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Evaluation of risk of secondary cancer occurrence after proton radiotherapy of ocular tumours
Radiation Measurements 46 (2011) 1944e1947
Contents lists available at ScienceDirect
Radiation Measurements journal homepage: www.elsevier.com/locate/radmeas
Evaluation of risk of secondary cancer occurrence after proton radiotherapy of ocular tumours L. Stolarczyk a, *, T. Cywicka-Jakiel a, T. Horwacik a, P. Olko a, J. Swakon a, M.P.R. Waligorski b a b
The Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, ul. Radzikowskiego152, 31-342 Krakow, Poland Maria Skłodowska-Curie Memorial Institute, Centre of Oncology, Krakow Division, ul. Garncarska11, 31-115, Krakow, Poland
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 November 2010 Received in revised form 2 May 2011 Accepted 23 May 2011
Reduction of undesired exposure to scattered neutron and gamma radiation associated with proton therapy should reduce the risk of occurrence of secondary cancers, especially in paediatric patients. By replacing the patient with a RANDOÒ antropomorphic phantom, we determined the undesired radiation doses during the entire course of treatment at the ocular proton radiotherapy facility at IFJ PAN in Kraków and estimated the associated risk of secondary cancers. The highest exposure from the scattered radiation, per therapeutic proton absorbed dose, was found in the brain close to the target volume. Using TASTRAK PADC track detectors we estimated the fast neutron dose equivalent in the brain at 15.2 mSv/Gy, a value consistent with 17.06 mSv/Gy obtained from MCNPX 2.5.0 Monte Carlo calculations. The ambient dose equivalent, H*(10), determined with WENDI II and FHT 192 detectors at the position of the patient (50 cm below the isocentre), was 2.41 mSv/Gy from neutrons and 0.43 mSv/Gy from g-rays, respectively. Based on estimated values of organ dose equivalents, we evaluate the whole-body risk of fatal secondary cancers per course of treatment at below 0.001%. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Eye tumour proton radiotherapy Secondary radiation
1. Introduction Sharp distal dose fall-off, adjustable maximum range and modulation with depth, allowing dose to be delivered precisely and uniformly to the tumour volume while sparing adjacent healthy tissues, are the main advantages of proton radiotherapy. In the case of proton radiotherapy of ocular tumours, the clinical recommendations are large tumours (>5 mm in diameter) and tumours located close to critical structures, such as the optic disc, fovea or optic nerve (Fuss et al., 2001). However, even at the relatively low proton energies of 55e80 MeV typically used for eyeball treatment, undesired neutron and gamma radiation is produced in the beam line components and within the patient’s body by proton-induced nuclear reactions (Agosteo et al., 1998; Yan et al., 2002; Kacperek, 2009; Wroe et al., 2009). Although the doseeresponse relationship for radiation-induced cancer for different organs is still under investigation (Brenner et al., 2003), according to the International Commission on Radiological Protection (ICRP, 2007) low doses from scattered radiation may increase the probability of developing secondary cancers in organs distal to the target volume. Following ICRP recommendations, the
* Corresponding author. Tel.: þ48 126628156. E-mail address: [email protected] (L. Stolarczyk). 1350-4487/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.radmeas.2011.05.046
proton therapy beam line at the Institute of Nuclear Physics (IFJ PAN) in Kraków has been optimized in order to minimize the undesired dose to the patient. This involved modifications of the beam forming system and adding patient shielding in the treatment room (Cywicka-Jakiel et al., 2010). The aim of this work was to estimate out-of-field photon and neutron doses received by the patient at the IFJ PAN proton radiotherapy facility following the first attempt at its optimization (Cywicka-Jakiel et al., 2010). We also wished to compare results of measurements with passive detectors with results of measurements with active dosimeters and with results of Monte Carlo calculations. Finally, we wished to assess the risk of secondary cancer occurrence associated with the measured organ doses using organ-specific nominal risk coefficients of fatal cancer (ICRP, 2007).
2. Method 2.1. Geometry of measurements The eye proton radiotherapy facility at IFJ PAN consists of the AICe144 cyclotron (designed and constructed at the Institute of Nuclear Physics), the beam delivery system and a suitably equipped treatment room (Michalec et al., 2010; Swakon et al., 2010). A single beam-scattering foil is located in the shielded area, 10.9 m
L. Stolarczyk et al. / Radiation Measurements 46 (2011) 1944e1947
upstream of the isocentre. During measurements described in this work the initial energy of the proton beam was 60 MeV and the beam diameter was reduced to 25 mm after the scattering foil, at the distance of about 6.7 m from the isocentre. The patient’s shielding was installed, partly on the optical bench. The main sources of secondary radiation inside the treatment room are the beam forming elements: range shifter, range modulator, collimators and the patient aperture (Stolarczyk et al., 2010). During measurements the patient was replaced by a RANDOÒ anthropomorphic phantom (The Phantom Laboratory), incorporating MTS-7 and MTS-6 LiF:Mg,Ti thermoluminescence detectors (TLD Poland). The volumes of organs, selected as being at particular risk for generating fatal secondary cancers (ICRP, 2007): the thyroid, lung, liver, stomach, bladder and genital regions, were identified inside the phantom by an anatomical atlas. Within volumes representing these organs, pairs of MTS-7/MTS-6 detectors were placed in respective measurement points inside the phantom. Considering the irradiation geometry and the placement of main sources of secondary radiation and their distance from the isocentre, we also decided to evaluate the exposure of brain volume, despite this organ not being as important as other tissues with respect to secondary cancer induction. Inside sections of the head of the RANDOÒ phantom measurements were performed with MTS-7, MTS-6 and with PADC track detectors (Track Analysis Systems Ltd). The results were normalized to absorbed dose from protons in the target volume Dp, which was 400 Gy in our measurements. Proton beam dosimetry was performed using a PTW Freiburg 23343 Markus ionization chamber positioned at the centre of the Spread Out Bragg Peak SOBP. Fully modulated SOBP (28 mm in water) and the largest patient collimator aperture (25 mm in diameter) were used to represent the clinical treatment configuration. The position of the RANDOÒ phantom (i.e. the air gap between the final collimator and the surface of the phantom representing the eye region was about 9 cm) was identical to that at which patients are treated in IFJ PAN. 2.2. Simulations Numerical simulations using the MCNPX 2.5.0 code (Pelowitz, 2005) were performed to calculate equivalent dose from “internal” neutrons originating inside the proton-irradiated part of the mathematical ADAM phantom (Kramer et al., 1986). For external neutrons arising from the interactions of protons with elements of the optical bench (e.g.: range shifter, ionisation chambers, collimators, patient aperture of 25 mm inner diameter), the ambient dose equivalent H*(10) in air was simulated as a conservative evaluation of the patient’s effective dose from external irradiation (Cywicka-Jakiel et al., 2010). A parallel and aligned proton beam of energy 60 MeV was modelled. Normalisation to the therapeutic dose at maximum of the pristine Bragg peak in a water phantom was assumed. Additional simulations were performed for MTS-6 and MTS-7 detectors to calculate kerma factors per fluence for the energy spectrum of secondary neutrons simulated in the brain of the ADAM phantom. 2.3. Dosimetry with thermoluminescence detectors MTS-6 and MTS-7 thermoluminescence detectors (TLD Poland) were placed inside the RANDOÒ anthropomorphic phantom. The absorbed dose due to g-rays Dg and the g-equivalent neutron dose Dn were measured. Prior to their irradiation, the TLD detectors were annealed for 1 h at 400 C, followed by cool-down to ambient temperature and next annealed for 2 h at 100 C. Individual
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calibration factors (ICF) for each detector were applied. The detectors were calibrated with g-rays from a 137Cs source at the secondary standard laboratory at IFJ PAN. A RADOS RE 2000 TLD reader (RadPro International) was used for detector readout. 2.4. Dosimetry with track detectors TASTRAK Polyallyl Diglycol Carbonate (PADC) track detectors (Track Analysis Systems Ltd) were used to assess the brain tissue dose equivalent HnPADC inside the head of the RANDOÒ phantom due to the fast neutron component of the radiation field (Benton, 2004). The detectors were placed along the beam axis, at distances of 10 cm and 13 cm from the isocentre (inside the brain section of the phantom, beyond the range of primary protons). The signal (tracks) registered by the detectors can therefore be considered as originating from charged particles generated in the interactions of secondary neutrons with nuclei of the tissueequivalent phantom material representing the brain. These particles were assumed to be emitted mostly in the direction of the forward hemisphere. The detectors were etched in a water solution of NaOH (7 N, 70 C, 12 h) and the observed tracks analysed to determine their etch-rate ratio V. The particle fluence spectrum as a function of V was constructed and then converted to LETNH2O (above10 keV/mm) particle fluence spectrum using an appropriate calibration function. The dose was calculated by integration of this spectrum over a 2p solid angle, and then the dose equivalent determined using the Q(LET) relationship (ICRP, 1991). Correlation of the neutron dose equivalent HnPADC measured with track detectors to the g-equivalent neutron dose Dn (defined as the TL signal induced by neutrons in MTS-6 expressed in terms of the g-ray dose producing an identical TL signal) gave the kTLD-PADC TLD-to-PADC dose conversion factor. kTLD-PADC was determined as the mean value of four points inside the brain section of the phantom, where both MTS-6 and PADC detectors were irradiated in the same geometrical and treatment conditions. A similar method of recalibration against the track detectors was applied for 6 LiF:Mg,Cu,P TLD measurements of the secondary neutron dose in the RANDOÒ phantom during simulated radiotherapy of the prostate using an 18 MV photon beam from a linear accelerator (Takam et al., 2009). The results determined with TLDs and track detectors were compared to values of ambient dose equivalent from neutrons Hn* ð10Þ and from g-rays Hg* ð10Þ measured with a 3He WENDI II neutron detector (Thermo Scientific) and an FHT 192 ionization chamber (Thermo Scientific), both placed at the treatment seat 50 cm below the isocentre. 3. Results and discussion In Fig. 1 we present values of g-rays dose and of g-equivalent neutron dose after normalisation to the proton absorbed dose to target (Dg/Dp and Dn/Dp respectively). A systematic decrease of Dg/ Dp and Dn/Dp with distance from the isocentre (along the long axis of the RANDOÒ phantom) can be observed. Exceptions from this general trend are noticeable for Dn/Dp at distances of 12.5 cm and 15 cm from the isocentre, which correspond to the neck region of the RANDOÒ phantom. This could be explained by the lower fraction of fast neutrons being thermalised in this part of the phantom. Following earlier work (Stolarczyk et al., 2010), the signal from neutrons to MTS-7 TL detectors was neglected. An overall uncertainty exceeding 30% should be ascribed to results given in Fig. 1 for MTS-6 TLDs (Silari et al., 2009; Fang-Yuh Hsu et al., 2010). The uncertainty of dose measurements using MTS-7 typically exceeds 10% (Stolarczyk et al., 2010). In Fig. 2 the fluence spectrum of secondary neutrons inside the brain of the mathematical ADAM phantom is presented along with
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35
- radiation dose D /Dp
The readings of MTS-7 and MTS-6 [ Gy/Gy]
30
-equivalent neutron dose Dn/Dp
25 20 15 10 5
2,0 1,5 1,0 0,5 0,0 0
10
20
30
40
50
60
70
80
Distance from the isocentre perpendicular to the proton beam direction [cm] Fig. 1. Distribution of absorbed dose from g-rays Dg/Dp and g-equivalent neutron dose Dn/Dp inside the RANDOÒ phantom as a function of the distance from the isocentre (perpendicularly to the proton beam direction). The values of Dg and Dn ware measured at the axis of the phantom.
the calculated response of the MTS-6 and MTS-7 detectors to the same spectrum. As the spectrum is attributed predominantly to fast neutrons of energies ranging between 0.1 MeV and 40 MeV, TASTRAK PADC track detectors should have been used together with MTS-6 in order to gain better information about doses due to fast neutrons. The value of neutron dose equivalent HnPADC/Dp measured with track detectors at four positions inside the brain of the RANDOÒ phantom varied from (13.6 2.1) mSv/Gy at 13 cm from isocentre to (16.4 2.3) mSv/Gy at 10 cm from isocentre, resulting in the mean value of HnPADC/Dp ¼ (15.2 1.6) mSv/Gy. Monte Carlo calculations yielded HnMC/Dp ¼ 17.06 mSv/Gy for the patient’s brain. This value arose from the equivalent dose attributed to internal neutrons within the brain of the ADAM model and to external neutrons arising from the patient’s brass aperture of 25 mm inner diameter, from ionisation chambers and collimators,
and from a PMMA plate of 1 cm thickness representing the range shifter. The readings of the MTS-6 detectors irradiated at the same measuring points as the TASTRAK PADC detectors varied between 21.4 mGy/Gy and 40.0 mGy/Gy at 13 cm and 10 cm from isocentre, respectively. Basing on MTS-6 and track detector readings, the assigned value of the conversion factor kTLD-PADC was 1.99 mGy/mSv. The values of dose equivalent Hg/Dp from g-rays measured with MTS-7 detectors and of neutron dose equivalent Hn/Dp obtained using the kTLD-PADC conversion factor from MTS-6 readings were confronted with values of ambient dose equivalent from g-rays Hg* ð10Þ=Dp and from neutrons Hn* ð10Þ=Dp measured with the FHT 192 ionization chamber and the 3He WENDI II neutron detector, respectively. For neutrons, the value of Hn* ð10Þ=Dp ¼ ð2:41 0:48ÞmSv=Gy measured with WENDI II situated 50 cm below isocentre agrees to within 20% with Hn =Dp ¼ ð3:00 0:80ÞmSv=Gy measured by MTS-6 TL detectors inside the RANDOÒ phantom at the same distance from the target volume. For g-rays Hg =Dp ¼ ð0:43 0:09ÞmSv=Gy and Hg* ð10Þ=Dp ¼ ð0:44 0:04ÞmSv=Gy. The values of organ dose equivalent measured with MTS-7 and MTS-6 detectors are presented in Table 1. The associated risk of secondary cancer was estimated for 54.4 Gy treatment dose (total treatment dose for eye melanoma). According to ICRP (ICRP, 2007), the risk RT of occurrence of secondary cancers in a given tissue is evaluated as RT ¼ HT * rT, where HT is the dose equivalent (neutron plus gamma) for the organ T and rT is an organ-specific nominal risk coefficient of fatal cancer (ICRP, 2007). In our estimate for the brain we assumed rbrain ¼ rskin, as the risk coefficient for the brain is not given by ICRP. We note that ICRP ascribes the same tissue weighting factors for the skin and brain (wt ¼ 0.01) and that skin has been ascribed the lowest fatal cancer probability coefficient of all the main organs identified by ICRP. The whole-body risk of fatal secondary cancer R was then taken as the sum of the risks for each organ (R ¼ SRT). This and previous works (Wroe et al., 2009; Stolarczyk et al., 2010) have shown that the highest levels of dose equivalent from secondary radiation are experienced close to the field edge. The values of neutron dose equivalent HnPADC inside the head of RANDOÒ reported here are about 10 times lower than those measured with PADC detectors by Zytkovicz et al. (2007) at the University of California CNL in a similar treatment configuration (67 MeV proton beam, 27 mm depth of penetration and 20 mm patient aperture diameter). In our work the detectors were exposed inside the phantom, while Zytkovicz et al. (2007) placed them on its front surface. In our facility we have installed additional patient shielding on the optical bench and reduced the diameter of the treatment beam reaching the patient aperture (Cywicka-Jakiel
Table 1 Values of Hg/Dp for g-rays, the g-equivalent neutron dose Dn/Dp and neutron dose equivalent Hn/Dp obtained using the kTLD-PADC conversion factor (1.99 mGy/mSv). The risk of secondary cancer is estimated for the total course of eye melanoma treatment dose (54.4 Gy to target volume) according to ICRP 37 (ICRP, 2007), where risk coefficient for brain is represented by that for skin (see text). Organ
Fig. 2. The MTS-6 and MTS-7 (left axis) detectors response (kerma factors per fluence). The detectors response was calculated for the neutron energy spectrum inside the brain of the ADAM phantom. This energy spectrum is shown on the right axis of the graph. For the responses of the MTS-6 and MTS-7 detectors relative errors ranged from 0.7% to 3.5% and from 0.7% to 3.2%, respectively. Average relative error of fluence in brain of the Adam phantom amounts to 3.1%
Dn/Dp Hn/Dp Percent risk RT Risk coefficient Hg/Dp [mSv/Gy] [mGy/Gy] [mSv/Gy] (total treatment dose) r [%/Sv]
Brain 0.02 1.56 Thyroid 0.02 0.94 Lung 1.01 0.50 Liver 0.29 0.23 Stomach 0.65 0.21 Bladder 0.12 0.09 Genital 0.16 0.13 region Whole-body risk of fatal secondary
29.13 16.46 10.84 5.92 5.33 3.21 3.65 cancer R
14.56 8.23 5.42 2.96 2.67 1.61 1.82
0.00002% 0.00001% 0.00033% 0.00005% 0.00010% 0.00001% 0.00002% 0.00054%
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et al., 2010). This optimization of the dose from scattered radiation resulted in a decrease of the neutron exposure measured with WENDI II positioned 50 cm below the isocentre, from 6.2 mSv/Gy (Stolarczyk et al., 2010) to 2.4 mSv/Gy (this work). The whole-body risk of fatal secondary cancer after ocular proton radiotherapy of cancer at the IFJ PAN facility, equal to 0.00054%, is over 5 orders of magnitude lower than the risk associated with deep tumour proton radiotherapy (Wroe et al., 2009) or IMRT radiotherapy (Kry et al., 2007). In order to assess the maximum risk of secondary cancer Rmax in accordance with ICRP (2007) (Rmax ¼ E * 5%/Sv) the effective dose E for the entire course of the eye proton therapy was calculated (for details, see Stolarczyk et al., 2010). The calculation was performed for the pessimistic case of modulated proton beam and beam diameter reduced by a patient collimator. Application of shielding and reduction of the diameter of the treatment beam reaching the patient aperture lead to reduction of effective dose to a level of about 0.48 mSv, less by a factor of two with respect to our earlier configuration (Stolarczyk et al., 2010) where the maximum effective dose was 1 mSv. In our present conditions, we estimate the maximum risk of occurrence of secondary cancers at Rmax ¼ 0.002% per full ocular treatment procedure. 4. Conclusions The secondary neutron and g-rays doses were determined for proton radiotherapy of ocular tumours using various types of proportional counters, and in the anthropomorphic RANDOÒ phantom using TLDs and track detectors. The results of measurements correspond well with MC calculations for the ADAM mathematical phantom. It has been shown that secondary radiation doses may be significantly reduced if additional collimator and patient shielding are used. The whole-body risk of secondary cancer (ICRP, 2007) for fully modulated SOBP and 25 mm diameter patient aperture was estimated as being below 0.001%. This value may increase as secondary radiation varies strongly with the configuration of beam formation elements (Stolarczyk et al., 2010). The risk associated with proton ocular radiotherapy is significantly lower in comparison with radiotherapy of deeply situated tumours and is small enough to recommend ocular proton therapy even in paediatric cases. Acknowledgements This work was supported by a grant from Iceland, Lichtenstein and Norway through the EEA Financial Mechanism and the Norwegian Financial Mechanism. It was also supported by the Polish Ministry of Science and Higher Education, grant No. N N505 261 535. Monte Carlo calculations were performed at the ACK Cyfronet AGH, Kraków, Poland. The mathematical ADAM phantom structure was obtained courtesy of Dr. F.W. Schultz from the Delft University of Technology, Delft, Netherlands.
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All readouts of TLD detectors were performed at the Laboratory of Individual and Environmental Dosimetry IFJ PAN. References Agosteo, S., Birattari, C., Caravaggio, M., Silari, M., Tosi, G., 1998. Secondary neutron and photon dose in proton therapy. Radiother. Oncol. 48, 293e305. Benton, E., 2004, PhD Thesis. Univesity College, Dublin. Brenner, D., Doll, R., Goodhead, D., Hall, E., 2003. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc. Natl. Acad. Sci. U S A 100, 13761e13766. Cywicka-Jakiel, T., Stolarczyk, L., Swakon, J., Olko, P., Waligorski, M., 2010. Individual patient shielding for a proton eye therapy facility. Radiat. Meas 45, 1127e1129. Fuss, M., Loredo, L., Blacharski, P., Grove, R., Slater, J., 2001. Proton radiation therapy for medium and large choroidal melanoma: preservation of the eye and its functionality. Int. J. Radiat. Oncol. Biol. Phys. 49, 1053e1059. Hsu, F., Chang, Y., Liu, M., Huang, S, Yu, C.h., 2010. Dose estimation of the neutrons induced by the high energy medical linear accelerator using dual-TLD chips. Radiat. Meas 45, 739e741. ICRP, 1991. Recommendations of the International Commission on Radiological Protection. In: ICRP Publication, vol. 60 Annals of ICRP 21. ICRP, 2007. Relative biological effectiveness (RBE), quality factor (Q), and radiation weighting factor (w(R)). A report of the International Commission on Radiological Protection. Ann. ICRP 37, 1e332. Kacperek, A., 2009. Protontherapy of eye tumours in the UK: a review of treatment at Clatterbridge. Appl. Radiat. Isot. 67, 378e386. Kramer, R., Zankl, M., Williams, G., Drexler, G., 1986. The Calculation of Dose from External Photon Exposures Using Reference Human Phantoms and Monte Carlo Methods: Part I: The Male (Adam) and Female (Eva) Adult Mathematical Phantoms. GSF Bericht S-885. GSF Forschungzentrum für Umwelt und Gesundheit, München. Kry, S., Followill, D., White, R., Stovall, M., Kuban, D., Salehpour, M., 2007. Uncertainty of calculated risk estimates for secondary malignancies after radiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 68, 1265e1271. Michalec, B., Swakon, J., Sowa, U., Ptaszkiewicz, M., Cywicka-Jakiel, T., Olko, P., 2010. Proton radiotherapy facility for ocular tumors at the IFJ PAN in Kraków Poland. Appl. Radiat. Isot. 68, 738e742. Pelowitz, D., 2005. MCNPX User’s Manual. Version 2.5.0. LA-CP-05-0369. Los Alamos National Laboratory. Silari, M., Agosteo, S., Beck, P., et al., 2009. Intercomparison of radiation protection devices in a high-energy stray neutron field. Part III: Instrument response. Radiat. Meas 44, 673e691. Stolarczyk, L., Olko, P., Cywicka-Jakiel, T., Ptaszkiewicz, M., Swakon, J., Dulny, B., Horwacik, T., Obryk, B., Waligorski, M., 2010. Assessment of undesirable dose to eye-melanoma patients after proton radiotherapy. Radiat. Meas 45, 1441e1444. Swakon, J., Olko, P., Adamczyk, D., Cywicka-Jakiel, T., Dabrowska, J., Dulny, B., Grzanka, L., Horwacik, T., Kajdrowicz, T., Michalec, B., Nowak, T., Ptaszkiewicz, M., Sowa, U., Stolarczyk, L., Waligorski, M., 2010. Facility for proton radiotherapy of eye cancer at IFJ PAN in Krakow, Radiat. Meas 45, 1472e1475. Takam, R., Bezak, E., Yeoh E., Liu, G., 2009. In-phantom peripheral organ doses from prostate irradiation using 18 MV external beam radiotherapy measured with 6LiF: Mg, Cu, P & 7LiF: Mg, Cu, P Glass-Rod TLDs. In: World Congress on Medical Physics and Biomedical Engineering, September 7e12, 2009, Munich, Germany. IFMBE Proceedings, vol. 25, pp. 557e560. Wroe, A., Clasie, B., Kooy, H., Flanz, J., Schulte, R., Rosenfeld, A., 2009. Out-of-field dose equivalents delivered by passively scattered therapeutic proton beams for clinically relevant field configurations. Int. J. Radiat. Oncol. Biol. Phys. 73, 306e313. Yan, X., Titt, U., Koehler, A.M., Newhauser, W.D., 2002. Measurement of neutron dose equivalent to proton therapy patients outside of the proton radiation field. Nucl. Instrum. Methods Phys. Res. A 476, 429e434. Zytkovicz, A., Daftari, I., Phillips, T., Chuang, C., Verhey, L., Petti, P., 2007. Peripheral dose in ocular treatments with CyberKnife and Gamma Knife radiosurgery compared to proton radiotherapy. Phys. Med. Biol. 52, 5957e5971.
Contents lists available at ScienceDirect
Radiation Measurements journal homepage: www.elsevier.com/locate/radmeas
Evaluation of risk of secondary cancer occurrence after proton radiotherapy of ocular tumours L. Stolarczyk a, *, T. Cywicka-Jakiel a, T. Horwacik a, P. Olko a, J. Swakon a, M.P.R. Waligorski b a b
The Henryk Niewodniczanski Institute of Nuclear Physics, Polish Academy of Sciences, ul. Radzikowskiego152, 31-342 Krakow, Poland Maria Skłodowska-Curie Memorial Institute, Centre of Oncology, Krakow Division, ul. Garncarska11, 31-115, Krakow, Poland
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 November 2010 Received in revised form 2 May 2011 Accepted 23 May 2011
Reduction of undesired exposure to scattered neutron and gamma radiation associated with proton therapy should reduce the risk of occurrence of secondary cancers, especially in paediatric patients. By replacing the patient with a RANDOÒ antropomorphic phantom, we determined the undesired radiation doses during the entire course of treatment at the ocular proton radiotherapy facility at IFJ PAN in Kraków and estimated the associated risk of secondary cancers. The highest exposure from the scattered radiation, per therapeutic proton absorbed dose, was found in the brain close to the target volume. Using TASTRAK PADC track detectors we estimated the fast neutron dose equivalent in the brain at 15.2 mSv/Gy, a value consistent with 17.06 mSv/Gy obtained from MCNPX 2.5.0 Monte Carlo calculations. The ambient dose equivalent, H*(10), determined with WENDI II and FHT 192 detectors at the position of the patient (50 cm below the isocentre), was 2.41 mSv/Gy from neutrons and 0.43 mSv/Gy from g-rays, respectively. Based on estimated values of organ dose equivalents, we evaluate the whole-body risk of fatal secondary cancers per course of treatment at below 0.001%. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Eye tumour proton radiotherapy Secondary radiation
1. Introduction Sharp distal dose fall-off, adjustable maximum range and modulation with depth, allowing dose to be delivered precisely and uniformly to the tumour volume while sparing adjacent healthy tissues, are the main advantages of proton radiotherapy. In the case of proton radiotherapy of ocular tumours, the clinical recommendations are large tumours (>5 mm in diameter) and tumours located close to critical structures, such as the optic disc, fovea or optic nerve (Fuss et al., 2001). However, even at the relatively low proton energies of 55e80 MeV typically used for eyeball treatment, undesired neutron and gamma radiation is produced in the beam line components and within the patient’s body by proton-induced nuclear reactions (Agosteo et al., 1998; Yan et al., 2002; Kacperek, 2009; Wroe et al., 2009). Although the doseeresponse relationship for radiation-induced cancer for different organs is still under investigation (Brenner et al., 2003), according to the International Commission on Radiological Protection (ICRP, 2007) low doses from scattered radiation may increase the probability of developing secondary cancers in organs distal to the target volume. Following ICRP recommendations, the
* Corresponding author. Tel.: þ48 126628156. E-mail address: [email protected] (L. Stolarczyk). 1350-4487/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.radmeas.2011.05.046
proton therapy beam line at the Institute of Nuclear Physics (IFJ PAN) in Kraków has been optimized in order to minimize the undesired dose to the patient. This involved modifications of the beam forming system and adding patient shielding in the treatment room (Cywicka-Jakiel et al., 2010). The aim of this work was to estimate out-of-field photon and neutron doses received by the patient at the IFJ PAN proton radiotherapy facility following the first attempt at its optimization (Cywicka-Jakiel et al., 2010). We also wished to compare results of measurements with passive detectors with results of measurements with active dosimeters and with results of Monte Carlo calculations. Finally, we wished to assess the risk of secondary cancer occurrence associated with the measured organ doses using organ-specific nominal risk coefficients of fatal cancer (ICRP, 2007).
2. Method 2.1. Geometry of measurements The eye proton radiotherapy facility at IFJ PAN consists of the AICe144 cyclotron (designed and constructed at the Institute of Nuclear Physics), the beam delivery system and a suitably equipped treatment room (Michalec et al., 2010; Swakon et al., 2010). A single beam-scattering foil is located in the shielded area, 10.9 m
L. Stolarczyk et al. / Radiation Measurements 46 (2011) 1944e1947
upstream of the isocentre. During measurements described in this work the initial energy of the proton beam was 60 MeV and the beam diameter was reduced to 25 mm after the scattering foil, at the distance of about 6.7 m from the isocentre. The patient’s shielding was installed, partly on the optical bench. The main sources of secondary radiation inside the treatment room are the beam forming elements: range shifter, range modulator, collimators and the patient aperture (Stolarczyk et al., 2010). During measurements the patient was replaced by a RANDOÒ anthropomorphic phantom (The Phantom Laboratory), incorporating MTS-7 and MTS-6 LiF:Mg,Ti thermoluminescence detectors (TLD Poland). The volumes of organs, selected as being at particular risk for generating fatal secondary cancers (ICRP, 2007): the thyroid, lung, liver, stomach, bladder and genital regions, were identified inside the phantom by an anatomical atlas. Within volumes representing these organs, pairs of MTS-7/MTS-6 detectors were placed in respective measurement points inside the phantom. Considering the irradiation geometry and the placement of main sources of secondary radiation and their distance from the isocentre, we also decided to evaluate the exposure of brain volume, despite this organ not being as important as other tissues with respect to secondary cancer induction. Inside sections of the head of the RANDOÒ phantom measurements were performed with MTS-7, MTS-6 and with PADC track detectors (Track Analysis Systems Ltd). The results were normalized to absorbed dose from protons in the target volume Dp, which was 400 Gy in our measurements. Proton beam dosimetry was performed using a PTW Freiburg 23343 Markus ionization chamber positioned at the centre of the Spread Out Bragg Peak SOBP. Fully modulated SOBP (28 mm in water) and the largest patient collimator aperture (25 mm in diameter) were used to represent the clinical treatment configuration. The position of the RANDOÒ phantom (i.e. the air gap between the final collimator and the surface of the phantom representing the eye region was about 9 cm) was identical to that at which patients are treated in IFJ PAN. 2.2. Simulations Numerical simulations using the MCNPX 2.5.0 code (Pelowitz, 2005) were performed to calculate equivalent dose from “internal” neutrons originating inside the proton-irradiated part of the mathematical ADAM phantom (Kramer et al., 1986). For external neutrons arising from the interactions of protons with elements of the optical bench (e.g.: range shifter, ionisation chambers, collimators, patient aperture of 25 mm inner diameter), the ambient dose equivalent H*(10) in air was simulated as a conservative evaluation of the patient’s effective dose from external irradiation (Cywicka-Jakiel et al., 2010). A parallel and aligned proton beam of energy 60 MeV was modelled. Normalisation to the therapeutic dose at maximum of the pristine Bragg peak in a water phantom was assumed. Additional simulations were performed for MTS-6 and MTS-7 detectors to calculate kerma factors per fluence for the energy spectrum of secondary neutrons simulated in the brain of the ADAM phantom. 2.3. Dosimetry with thermoluminescence detectors MTS-6 and MTS-7 thermoluminescence detectors (TLD Poland) were placed inside the RANDOÒ anthropomorphic phantom. The absorbed dose due to g-rays Dg and the g-equivalent neutron dose Dn were measured. Prior to their irradiation, the TLD detectors were annealed for 1 h at 400 C, followed by cool-down to ambient temperature and next annealed for 2 h at 100 C. Individual
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calibration factors (ICF) for each detector were applied. The detectors were calibrated with g-rays from a 137Cs source at the secondary standard laboratory at IFJ PAN. A RADOS RE 2000 TLD reader (RadPro International) was used for detector readout. 2.4. Dosimetry with track detectors TASTRAK Polyallyl Diglycol Carbonate (PADC) track detectors (Track Analysis Systems Ltd) were used to assess the brain tissue dose equivalent HnPADC inside the head of the RANDOÒ phantom due to the fast neutron component of the radiation field (Benton, 2004). The detectors were placed along the beam axis, at distances of 10 cm and 13 cm from the isocentre (inside the brain section of the phantom, beyond the range of primary protons). The signal (tracks) registered by the detectors can therefore be considered as originating from charged particles generated in the interactions of secondary neutrons with nuclei of the tissueequivalent phantom material representing the brain. These particles were assumed to be emitted mostly in the direction of the forward hemisphere. The detectors were etched in a water solution of NaOH (7 N, 70 C, 12 h) and the observed tracks analysed to determine their etch-rate ratio V. The particle fluence spectrum as a function of V was constructed and then converted to LETNH2O (above10 keV/mm) particle fluence spectrum using an appropriate calibration function. The dose was calculated by integration of this spectrum over a 2p solid angle, and then the dose equivalent determined using the Q(LET) relationship (ICRP, 1991). Correlation of the neutron dose equivalent HnPADC measured with track detectors to the g-equivalent neutron dose Dn (defined as the TL signal induced by neutrons in MTS-6 expressed in terms of the g-ray dose producing an identical TL signal) gave the kTLD-PADC TLD-to-PADC dose conversion factor. kTLD-PADC was determined as the mean value of four points inside the brain section of the phantom, where both MTS-6 and PADC detectors were irradiated in the same geometrical and treatment conditions. A similar method of recalibration against the track detectors was applied for 6 LiF:Mg,Cu,P TLD measurements of the secondary neutron dose in the RANDOÒ phantom during simulated radiotherapy of the prostate using an 18 MV photon beam from a linear accelerator (Takam et al., 2009). The results determined with TLDs and track detectors were compared to values of ambient dose equivalent from neutrons Hn* ð10Þ and from g-rays Hg* ð10Þ measured with a 3He WENDI II neutron detector (Thermo Scientific) and an FHT 192 ionization chamber (Thermo Scientific), both placed at the treatment seat 50 cm below the isocentre. 3. Results and discussion In Fig. 1 we present values of g-rays dose and of g-equivalent neutron dose after normalisation to the proton absorbed dose to target (Dg/Dp and Dn/Dp respectively). A systematic decrease of Dg/ Dp and Dn/Dp with distance from the isocentre (along the long axis of the RANDOÒ phantom) can be observed. Exceptions from this general trend are noticeable for Dn/Dp at distances of 12.5 cm and 15 cm from the isocentre, which correspond to the neck region of the RANDOÒ phantom. This could be explained by the lower fraction of fast neutrons being thermalised in this part of the phantom. Following earlier work (Stolarczyk et al., 2010), the signal from neutrons to MTS-7 TL detectors was neglected. An overall uncertainty exceeding 30% should be ascribed to results given in Fig. 1 for MTS-6 TLDs (Silari et al., 2009; Fang-Yuh Hsu et al., 2010). The uncertainty of dose measurements using MTS-7 typically exceeds 10% (Stolarczyk et al., 2010). In Fig. 2 the fluence spectrum of secondary neutrons inside the brain of the mathematical ADAM phantom is presented along with
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35
- radiation dose D /Dp
The readings of MTS-7 and MTS-6 [ Gy/Gy]
30
-equivalent neutron dose Dn/Dp
25 20 15 10 5
2,0 1,5 1,0 0,5 0,0 0
10
20
30
40
50
60
70
80
Distance from the isocentre perpendicular to the proton beam direction [cm] Fig. 1. Distribution of absorbed dose from g-rays Dg/Dp and g-equivalent neutron dose Dn/Dp inside the RANDOÒ phantom as a function of the distance from the isocentre (perpendicularly to the proton beam direction). The values of Dg and Dn ware measured at the axis of the phantom.
the calculated response of the MTS-6 and MTS-7 detectors to the same spectrum. As the spectrum is attributed predominantly to fast neutrons of energies ranging between 0.1 MeV and 40 MeV, TASTRAK PADC track detectors should have been used together with MTS-6 in order to gain better information about doses due to fast neutrons. The value of neutron dose equivalent HnPADC/Dp measured with track detectors at four positions inside the brain of the RANDOÒ phantom varied from (13.6 2.1) mSv/Gy at 13 cm from isocentre to (16.4 2.3) mSv/Gy at 10 cm from isocentre, resulting in the mean value of HnPADC/Dp ¼ (15.2 1.6) mSv/Gy. Monte Carlo calculations yielded HnMC/Dp ¼ 17.06 mSv/Gy for the patient’s brain. This value arose from the equivalent dose attributed to internal neutrons within the brain of the ADAM model and to external neutrons arising from the patient’s brass aperture of 25 mm inner diameter, from ionisation chambers and collimators,
and from a PMMA plate of 1 cm thickness representing the range shifter. The readings of the MTS-6 detectors irradiated at the same measuring points as the TASTRAK PADC detectors varied between 21.4 mGy/Gy and 40.0 mGy/Gy at 13 cm and 10 cm from isocentre, respectively. Basing on MTS-6 and track detector readings, the assigned value of the conversion factor kTLD-PADC was 1.99 mGy/mSv. The values of dose equivalent Hg/Dp from g-rays measured with MTS-7 detectors and of neutron dose equivalent Hn/Dp obtained using the kTLD-PADC conversion factor from MTS-6 readings were confronted with values of ambient dose equivalent from g-rays Hg* ð10Þ=Dp and from neutrons Hn* ð10Þ=Dp measured with the FHT 192 ionization chamber and the 3He WENDI II neutron detector, respectively. For neutrons, the value of Hn* ð10Þ=Dp ¼ ð2:41 0:48ÞmSv=Gy measured with WENDI II situated 50 cm below isocentre agrees to within 20% with Hn =Dp ¼ ð3:00 0:80ÞmSv=Gy measured by MTS-6 TL detectors inside the RANDOÒ phantom at the same distance from the target volume. For g-rays Hg =Dp ¼ ð0:43 0:09ÞmSv=Gy and Hg* ð10Þ=Dp ¼ ð0:44 0:04ÞmSv=Gy. The values of organ dose equivalent measured with MTS-7 and MTS-6 detectors are presented in Table 1. The associated risk of secondary cancer was estimated for 54.4 Gy treatment dose (total treatment dose for eye melanoma). According to ICRP (ICRP, 2007), the risk RT of occurrence of secondary cancers in a given tissue is evaluated as RT ¼ HT * rT, where HT is the dose equivalent (neutron plus gamma) for the organ T and rT is an organ-specific nominal risk coefficient of fatal cancer (ICRP, 2007). In our estimate for the brain we assumed rbrain ¼ rskin, as the risk coefficient for the brain is not given by ICRP. We note that ICRP ascribes the same tissue weighting factors for the skin and brain (wt ¼ 0.01) and that skin has been ascribed the lowest fatal cancer probability coefficient of all the main organs identified by ICRP. The whole-body risk of fatal secondary cancer R was then taken as the sum of the risks for each organ (R ¼ SRT). This and previous works (Wroe et al., 2009; Stolarczyk et al., 2010) have shown that the highest levels of dose equivalent from secondary radiation are experienced close to the field edge. The values of neutron dose equivalent HnPADC inside the head of RANDOÒ reported here are about 10 times lower than those measured with PADC detectors by Zytkovicz et al. (2007) at the University of California CNL in a similar treatment configuration (67 MeV proton beam, 27 mm depth of penetration and 20 mm patient aperture diameter). In our work the detectors were exposed inside the phantom, while Zytkovicz et al. (2007) placed them on its front surface. In our facility we have installed additional patient shielding on the optical bench and reduced the diameter of the treatment beam reaching the patient aperture (Cywicka-Jakiel
Table 1 Values of Hg/Dp for g-rays, the g-equivalent neutron dose Dn/Dp and neutron dose equivalent Hn/Dp obtained using the kTLD-PADC conversion factor (1.99 mGy/mSv). The risk of secondary cancer is estimated for the total course of eye melanoma treatment dose (54.4 Gy to target volume) according to ICRP 37 (ICRP, 2007), where risk coefficient for brain is represented by that for skin (see text). Organ
Fig. 2. The MTS-6 and MTS-7 (left axis) detectors response (kerma factors per fluence). The detectors response was calculated for the neutron energy spectrum inside the brain of the ADAM phantom. This energy spectrum is shown on the right axis of the graph. For the responses of the MTS-6 and MTS-7 detectors relative errors ranged from 0.7% to 3.5% and from 0.7% to 3.2%, respectively. Average relative error of fluence in brain of the Adam phantom amounts to 3.1%
Dn/Dp Hn/Dp Percent risk RT Risk coefficient Hg/Dp [mSv/Gy] [mGy/Gy] [mSv/Gy] (total treatment dose) r [%/Sv]
Brain 0.02 1.56 Thyroid 0.02 0.94 Lung 1.01 0.50 Liver 0.29 0.23 Stomach 0.65 0.21 Bladder 0.12 0.09 Genital 0.16 0.13 region Whole-body risk of fatal secondary
29.13 16.46 10.84 5.92 5.33 3.21 3.65 cancer R
14.56 8.23 5.42 2.96 2.67 1.61 1.82
0.00002% 0.00001% 0.00033% 0.00005% 0.00010% 0.00001% 0.00002% 0.00054%
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et al., 2010). This optimization of the dose from scattered radiation resulted in a decrease of the neutron exposure measured with WENDI II positioned 50 cm below the isocentre, from 6.2 mSv/Gy (Stolarczyk et al., 2010) to 2.4 mSv/Gy (this work). The whole-body risk of fatal secondary cancer after ocular proton radiotherapy of cancer at the IFJ PAN facility, equal to 0.00054%, is over 5 orders of magnitude lower than the risk associated with deep tumour proton radiotherapy (Wroe et al., 2009) or IMRT radiotherapy (Kry et al., 2007). In order to assess the maximum risk of secondary cancer Rmax in accordance with ICRP (2007) (Rmax ¼ E * 5%/Sv) the effective dose E for the entire course of the eye proton therapy was calculated (for details, see Stolarczyk et al., 2010). The calculation was performed for the pessimistic case of modulated proton beam and beam diameter reduced by a patient collimator. Application of shielding and reduction of the diameter of the treatment beam reaching the patient aperture lead to reduction of effective dose to a level of about 0.48 mSv, less by a factor of two with respect to our earlier configuration (Stolarczyk et al., 2010) where the maximum effective dose was 1 mSv. In our present conditions, we estimate the maximum risk of occurrence of secondary cancers at Rmax ¼ 0.002% per full ocular treatment procedure. 4. Conclusions The secondary neutron and g-rays doses were determined for proton radiotherapy of ocular tumours using various types of proportional counters, and in the anthropomorphic RANDOÒ phantom using TLDs and track detectors. The results of measurements correspond well with MC calculations for the ADAM mathematical phantom. It has been shown that secondary radiation doses may be significantly reduced if additional collimator and patient shielding are used. The whole-body risk of secondary cancer (ICRP, 2007) for fully modulated SOBP and 25 mm diameter patient aperture was estimated as being below 0.001%. This value may increase as secondary radiation varies strongly with the configuration of beam formation elements (Stolarczyk et al., 2010). The risk associated with proton ocular radiotherapy is significantly lower in comparison with radiotherapy of deeply situated tumours and is small enough to recommend ocular proton therapy even in paediatric cases. Acknowledgements This work was supported by a grant from Iceland, Lichtenstein and Norway through the EEA Financial Mechanism and the Norwegian Financial Mechanism. It was also supported by the Polish Ministry of Science and Higher Education, grant No. N N505 261 535. Monte Carlo calculations were performed at the ACK Cyfronet AGH, Kraków, Poland. The mathematical ADAM phantom structure was obtained courtesy of Dr. F.W. Schultz from the Delft University of Technology, Delft, Netherlands.
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