Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

doi:10.1016/j.ijrobp.2013.12.039

International Journal of Radiation OncologyBiologyPhysics

Volume 88, Issue 5, 1 April 2014, Pages 1136-1141

https://doi.org/10.1016/j.ijrobp.2013.12.039 Get rights and content

Purpose

To compare the relative biological effectiveness (RBE)–weighted tolerance doses for temporal lobe reactions after carbon ion radiation therapy using 2 different versions of the local effect model (LEM I vs LEM IV) for the same patient collective under identical conditions.

Methods and Materials

In a previous study, 59 patients were investigated, of whom 10 experienced temporal lobe reactions (TLR) after carbon ion radiation therapy for low-grade skull-base chordoma and chondrosarcoma at Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany in 2002 and 2003. TLR were detected as visible contrast enhancements on T1-weighted MRI images within a median follow-up time of 2.5 years. Although the derived RBE-weighted temporal lobe doses were based on the clinically applied LEM I, we have now recalculated the RBE-weighted dose distributions using LEM IV and derived dose-response curves with Dmax,V-1 cm³ (the RBE-weighted maximum dose in the remaining temporal lobe volume, excluding the volume of 1 cm³ with the highest dose) as an independent dosimetric variable. The resulting RBE-weighted tolerance doses were compared with those of the previous study to assess the clinical impact of LEM IV relative to LEM I.

Results

The dose-response curve of LEM IV is shifted toward higher values compared to that of LEM I. The RBE-weighted tolerance dose for a 5% complication probability (TD₅) increases from 68.8 ± 3.3 to 78.3 ± 4.3 Gy (RBE) for LEM IV as compared to LEM I.

Conclusions

LEM IV predicts a clinically significant increase of the RBE-weighted tolerance doses for the temporal lobe as compared to the currently applied LEM I. The limited available photon data do not allow a final conclusion as to whether RBE predictions of LEM I or LEM IV better fit better clinical experience in photon therapy. The decision about a future clinical application of LEM IV therefore requires additional analysis of temporal lobe reactions in a comparable photon-treated collective using the same dosimetric variable as in the present study.

Introduction

As the world's third facility, the Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt, Germany started treatment of cancer patients with carbon ions in 1997. Within a 10-year pilot project, more than 400 patients underwent irradiation. The encouraging clinical results (1) paved the way for the construction of the Heidelberg Ion-Beam Therapy Center (HIT), a hospital-based facility that started patient treatment in November 2009. Today, 6 carbon ion facilities are operational worldwide, and 4 more are in the advanced planning or construction phase (2).

One of the major advantages of carbon ions relative to photons or protons is the increased relative biological effectiveness (RBE) in the target region relative to the entrance channel. The resulting biological effective dose (also termed RBE-weighted dose) is determined by the product of RBE and absorbed dose. RBE is a complex quantity that depends on physical as well as biological quantities. In treatment planning, it has to be derived either from simple empirical models (3) or from more sophisticated track-structure models, such as the local effect model (LEM) (4). LEM was developed and clinically applied during the pilot project at GSI. It has subsequently also been incorporated into the treatment planning software at HIT. Thus, until now, the first version of the local effect model, LEM I, has been used to optimize the RBE-weighted dose distributions of more than 1500 patients, and clinical results suggest that RBE predictions of LEM I are reasonably accurate 1, 5.

On the other hand, animal studies on the tolerance of the rat spinal cord and in vitro studies on cell survival have reported that LEM I underestimates the RBE in the spread-out Bragg peak (SOBP) by 25% and overestimates the RBE for low absorbed doses in the entrance channel by 20% 6, 7. In addition, a comparison of the LEM I–based RBE-weighted depth-dose profile with that of protons showed that high RBE values may also occur outside the target, implying that LEM I does not predict a biological advantage of carbon ions as compared to protons (8). These findings have raised some doubts about the accuracy of LEM I and motivated further developments (7) that have resulted in a new version of the local effect model, termed LEM IV (9).

LEM IV considers the complexity of radiation damage in terms of the microscopic double-strand break distribution on the DNA rather than only the effect of the local dose. The modification results in a more pronounced increase of RBE with linear energy transfer (LET) from the entrance region toward the distal end of the SOBP. Benchmarking tests reported that the RBE-weighted depth-dose profile of LEM IV describes experimental in vivo and in vitro data significantly better than does LEM I 9, 10.

To decide which version of the local effect model predicts RBE more reliably, the apparent contradiction between the good clinical results obtained with LEM I on one hand and the better description of experimental in vivo and in vitro data by LEM IV on the other hand has to be further investigated. In this respect, the analysis of clinical data is of major importance.

A treatment-planning comparison of LEM I and LEM IV for idealized target geometries (11) showed that the predicted median RBE-weighted doses for a typical target volume are very similar for both models. In contrast to the dose in the target volume, we are now considering the dose in normal tissue. As a first step in this direction, radiation-induced temporal lobe reactions after carbon ion therapy were previously analyzed, and a dose-response curve with the LEM I–based RBE-weighted dose as an independent dosimetric variable was derived (1). The predicted tolerance doses appeared to be comparable to those of photons available at that time, indicating a reasonable accuracy of LEM I. In the present study, we repeat this analysis for the same patient collective and under identical conditions using LEM IV instead of LEM I to calculate the RBE-weighted doses. Tolerance doses predicted by LEM I and LEM IV are reassessed by comparison to recently published clinical data, aiming to answer the question as to whether LEM I or LEM IV gives a more accurate description of the RBE in normal brain tissue.

Section snippets

Methods and Materials

The patient collective and endpoint of this study are the same as in the previous analysis (1). Therefore only a brief description is given here.

Dosimetric analysis

Figure 1 shows a representative comparison of RBE-weighted dose distributions of both models for the temporal lobe. It can be seen that the dose gradient around the planning target volume (PTV) is stronger for LEM IV than for LEM I. Generally, a large area of the temporal lobe receives less dose in the case of LEM IV. However, small areas located directly adjacent to or overlapping the PTV are subject to higher doses. Figure 2 and Table 1 summarize the dosimetric variables for all patients: The

Discussion

For carbon ion radiation therapy, the prediction of the biological effective dose depends on the RBE model involved in treatment planning (11). The aim of the present comparative treatment planning study, therefore, was to analyze the clinical impact of a new radiobiological model (LEM IV) by comparing it against a standard model used routinely in clinical practice (LEM I) with respect to predictions of tolerances to radiation-induced TLR.

Conclusions

Although LEM IV seems to give a better description of experimental in vivo data as compared with LEM I (11), a decision based on clinical data remains more difficult. The derived dose-response curves indicate a clinically significant increase of the RBE-weighted TD₅ by 9.5 Gy (RBE) for LEM IV as compared to the currently clinically applied LEM I. As the comparison of the derived tolerance doses with available photon data is associated with several methodological uncertainties, it is currently

Acknowledgments

The authors thank Michael Scholz, PhD, Thomas Friedrich, PhD, and Rebecca Grün for valuable comments on the manuscript.

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The analyzed patient collective is identical to that studied previously [16,17] and included 59 patients treated with carbon ions for chordoma (n = 40) and low-grade chondrosarcoma (n = 19) of the skull base at GSI in 2002 and 2003.
To compare the relative biological effectiveness (RBE)-weighted dose distributions in the target volume of chordoma and chondrosarcoma patients when using two different versions of the local effect model (LEM I vs. IV) under identical conditions.
The patient collective included 59 patients treated with 20 fractions of carbon ion radiotherapy for chordoma and low-grade chondrosarcoma of the skull base at the Helmholtzzentrum für Schwerionenforschung (GSI) in 2002 and 2003. Prescribed doses to the planning target volume (PTV) were 60 (n = 49), 66 (n = 2) and 70 (n = 8) Gy (RBE). The original treatment plans that were initially biologically optimized with LEM I, were now recalculated using LEM IV based on the absorbed dose distributions. The resulting RBE-weighted dose distributions were quantitatively compared to assess the clinical impact of LEM IV relative to LEM I in the target volume.
LEM IV predicts 20–30 Gy (RBE) increased maximum doses as compared to LEM I, while minimum doses are decreased by 2–5 Gy (RBE). Population-based mean and median doses deviated by less than 2 Gy (RBE) between both models.
LEM I and LEM IV-based RBE-weighted doses in the target volume may be significantly different. Replacing the applied model in patient treatments may therefore lead to local over- or underdosages in the tumor. If LEM IV is to be tested clinically, comparisons of the RBE-weighted dose distributions of both models are required for the individual patients to assess whether the LEM IV-plan would also be acceptable and prescribed dose as well as clinical outcome data have to be carefully reassessed.
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It was therefore not possible to relate this parameter with the effect probability and perform comparisons with our previous studies [16,17]. In accordance with our previous studies [16,17], we selected Dmax,V-1cm3 as independent dosimetric parameter for the dose–response analysis. As the exact value of the tolerance doses depends on this selection, the question arises, which dosimetric variable correlates best with the occurrence of the clinical endpoint.
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62 patients treated with protons for skull base tumors were analyzed for TLRs using magnetic resonance imaging. Within the mean follow-up time of 38 months, TLRs were observed in six patients. Dose–response curves based on the RBE-weighted maximum dose, excluding the 1 cm³-volume with the highest dose, were derived and compared to previously published dose–response curves for carbon ions, which were obtained using LEM I or IV, respectively.
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However, despite resolution of contrast-enhancement on follow-up MRI, two patients developed seizures and are currently under anticonvulsive medication. While the rate of temporal lobe changes corresponds to dose deposited in the temporal lobe and is in line with prior observations [40,41], there may be long-term changes in cerebral tissue, which do not correlate with standard diagnostic MRI sequences used for follow-up. Fortunately, we observed only one case of tissue necrosis followed by grade IV ICA blowout not resulting in neurological symptoms and one case of chronic CSF leakage in a patient following adjuvant RT for extensively resected ACC of the paranasal sinus.
Locoregional control (LC) in malignant salivary gland tumors is dose-dependent, initial results with particle therapy were promising. We report our experience with raster-scanned, intensity-controlled carbon ion therapy (C12) and IMRT in 309 patients with pathologically confirmed adenoid cystic carcinoma (ACC) of the head and neck.
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Due to the different endpoints and models integrated in both approaches, RBE values can be different for the same beam. Conversion from a dose distribution based on one RBE model into another is possible and has been reported in previous studies [33,34]. By making use of the latter approaches, it is feasible to adapt the result of this study for C-ion RT facilities running a different RBE model.
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The resulting NTCP parameters were the volume effect parameter; n = 0.035 (95% CI: 0.024–0.047), the steepness of the NTCP curve; m = 0.10 (0.084–0.13), the tolerance dose associated with 50% probability of complication; TD₅₀ = 63.6 Gy (RBE) (61.8–65.4 Gy (RBE)) for Grade ⩾ 1, n = 0.012 (0.0050–0.023), m = 0.046 (0.033–0.062), TD₅₀ = 69.1 Gy (RBE) (67.6–70.9 Gy (RBE)) for Grade ⩾ 2.
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Physics ContributionTemporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Methods and Materials

Dosimetric analysis

Discussion

Conclusions

Acknowledgments

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

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Physics Contribution
Temporal Lobe Reactions After Carbon Ion Radiation Therapy: Comparison of Relative Biological Effectiveness–Weighted Tolerance Doses Predicted by Local Effect Models I and IV