Carbon Ion Irradiation of the Rat Spinal Cord: Dependence of the Relative Biological Effectiveness on Linear Energy Transfer

doi:10.1016/j.ijrobp.2014.05.008

International Journal of Radiation OncologyBiologyPhysics

Volume 90, Issue 1, 1 September 2014, Pages 63-70

https://doi.org/10.1016/j.ijrobp.2014.05.008 Get rights and content

Purpose

To measure the relative biological effectiveness (RBE) of carbon ions in the rat spinal cord as a function of linear energy transfer (LET).

Methods and Materials

As an extension of a previous study, the cervical spinal cord of rats was irradiated with single doses of carbon ions at 6 positions of a 6-cm spread-out Bragg peak (16-99 keV/μm). The TD₅₀ values (dose at 50% complication probability) were determined according to dose-response curves for the development of paresis grade 2 within an observation time of 300 days. The RBEs were calculated using TD₅₀ for photons of our previous study.

Results

Minimum latency time was found to be dose-dependent, but not significantly LET-dependent. The TD₅₀ values for the onset of paresis grade 2 within 300 days were 19.5 ± 0.4 Gy (16 keV/μm), 18.4 ± 0.4 Gy (21 keV/μm), 17.7 ± 0.3 Gy (36 keV/μm), 16.1 ± 1.2 Gy (45 keV/μm), 14.6 ± 0.5 Gy (66 keV/μm), and 14.8 ± 0.5 Gy (99 keV/μm). The corresponding RBEs increased from 1.26 ± 0.05 (16 keV/μm) up to 1.68 ± 0.08 at 66 keV/μm. Unexpectedly, the RBE at 99 keV/μm was comparable to that at 66 keV/μm.

Conclusions

The data suggest a linear relation between RBE and LET at high doses for late effects in the spinal cord. Together with additional data from ongoing fractionated irradiation experiments, these data will provide an extended database to systematically benchmark RBE models for further improvements of carbon ion treatment planning.

Introduction

The treatment of head and neck tumors with light ions gained increased interest during the last years 1, 2, 3. This is due to the highly conformal dose distributions originating from the inverted depth-dose profile (Bragg peak) of charged particles. Although this property is shared by protons and heavier ions (eg, carbon ions), the latter show an increased relative biological effectiveness (RBE) with increasing depth (1). The RBE is a highly complex quantity and depends on linear energy transfer (LET), dose, and on biological factors like tissue type and endpoint. In treatment planning, the RBE has to be considered by mathematical models 4, 5, 6, and the resulting dose distribution is optimized in terms of biologically effective rather than absorbed dose, which introduces substantial uncertainty. This is of special importance for the late-responding tissues of the central nervous system (CNS), which is the dose-limiting tissue in the treatment of head and neck tumors.

To improve safety of patients in carbon ion therapy RBE models have to be benchmarked, and for this, systematic experimental studies that reflect the main dependencies of the RBE are required. To investigate late effects in the CNS, the rat spinal cord is a well-established model (7), which has also been applied to measure RBEs for carbon ions 8, 9, 10, 11. The largest data set originates from our previously published studies 8, 9 and provides RBEs in the entrance region and the middle of a 1-cm spread-out Bragg Peak (SOBP) for different fractionation schemes. This early study, however, covers only extreme LET values, and therefore in the present study the LET dependence of the RBE is systematically investigated by irradiating the spinal cord with single doses of carbon ions at different positions of a 6-cm SOBP.

Section snippets

Animals

A total of 229 young adult female (204 ± 23 g) Sprague-Dawley rats (Charles River Laboratories, Sulzfeld, Germany) were used (Table 1). Irradiations were performed under general gaseous anesthesia with a mixture of 4% Sevoflurane (Abbott, Wiesbaden, Germany) and oxygen at 2 L/min using a 50-mL disposable syringe as a mask. All experiments were approved by the governmental review committee on animal care, and animals were kept under standard conditions at the German Cancer Research Center (DKFZ)

Results

Irradiation procedures were well tolerated by the animals. No weight reduction was observed during the course of the experiments, and none of the animals died from acute radiation toxicity. Within the first 3 weeks after treatment, a slight or complete transient hair loss as well as moist desquamation restricted to the irradiation field were observed on the ventral and dorsal (except for 99 keV/μm) side of the rat. Out of 229 rats, 7 had to be excluded due to either death of unknown cause or to

Discussion

We used the rat cervical spinal cord to determine the dependence of RBE on LET along a 6-cm carbon ion SOBP. This is a well established model to evaluate the response of normal CNS tissue to irradiation 17, 18, 19, 20, 21, 22, 23. At the time point of irradiation all animals had the same age to prevent age dependencies in the radiation response 23, 24. It has been shown that TD₅₀ values are dependent on the irradiated volume 17, 20 and that there are regional differences in radiosensitivity

Conclusion

In summary, our single dose in vivo data suggest a linear relation between RBE and LET at high doses for late effects in the spinal cord. Minimum latency time was found to be dose-dependent, but not significantly LET-dependent. Additional systematic investigations of these dependencies are of fundamental importance for the clinical development of carbon ion therapy. Together with additional data from ongoing fractionated irradiation experiments, these data will provide an extended and

Acknowledgments

The authors thank Angela Funk and Andreas Griesbach (German Cancer Research Center) for their excellent technical support; Prof. Albert van der Kogel (University Nijmegen, The Netherlands) and Prof. Eric W. Hahn (UT Southwestern Medical School, Dallas, TX) for their help with the experimental setup and design of the study; and the Helmholtz Center for Heavy Ion Research (GSI) and the Heidelberg Ion Beam Therapy Center (HIT) for providing the excellent experimental conditions with highly

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Citation Excerpt :
The present study is the first systematic study of the LET- and dose-dependence of the RBE in the rat spinal cord for helium ions. It uses the same field sizes, the same SOBP, the same spinal cord positions and the same fraction numbers as previous studies with carbon ions [29–31,33] and protons [32], which allows for a direct comparison of the RBE. The photon reference curves were taken from a previous study [27] as they have shown to be highly reproducible even over long periods [27,47].
Determination of the relative biological effectiveness (RBE) of helium ions as a function of linear energy transfer (LET) for single and split doses using the rat cervical spinal cord as model system for late-responding normal tissue.
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: This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (KFO 214).

: Conflict of interest: none.

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Biology ContributionCarbon Ion Irradiation of the Rat Spinal Cord: Dependence of the Relative Biological Effectiveness on Linear Energy Transfer

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Animals

Results

Discussion

Conclusion

Acknowledgments

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Nucl Instrum Methods Phys Res

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Biology Contribution
Carbon Ion Irradiation of the Rat Spinal Cord: Dependence of the Relative Biological Effectiveness on Linear Energy Transfer