Microdosimetric characterisation of a therapeutic proton beam used for conjunctival melanoma treatments

Microdosimetric characterisation of a therapeutic proton beam used for conjunctival melanoma treatments

Radiation Measurements 45 (2010) 1387e1390 Contents lists available at ScienceDirect Radiation Measurements journal homepage: www.elsevier.com/locat...

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Radiation Measurements 45 (2010) 1387e1390

Contents lists available at ScienceDirect

Radiation Measurements journal homepage: www.elsevier.com/locate/radmeas

Microdosimetric characterisation of a therapeutic proton beam used for conjunctival melanoma treatments L. De Nardo a, P. Colautti b, *, J. Hérault c, V. Conte b, D. Moro a, b a

Dipartimento di Fisica dell’Università di Padova, via Marzolo 8, I-35131 Padova, Italy INFN, Laboratori Nazionali di Legnaro, Viale ’dell’Università 2, I-35020 Legnaro, Padova, Italy c Cyclotron Biomédical, Centre A. Lacassagne, F-06200 Nice, France b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 9 November 2009 Accepted 22 May 2010

In this study we have investigated the radiation quality of proton beams used to treat conjunctival melanomas at the Biomedical Cyclotron in Nice. To quantify radiation quality we have used a mini tissueequivalent proportional counter (TEPC). Microdosimetric spectra have been measured at different depths and lateral positions in a Plexiglas eye phantom. A weighting function, which was derived from evaluations of the early effects on the mouse intestine, was applied to the spectra to obtain the microdosimetric assessment of relative biological effectiveness (RBEm). Data show that RBEm varies significantly in the eye phantom, from 1.1 to 1.7. However, within the conjunctiva the RBE-weighted dose varies in a similar fashion to the absorbed, although it is up to 20% higher than the corresponding absorbed dose. Ó 2010 Elsevier Ltd. All rights reserved.

Keywords: Proton beam Microdosimetry RBE

1. Introduction A conjunctival melanoma is a rare tumour representing about 3% of all ocular melanomas. The radiotherapy treatment of conjunctival malignancy is reported to be ineffective (Wuestemeyer et al., 2006) when using conventional external beam radiation, due to its deleterious effect on visual acuity. At the Centre Antoine Lacassagne in Nice (France) a method is used that avoids unnecessary irradiation of the lens, ciliary body, and retina (Wuestemeyer et al., 2006). It uses the 65 MeV proton beam provided by the MEDICYC cyclotron. However, the complexity of the irradiation, in which a Spread-Out Bragg Peak (SOBP) is used with a hemispherical Plexiglas compensator, raises questions about the variability of radiation quality throughout the irradiated field. In our previous studies we had used mini TEPCs and the weighting function model to calculate RBEm of the Nice therapeutic beam (Cesari et al., 2001; De Nardo et al., 2004a). Measurements had revealed that RBEm varies from 1.1 to 1.4 in the SOBP and reaches values as high as 2.7 at the distal edge. Those data were in good agreement with the calculations of Paganetti et al. (1997) and with radiobiological measurements (Courdi et al., 1994; Bettega et al., 2000). Moreover, measurements performed outside the collimator edge had shown that RBEm increased by 10% (De Nardo et al.,

* Corresponding author. E-mail address: [email protected] (P. Colautti). 1350-4487/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.radmeas.2010.05.034

2004a) at 2.5 mm from the collimator edge, which was higher than those calculated by Van Luijk et al. (2001). The aim of this study was to measure the radiation quality in a phantom simulating a conjunctival melanoma under treatment conditions and to compare the absorbed dose and RBE-weighted dose distributions. 2. Materials and methods 2.1. The experimental set-up The proton beam from the MEDICYC cyclotron has a maximum range in water of 32 mm, which is easily reducible to any range by introducing Plexiglas plates in the treatment nozzle. A “half SOBP” is used for conjunctival melanoma treatments (Hérault et al., 2007). The “half SOBP” extends from 15 mm to 30 mm of ocular tissue. To achieve the optimal beam shaping, the beam passes through a semi-spherical Plexiglas compensator (see left side of Fig. 1). The technique ensures high-dose coverage in the shape of a spherical shell that includes the eyelids and 2 mm of sclera, thus sparing sensitive structures. On the right side of Fig. 1, the phantom used to simulate the therapeutic radiation field, is shown again. The proton beam collimator is 30 mm in diameter. The Plexiglas compensator, the radius of which is 9.9 mm, is placed on a 0.7 mm Plexiglas plate. Downstream of the compensator a 5.4 mm Plexiglas plate simulates the 6 mm (ocular tissue) echographic bolus, which is placed on the ’patient’s eye during the treatment (Sauerwein et al., 2009).

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Fig. 1. Left side: irradiation layout of the conjunctive tumour treatment with 65 MeV protons. Right side: the phantom used for measurements.

Fig. 2. The mini TEPC used for microdosimetric measurements. The sensitive volume is the small grey area at the centre.

Measurements have been performed by inserting Plexiglas layers of increasing thickness between the mini TEPC and the bolus. Behind the mini TEPC, a thick Plexiglas layer simulates the ’patient’s head. 2.2. Microdosimetric measurements and data processing Microdosimetric measurements were performed with the mini TEPC, a diagram of which is in Fig. 2. The TEPC sensitive volume is a cylinder of 0.9 mm height and diameter. The counter external size is 2.7 mm, the total wall thickness (A-150 plastic, Rexolite insulator, titanium sleeve) is equivalent to 1.58 mm of ocular tissue. More details about the mini TEPC have been published elsewhere (De Nardo et al., 2004b). The counter was flushed continuously with propane-based tissue-equivalent gas at a pressure of 71. 5 k Pa. The simulated site size was 0.1 mg/cm2 (1 mm at density of 1 g/cm3). The counter was mounted on a 2-axis micro screw movable platform. Therefore, the counter could be accurately placed on the beam line and moved laterally to it with 0.1 mm precision. The sensitive volume zero position (on the central axis) was checked with the

radiographic apparatus used prior to therapy for the beam alignment check. Measurements where performed by placing six different Plexiglas plates with thicknesses of 3.6, 6.3, 7.0, 8.0, 9.2 and 18.1 mm in between the mini TEPC and the upstream bolus. For each Plexiglas plate microdosimetric spectra were collected at different lateral positions, both inside and outside the collimated proton beam. For all the spectra, more than 106 total counts were collected. The lineal energy calibration of the microdosimetric spectra was performed by assigning a y-value of 146 keV/mm to the proton edge. Microdosimetric spectra were then processed in the usual way (Cesari et al., 2001; De Nardo et al., 2004a) to generate the densityprobability functions d(y), which were in turn used to calculate RBEm by using the weighting function r(y) of Loncol et al. (1994) for early effects in mouse intestinal crypt cells:

Z RBEm ¼

rðyÞdðyÞdy

(1)

2.3. Dose measurements In order to calculate relative RBE-weighted doses, relative absorbed dose measurements were performed by using a small commercial silicon diode with a sensitive volume of 1  3  0.1 mm3 (Siemens-BPW34FS). Measurements were performed in a small water tank of 13  10  6 cm3, which is routinely used at the MEDICYC cyclotron facility. Water thicknesses between the diode and the compensator were chosen to be equivalent to the Plexiglas thicknesses used for microdosimetric measurements. A remote control system moved the diode laterally with 0.1 mm precision. 3. Results 3.1. RBEm data

Fig. 3. RBEm for mouse crypt cell damage against the distance X from the proton beam axis for different Plexiglas depths.

RBEm values are plotted in Fig. 3 as a function of the distance X from the proton beam axis and for different Plexiglas thicknesses. Following Guellette et al. (2004), we have estimated an overall uncertainty of 3% for all measurements. Uncertainties are shown

L. De Nardo et al. / Radiation Measurements 45 (2010) 1387e1390

Fig. 4. Relative absorbed dose against the distance X from the proton beam axis for different Plexiglas depths. The two dashed vertical lines represent the collimator edge.

only for two data sets. The “half SOBP” extends from 15 mm to 30 mm of ocular tissue, see De Nardo et al., (2004a) For the “half SOBP”, which we will call simply SOBP in the following discussion, the distal edge is assumed to extend from a depth 30 mm to a depth of 32 mm of ocular tissue. In order to reach the sensitive volume of the mini TEPC, protons have to traverse the compensator, the bolus, the Plexiglas layer and the counter wall. The total thickness traversed is maximum at X ¼ 0 mm and minimum outside the compensator, i.e., for X > 9.9 mm. With a 3.6 mm Plexiglas thickness, the measuring point is at the half of the SOBP at X ¼ 2.5 mm and at the proximal edge at X ¼ 10 mm. With 9.2 mm of Plexiglas layer, the measuring point is at the beginning of the distal edge of the SOBP at X ¼ 2.5 and at half the SOBP at X ¼ 10. With 18.1 mm of Plexiglas layer, the total thickness at X ¼ 2.5 is 42.6 mm of ocular tissue, far beyond the maximum proton range. At X ¼ 10, the total thickness is 28.5 mm of

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ocular tissue, at the end of the SOBP. RBEm-values decrease with increasing X-values for all Plexiglas thicknesses. Only outside the collimator edge do RBEm values increase again with X, up to about 10% at X ¼ 20 mm, on agreement with data of De Nardo et al. (2004a). The maximum RBEm-value has been measured to be 1.7 in a position corresponding to 32.3 mm of ocular tissue. At this position we had previously measured RBEm ¼ 2.5 without a compensator (De Nardo et al., 2004a). This decreased beam quality factor is likely to be due to higher-energy protons, which scatter from thinner parts of the compensator, giving rise to lower y-values in the microdosimetric spectra. This scattered-proton component is also responsible for the unexpected results obtained for 18.1 mm of Plexiglas layer. At X ¼ 2.5 mm all the measured events are in fact due to scattered protons. Primary protons can contribute only for 10 < X < 15, where the total thickness is 28.5 mm of ocular tissue. In this region we have measured RBEm ¼ 1.3, which is consistent with measurements without a compensator (De Nardo et al., 2004a).

3.2. Relative absorbed dose data In Fig. 4 measured relative absorbed doses are plotted against the distance X from the proton beam axis and for water depths corresponding to the Plexiglas thicknesses for which the microdosimetric measurements were made. Measurements have been performed across the entire proton beam. X ¼ 0 is the central beam position. Curves appear to be nearly symmetric about the beam axis, confirming the good proton beam symmetry. Data have been normalized to the maximum relative dose, which occurs at about X ¼ 11 mm, just outside the maximum radius of the compensator. Such a maximum occurs where the total thickness is a minimum and because of the multiple Coulomb scattering experienced by protons in the spherical compensator. At X ¼ 0 mm a relative dose minimum occurs for 6.3 mm of equivalent Plexiglas thickness. Such minimum becomes deeper with increasing measurement depth.

Fig. 5. Iso-RBEm line map at the eye mid plan. X is the lateral distance from the proton beam axis and Y is the depth in ocular tissue. The circle represents the eye conjunctive.

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Fig. 6. Left side: Iso-dose line map at the eye mid plan. X is the lateral distance from the proton beam axis and Y is the depth in ocular tissue. Right side: biological-effective iso-dose map at the eye mid plan.

This occurs because at X ¼ 0 mm the total ocular thickness is about 30 mm after traversing 6.3 mm of Plexiglas: just at the end of the SOBP. At greater depths, the dose decreases sharply because the measuring point is on the distal edge of the SOBP. 3.3. 2D iso-value maps RBEm data of Fig. 3 have been used to generate the iso-quality map of Fig. 5. We have supposed that the dose symmetry seen in Fig. 4 also applies to the RBEm data. Therefore, experimental data, collected only for positive X-values, have been reflected for equivalent negative X-values. RBEm values in positions where no measurements had been performed were calculated by linear interpolation. The Spyglass Transform software was used to generate the 2D map of Fig. 5. In this figure, the circle represents the conjunctiva in the eye in mid-plane. The darker part of the circle represents the area to be treated. The figure shows that the radiation quality (RBEm) in this area is quite uniform between 1.2 and 1.4. An area of high RBEm values (1.5e1.7), is visible just beyond the conjunctiva, in a region of high risk because of the presence of the crystalline lens. The relative absorbed dose data of Fig. 4 have been re-normalised with respect the dose value in the conjunctiva at position X ¼ 0 mm. Data are then processed as above to give the 2D map in Fig. 6 (left side). The majority of treated conjunctiva absorbs a dose that is 70e100% of the maximum dose, which is located outside the eye. Inside the eye, the dose drops sharply. In order to assess the relevance of the radiation quality changes shown in Fig. 5, a 2D map of the RBE-weighted dose (product of the relative absorbed dose and RBEm) is shown on the right side of Fig. 6. This dose map varies in a similar way to the absorbed dose map in most of the treated conjunctiva, but its relative value is increased to between 90% and 120%. Inside the eye, the BBE-weighted dose also drops sharply. Therefore, the high RBEm region shown in Fig. 5 is not really problem due to the very low absorbed doses there. 4. Conclusion In this paper we have used a mini TEPC to perform microdosimetric measurements and to calculate the RBEm in a phantom simulating the conditions for treating a conjunctival melanoma at the Antoine Lacassagne Centre in Nice. We have also performed relative absorbed dose measurements by using a silicon diode. Radiation quality, namely RBEm, varies in a complex way in the phantom, giving values between 1.1 and 1.7. However, the

distribution of absorbed dose reduces the therapeutic significance of the observed radiation quality variations. In fact, the expected biological effect distribution in the conjunctiva varies in a similar way to absorbed dose changes. Also biological effects on healthy tissue seem to be well predicted by the absorbed dose distribution only. In spite of that, since we have observed significant RBEm variation changes within only 1 mm, more detailed microdosimetric measurements would be advisable to obtain a more precise radiation quality map. Acknowledgements This work has been supported by the 5th Scientific Commission of the Italian Institute of Nuclear Physics. References Bettega, D., Calzolari, P., Chauvel, P., Courdi, A., Herault, J., Iborra, N., Marchesini, R., Massariello, P., Poli, G.L., Tallone, L., 2000. Radiobiological studies of the 65 MeV therapeutic proton beam at Nice using human tumour cells. Int. J. Rad Biol. 76, 1297e1303. Cesari, V., Iborra, N., De Nardo, L., Querini, P., Conte, V., Colautti, P., Tornielli, G., Chauvel, P., 2001. Microdosimetric measurements of the Nice therapeutic proton beam. Physica Med. XVII (Suppl. 3), 76e82. Courdi, A., Brassart, N., Herault, J., Chauvel, P., 1994. The depth-dependent radiation response of human melanoma cells to 65 MeV protons. Br. J. Rad. 67, 800e804. De Nardo, L., Cesari, V., Iborra, N., Conte, V., Colautti, P., Héreault, J., Tornielli, G., Chauvel, P., 2004a. Microdosimetric assessment of Nice therapeutic proton beam biological quality. Physica Med. XX, 71e77. De Nardo, L., Cesari, V., Donà, G., Magrin, G., Colautti, P., Conte, V., Tornielli, G., 2004b. Mini-TEPCs for radiation therapy. Radiat. Prot. Dosimetry 108, 345e352. Guellette, J., Octave-Prignon, M., De Coster, M., Wambersie, B.-M., Gregoire, V., 2004. Intestinal crypt cell regeneration in mice: a biological system for quality assurance in non-conventional radiation therapy. Radiother.Oncol. 73, 148e154. Hérault, J., Iborra, N., Serrano, B., Chauvel, P., 2007. Spread-out Bragg peak and monitor units calculation with the Monte Carlo Code MCNPX. Med. Phys. 34, 680e688. Loncol, T., Cosgrove, V., Denis, J.M., Gueulette, J., Mazal, A., Menzel, H.G., Pihet, P., Sabattier, R., 1994. Radiobiological effectiveness of radiation beams with broad LET spectra: microdosimetric analysis using biological weighting functions. Radiat. Prot. Dosim. 52, 347e352. Paganetti, H., Olko, P., Kobus, H., Becker, R., Smitz, T., Waligorski, M.P.R., Filges, D., MüllerGärtner, H.W.,1997. Calculation of relative biological effectiveness for proton beams using biological weighting functions. Int. J. Radiat. Oncol. 37, 719e729. Sauerwein, W., Wittig, A., Westekemper, H., Herault, J., Mammar, H., Brualla, L., Steul, K.P., Bornfeld, N., 28 Sept.e3 Oct. 2009. Proton Radiotherapy in the Management of Extended Conjunctival Malignancies. PTCOG 48, Heidelberg. Van Luijk, P., Van’t Veld, A.A., Zelle, H.D., Schippers, J.M., 2001. Collimator scatter and 2D dosimetry in small proton beams. Phys. Med. Biol. 46, 653e670. Wuestemeyer, H., Sauerwein, W., Meller, D., Chauvel, P., Schueler, A., Steuhl, K.P., Bornfeld, N., Anastassiou, G., 2006. Proton radiotherapy as an alternative to exenteration in the management of extended conjunctival melanoma. Graefe’s Arch. Clin. Exp. Ophthalmol. 244, 438e446.