compared with the reference plan, joint optimization strategies yield inhomogeneous photon and carbon ion dose distributions that cumulatively deliver a homogeneous biological effect distribution. In the optimal distributions, the dose to CTV is mostly delivered by photons and carbon ions are restricted to the GTV with variations depending on tumor size and location. Improvements in conformity of high-dose regions are reflected by a mean EQD2 reduction of 3.29 § 1.22 Gy in a dose fall-off margin around the CTV. Carbon ions may deliver higher doses to the center of the GTV, and photon contributions are increased at interfaces with CTV and critical structures. This results in a mean EQD2 reduction of 8.3 § 2.28 Gy, in which the brain stem abuts the target volumes. Conclusions: We have developed a biophysical model to optimize combined photon−carbon ion treatments. For 6 glioblastoma patient cases, we show that our approach results in a more targeted application of carbon ions that (1) reduces dose in normal tissues within the target volume, which can only be protected through fractionation; and(2) boosts central target volume regions to reduce integral dose. Joint optimization of IMRT−CIRT treatments enable the exploration of a new spectrum of plans that can better address physical and radiobiological treatment planning challenges.

Carbon Ion Irradiation Downregulates Notch Signaling in Glioma Cell Lines, Impacting Cell Migration and Spheroid Formation

“…Moreover, the use of a Notch inhibitor such as DAPT with CII could have beneficial effects as the combination of DAPT and CII significantly inhibited the cell growth when compared to either DAPT or CII alone ( Figure S8 ). Although very primitive, the results of the present studies also suggest a potential benefit of priming with CIRT before applying photon-based RT while planning in the photon-CIRT combinational therapy [ 40 ] for GBM, as prior treatment with photons may upregulate Notch signaling and compromise the clinical efficacy of CIRT.…”

Fraction optimization for hybrid proton‐photon treatment planning

“…The hybrid proton-photon and fraction optimization method proposed here is general, in the sense it should be applicable to other multi-modality RT problems, such as multi-ion RT [29][30][31] using proton, carbon or helium, photon-ion hybrid RT, 31,32 photon-electron RT, 33 and proton-photon-electron RT. 34…”

A novel stochastic optimization method for handling misalignments of proton and photon doses in combined treatments

“…Alternatively, one could jointly optimize IMRT and IMPT plans based on the cumulative biological effect to take into account the variable RBE of protons. This approach has already been proposed by Bennan et al (2021) in the context of combined photon-carbon ion treatments and could also be used for the combination of other modalities when the biological model is known.…”