Med Phys. 2015 Oct;42(10):5928-36.

Spatial fractionation of the dose using neon and heavier ions: A Monte Carlo study.

Peucelle C1, Martínez-Rovira I1, Prezado Y1.
  • 1IMNC-UMR 8165, CNRS Paris 7 and Paris 11 Universities, 15 rue Georges Clemenceau, Orsay Cedex 91406, France.

 

Abstract

PURPOSE:

This work explores a new radiation therapy approach which might trigger a renewed use of neon and heavier ions to treat cancers. These ions were shown to be extremely efficient in radioresistant tumor killing. Unfortunately, the efficient region also extends into the normal tissue in front of the tumor. The strategy the authors propose is to profit from the well-established sparing effect of thin spatially fractionated beams, so that the impact on normal tissues might be minimized while a high tumor control is achieved. The main goal of this work is to provide a proof of concept of this new approach. With that aim, a dosimetric study was carried out as a first step to evaluate the interest of further explorations of this avenue.

METHODS:

The gate/geant4 v.6.1 Monte Carlo simulation platform was employed to simulate arrays of rectangular minibeams (700 μm × 2 cm) of four ions (Ne, Si, Ar, and Fe). The irradiations were performed with a 2 cm-long spread-out Bragg peak centered at 7 cm-depth. Dose distributions in a water phantom were scored considering two minibeams center-to-center distances: 1400 and 3500 μm. Peak and valley doses, peak-to-valley dose ratios (PVDRs), beam penumbras, and relative contribution of nuclear fragments and electromagnetic processes were assessed as figures of merit. In addition, the type and proportion of the secondary nuclear fragments were evaluated in both peak and valley regions.

RESULTS:

Extremely high PVDR values (>100) and low valley doses were obtained. The higher the atomic number (Z) of the primary ion is, the lower the valleys and the narrower the penumbras. Although the yield of secondary nuclear products increases with Z, the actual dose being deposited by the secondary nuclear fragments in the valleys starts to be the dominant contribution at deeper points, helping in the sparing of proximal normal tissues. Additionally, a wider center-to-center distance leads to a minimized contribution of heavier secondary fragments in valleys.

CONCLUSIONS:

The computed dose distributions suggest that a spatial fractionation of the dose combined to the use of submillimetric field sizes might allow profiting from the high efficiency of neon and heavier ions for the treatment of radioresistant tumors, while preserving normal tissues. The authors’ results support the further exploration of this avenue. Next steps include the realization of biological experiment to confirm the shifting of normal tissue complication probability curves.

PMID: 26429267

 

Supplement:

The treatment of radioresistant tumors, in particular hypoxic tumors, remains one of the major challenges in radiotherapy (RT). Tumor hypoxia leads to resistance to radiotherapy and anticancer chemotherapy, as well as predisposing for increased tumor metastasis [1]. Compared to conventional RT, heavy ion therapy is less dependent on the oxygen effect since the produced ionization column is dense enough to be able to induce direct multiple strand breaks in the DNA, thus leading to damages that are often non-reparable by the usual cellular mechanisms. Radiobiological findings in the laboratory indicated that resistant cells of hypoxic tumors could be effectively destroyed with very heavy ion beams, such as silicon and argon [2]. However, clinical results with a few patients performed with argon in 1979 and with silicon in 1982 lead to adverse late tissue results, and the use of these beams was discontinued. 

Nevertheless, the gain in tissue sparing that might be provided by the use of submillimetric field sizes and the spatial fractionation of the dose in minibeam radiation therapy [3-6] might allow profiting from the remarkable effectiveness of very heavy ions. This could offer a new hope for aggressive hypoxic tumors, whose treatment with conventional methods is very limited.  

The biological basis of normal tissue preservation after minibeam radiation therapy (MBRT) irradiations, is not well understood yet. One participant is the so-called dose volume-effect: the smaller the field size, the higher the tolerance of normal tissues [7].  There are indications that some other effects may be participating. The role of the so-called non-targeted effects needs to be disentangled. Those include cell signaling effects like cohort effects (signal mediated effects between cells irradiated with high and low doses within an irradiated volume [8]) and others, like abscopal effects (a phenomenon where localized irradiation of a particular tumor site causes a response in an organ/site distant to the irradiated area [9]). Another possible player, likely associated to cell communication, was hypothesized to be hyperplasia and migration of endothelium and glial cells in the valleys (therefore, minimally irradiated) [10], being capable to repair/replace the damaged tissue in the peaks (high dose areas). Related to that is the possible contribution of the so-called microscopic prompt tissue-repair effect [11], leading to a fast repair of vascular damage. This phenomenon has been observed when microscopic beams (50 μm) are used (as in microbeam radiation therapy), but it needs to be evaluated for the thicker beams used in MBRT. Those phenomena challenge many of the current paradigms in conventional radiation therapy, since they seem to implicate different biological mechanisms from those involved when direct damage by ionizing radiation takes place.  

Concerning dosimetry, the dose profiles in such spatially fractionated techniques consist in peaks and valleys. The ratio between these two magnitudes is called peak-to-valley dose ratio (PVDR). Dilmanian et al. put in evidence that in order to spare normal tissue, high PVDR values with low valley doses (below the tolerance dose for a seamless irradiation) are required [10]. 

This work was the first exploration of a potential renewed use of neon and heavier ions in RT, exploiting the sparing effect of thin (700 μm) spatially fractionated beams. With that aim, a Monte Carlo (Geant4/GATE v.6.1) dosimetric study was performed. The feasibility of irradiation of a deep seated tumor with arrays of several heavy ion minibeams (700 μm x 2 cm), from neon (Z=10) to iron (Z=26), was evaluated (see figure 1). Within this study, a magnetic collimation for minibeams generation was assumed. Two center-to-center distances were compared: 1400 and 3500 μm. The simulations were performed in a cylindrical water phantom with dimensions mimicking a human head.

 

 

fig1

Figure 1: Illustration of the simulation geometry

 

Extremely high PVDR (>100) and low valley doses were achieved. In general terms, the higher the Z, the higher the PVDR and the lower the valleys. This might offer a net gain in normal tissue sparing.  

One important issue in heavy ion therapy is the fragmentation tail created by the nucleus-nucleus collisions that extends beyond the Bragg peak. We showed that the valley doses in the tail region were lower than 8% of the prescription dose for any ion. A significant reduction (< 2.5 %) was observed when the c-t-c was enlarged.   

In addition, a critical point in such an evaluation is the role of secondary particle contamination of the valley doses, which must be kept below the tolerance dose to conventional seamless irradiation to preserve the sparing effect [3]. Interestingly, for the heavier ions the dose being deposited by the secondary ions in the valleys starts to be the dominant contribution at deeper points, helping in the sparing of proximal normal tissues. Therefore, heavier projectiles seem to be favored, although only biological experiments will be able to confirm our results. 

In addition, enlarging the spacing between two consecutive minibeams could minimize the contribution of heavier fragmentation products (high LET and potentially high RBE) in the valleys.  

The previous points suggest a preferential use of a 3500 μm c-t-c distance in order to minimize the contribution of heavy nuclear products to the valleys, and thus, to favor tissue sparing.  

The reduced lateral scattering of such heavy ions, as well as the narrow penumbras observed (< 500 μm at all depths) allow the spatial fractionation to be kept all along the minibeam paths. A homogeneous dose distribution could be achieved with this technique by interlacing several arrays in the tumor, as it has already been accomplished in previous MBRT studies.

 

Importance of this work: 

This work is the first exploration of very heavy ion minibeam radiation therapy. The significant gain in normal tissue resistance offered by MBRT might be the key to open the door to a renewed use of very heavy ions (neon or heavier) for therapy, which showed a very high effectiveness in tumor killing, but whose use has been discontinued due to the accompanying grave side-effects. The advantageous dose distributions achieved in this first study support the further exploration of this avenue. Next steps include the realization of biological experiments that could confirm the shifting of the normal tissue complication probability curves.

 

References:

[1] J. M. Brown, “Tumor hypoxia in cancer therapy”, Methods Enzymol. 435, 297–321 (2007). 

[2] J. R. Castro et al., “Experience in charged particle irradiation of tumors of the skull base: 1977-1992”, Int. J. Radiat. Oncol. Biol. Phys. 29, 647–655 (1994). 

[3] Y. Prezado et al., “Tolerance to dose escalation in minibeam radiation therapy applied to normal rat brain: Long-term clinical, radiological and histopathological analysis”, Radiat. Res. 184, 314–321 (2015). 

[4] F. A. Dilmanian et al., “Interlaced x-ray microplanar beams: A radiosurgery approach with clinical potential”, Proc. Natl. Acad. Sci. U. S. A. 103, 9709–9714 (2006). 

[5] P. Deman et al., “Monochromatic minibeams radiotherapy: From healthy tissue-sparing effect studies toward first experimental glioma bearing rats therapy”, Int. J. Radiat. Oncol. Biol., Phys. 82, e693–e702 (2012).  

[6] Y. Prezado et al., “Increase of lifespan for glioma-bearing rats by using minibeam radiation therapy”, J. Synchrotron Radiat. 19, 60–65 (2012). 

[7] J. W. Hopewell and K. R. Trottb, “Volume effects in radiobiology as applied to radiotherapy”, Radiother. Oncol. 56, 283–288 (2000).

[8] A. Marin et al., “Bystander effects and radiotherapy”, Reports of Practical Oncology and Radiotherapy 20, 12–21 (2015). 

[9] S. Siva et al., “Abscopal effects of radiation therapy: A clinical review for the radiobiologist”, Cancer Letters 356, 82–90 (2015). 

[10] F. A. Dilmanian et al., “Response of rat intracranial 9L gliosarcoma to microbeam radiation therapy”, Neuro-Oncol.4, 26–38 (2002). 

[11] R. Serduc et al., “In vivo two-photon microscopy study of short-term effects of microbeam irradiation on normal mouse brain microvasculature”, Int. J. Radiat. Oncol. Biol. Phys. 64, 1519–1527 (2006).

 

 

 

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