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FEASIBILITY OF USING 6 MV PHOTON BEAMS IN CONTRAST-ENHANCED RADIOTHERAPY
Vorobyeva ES1, Lipengolts AA123 Cherepanov AA2, Grigorieva EYu2, Nechkina IN2, Kalygina NS2, Sokovikov AV4, Kulakov VN1, Sheino IN1
1 Laboratory of radiotherapy methods and technologies, Department of Medical Radiation Technologies, A. I. Burnazyan Federal Medical Biophysical Center, Moscow, Russia
2 Laboratory of radionuclide and radiation technologies in experimental oncology, Research Institute of Clinical and Experimental Radiology, N. N. Blokhin National Medical Research Center of Oncology, Moscow, Russia
3 National Research Nuclear University MEPh, Moscow, Russia
4 MedService Ltd., Moscow, Russia
Contrast-enhanced radiotherapy (CERT) is a type of radiation therapy used to enhance the radiation dose absorbed by the tumor while sparing surrounding healthy tissues. The present study aims to assess feasibility of using 6 MV photons to increase radiation absorption in CERT. The dose absorbed by iodinated water was directly measured by ferrosulphate dosimetry. Concentrations of iodine (a dose-enhancing agent) ranged from 2.5 to 50 mg/ml. Solutions were exposed to 5 Gy radiation generated by the clinical linear accelerator SL75-5MT (Russia). The radiation dose applied did not account for increased absorbance due to the presence of iodine atoms. No reliable increase in the absorbed dose was observed for iodine concentrations ranging from 2.5 to 20 mg/ml. For 50 mg/ml concentrations the absorbed dose increased by 13% ± 5 % (p < 0.05). Normally, dose-enhancing concentrations observed in CERT studies range from 2.5 to 15 mg/ml, therefore, as demonstrated by our findings, employing 6 MV photon energy spectra in order to reach a therapeutically significant effect is unreasonable.
Keywords: contrast-enhanced radiotherapy, ferrosulphate dosimetry, megavolts radiation, dose enhancement factor
Correspondence should be addressed: Alexey Lipengolts Kashirskoe shosse, d. 24, Moscow, Russia, 115478; lipengolts@mail.ru
Received: 25.08.2017 Accepted: 30.08.2017
ВОЗМОЖНОСТЬ ПРОВЕДЕНИЯ ФОТОН-ЗАХВАТНОЙ ТЕРАПИИ С ИСПОЛЬЗОВАНИЕМ 6 МВ ФОТОННОГО ИЗЛУЧЕНИЯ
Е. С. Воробьева1, А. А. Липенгольц1*2*3 А. А. Черепанов2, Е. Ю. Григорьева2, И. Н. Нечкина2, Н. С. Калыгина2, А. В. Соковиков4, В. Н. Кулаков1, И. Н. Шейно1
1 Лаборатория методов и технологий лучевой терапии, отдел радиационных технологий медицинского назначения, Федеральный медицинский биофизический центр имени А. И. Бурназяна, Москва
2 Лаборатория радионуклидных и лучевых технологий в экспериментальной онкологии, НИИ клинической и экспериментальной радиологии, Национальный медицинский исследовательский центр онкологии имени Н. Н. Блохина, Москва
3 Национальный исследовательский ядерный университет «МИФИ», Москва
4 ООО «МедСервис», Москва
Фотон-захватная терапия (ФЗТ) — метод лучевой терапии, который обеспечивает повышение поглощенной дозы в опухоли без дополнительной лучевой нагрузки на окружающие нормальные ткани. В работе представлены результаты экспериментального исследования возможности увеличения поглощенной дозы при ФЗТ за счет использования 6 МВ фотонного излучения. При помощи водных растворов ферросульфатных дозиметров было проведено прямое измерение величины поглощенной дозы в воде, содержащей йод (дозоповышающий агент) в концентрации от 2,5 до 50 мг/мл. Облучение растворов проводили на линейном медицинском терапевтическом ускорителе СЛ75-5-МТ (Россия) в дозе 5 Гр без учета возможного увеличения поглощенной дозы за счет присутствия атомов йода. Для концентраций йода 2,5-20 мг/мл достоверного увеличения поглощенной дозы зарегистрировано не было. Для концентрации йода 50 мг/мл увеличение поглощенной дозы составило 13 ± 5 % (p < 0,05). Поскольку типичные концентрации дозоповышающих агентов при введении в организм пациентов, как правило, находятся в диапазоне 2,5-15 мг/мл, использование 6 МВ фотонного излучения для достижения терапевтически значимого противоопухолевого эффекта не представляется целесообразным.
Ключевые слова: фотон-захватная терапия, ферросульфатная дозиметрия, мегавольтное излучение, фактор повышения дозы
Для корреспонденции: Липенгольц Алексей Андреевич Каширское шоссе, д. 24, г Москва, 115478; lipengolts@mail.ru
Статья получена: 25.08.2017 Статья принята к печати: 30.08.2017
Contrast-enhanced radiotherapy (CERT) is a new binary treatment modality that advantageously ensures enhancement of the radiation dose absorbed by a tumor while sparing surrounding healthy tissues. This effect is achieved by using
special drugs that contain dose-enhancing agents (DEAs), i. e. chemical elements with Z > 52 (I, Gd, Au, B, etc.) and thus have a better absorption capacity than constituents of soft biological tissues.
Fig. 1 shows mass energy absorption coefficients pen for a number of chemical elements plotted against photon energy. As demonstrated by the graph, elements with different Z have considerably different absorption capacity only when exposed to ionizing photons with an energy spectrum between 30 and 300-500 keV [1] characteristic of orthovoltage X-rays. Most studies on CERT employ sources of ionizing radiation that emit in this particular spectrum [2-7].
Clearly, the difference is negligible in the absorption capacity of DEAs and soft tissues exposed to >500 keV photon energies. However, a number of authors report an increased therapeutic effect following contrast-enhanced radiation treatment with megavoltage X-rays (>6 MV) [8-13]. In their experiments, dose enhancement was attempted by the use of gold nanoparticles, platinum compounds and gadolinium-containing nanostructures. Possible mechanisms of enhanced absorption were also suggested [14-16]. It was hypothesized that as primary radiation scatters in a DEA-loaded tumor, the latter accumulates the sufficient amount of low-energy photons capable of interacting with the DEA. As orthovoltage X-rays interact with the DEA, the environment surrounding the DEA atom gets ionized just a few nanometers away from it. Ionization
generates a large number of radical ions capable of affecting biological structures from a longer distance (up to several mm away from the atom).
Other researchers attempted to estimate an increase in the absorbed radiation dose using polymer gel dosimeters and EPR dosimeters (EPR stands for electron paramagnetic resonance) loaded with DEAs and irradiated with 6 MV photons. In the work [17] 18 mg/ml gold concentrations were introduced into polymer gel dosimeters, but no reliable dose enhancement was registered. In the experiments with the alanine EPR-dosimeter containing 30 mg/ml gold [18] dose enhancement was 10 %.
This brings up the question: is the therapeutic effect of 6 MV CERT due to the mere physical increase in the absorbed dose or to the sensitizing effect of radiation on tumor cells? We decided to find out how the absorbed radiation dose increases in iodinated water irradiated with 6 MV photons. Unlike other researchers who used polymer gel and alanine EPR dosimeters in which radical ions may not be so mobile as in water, we used aqueous solutions for our measurements because in water radical ions can travel unobstructed by large molecules and, therefore, can be registered more effectively.
10000
1000
100
10
0,1
0,01
Water Soft tissue Zn Pd Ag
1
TT7!-
10
100 1000 Photon energy, keV
Fig. 1. Dependence of mass energy absorption coefficient on incident photon energy
0,24
10000
Zl
<
0,22
0,20
o 0,18 -
.a
<
0,16 -0,14
2,5 5,0 7,5 10,0 12,5 15,0 17,5 20,0 Absorbed dose, Gy
Fig. 2. The graph shows dependence of absorbance of the ferrous sulphate dosimeter on the absorbed radiation dose
METHODS
To measure dose enhancement in aqueous iodinated solutions, we resorted to ferrous sulphate dosimetry. The main problem of absorbed dose quantification in the presence of DEAs is the short range of secondary radiation (from a few nanometers for Auger electrons to a few micrometers for photoelectrons and characteristic X-rays), which imposes certain limitations on the use of conventional dosimetry techniques. Here, liquid ferrous sulphate dosimetry offers a solution. This technique employs oxidation of Fe2+ to Fe3+ by highly reactive products of water radiolysis induced by ionizing radiation. The number of yielded Fe3+ ions depends on the absorbed radiation dose and therefore allows to calculate the exact value of the latter. The dosimeter solution can be "supplemented" with DEA; thus Fe3+ ions will be in close proximity to DEA atoms, and the effect of secondary radiation on the total absorbed dose can be estimated.
In our experiment dose enhancement was attempted with iodine (Ultravist 370, a iodine-based contrasting agent by Bayer, Germany), whose atomic number is 53. Iodine concentrations of 2.5, 5, 10, 20 and 50 mg/ml were created in the solutions of ferrous sulphate dosimeters. The solutions were prepared as described in [19].
Spectrophotometric measurements of absorbance at the peak of light absorption by Fe3+ ions are performed at 303 nm wavelength. The optical absorption spectrum of iopromide interferes with that of iron; therefore, we modified the dosimeter by adding ammonium rhodanide (thiocyanate) NH4SCN. Once ferric ions reacted with rhodanide, a intensely colored orangish-red Fe3+/ thiocyanate complex was formed with the absorption peak at 460 nm. We added 100 pl of 0.1 g/ml ammonium rhodanide solution to every irradiated iodinated dosimeter solution and then measured the absorption spectrum and absorbance for the Fe3+/thiocyanate complex using Cary 50 spectrophotometer (Varian Australia Pty, Australia).
An increase in the absorbed dose can be expressed using a dose enhancement factor (DEF): DEF = D , ,/D, where D , ,
v ; contrast ' contrast
is the dose absorbed by the irradiated dosimeter containing a dose-enhancing agent, as measured by spectrophotometry, and D is the absorbed dose in the absence of DEA. The absorbed dose was calculated based on the calibration curve for doses ranging from 2.5 to 20 Gy.
In our experiment we used the 6 MV clinical electron accelerator SL75-5-MT (Efremov Research Institute of Electrophysical Equipment, Russia) from the radiation therapy unit of Blokhin Russian Cancer Research Center. The accelerator generates bremsstrahlung radiation with photon energies up to 6 MeV. Prior to irradiation, the dosimeter solutions were placed in 40 mm Petri dishes, 2.5 ml of solution per dish. Irradiation time was 100 seconds, which is sufficient for iodine-free water to absorb 5 Gy. No tissue equivalent scatterers were used in this study, because its aim was to model conditions for surface irradiation, typical for in vitro and in vivo studies (in mice and rats with transplanted tumors).
Spectrophotometric measurements were done in 6 repeats for each DEA concentration. The mean absorbed dose and the standard error of the mean were calculated for each
concentration considering Student's coefficient. Statistical significance was estimated by the Mann-Whitney U-test.
RESULTS
The calibration curve in Fig. 2 shows that absorbance of the ferrous sulphate dosimeter is linearly dependent on the absorbed dose (doses range from 2.5 to 20 Gy).
Mean values of the dose enhancement factor for each studied iodine concentration are shown in the Table. A 13 % dose enhancement was observed at a concentration of 50 mg/ml. For other studied concentrations DEF was <1.
DISCUSSION
The obtained results show that typical concentrations of DEA accumulated in the tumor (2-50 mg/ml) do not have any clinically significant effect on the radiation dose absorbed during CERT with 6 MV photons. Absorbed dose enhancement does not exceed the uncertainty value at iodine concentrations <20 mg/ml. Significant dose enhancement (by 13 ± 5 %) was observed at a 50 mg/ml iodine concentration. The results of our study are consistent with the findings of other authors [17, 18]. It should be noted that iodine concentrations >20 mg/ml can be reached only by direct injections of DEA into the tumor, which is strongly disapproved of by the medical community. Systemically administered DEAs usually have iodine concentrations ranging between 2 and 15 mg/ml [2, 20]. To sum up, no clinically significant dose enhancement was registered in the solutions irradiated with 6 MV photons at typically used iodine concentrations, which means that no improved therapeutic effect should be expected.
CONCLUSIONS
Our findings suggest that standard sources of 6 MV energies used in clinical routine cannot ensure clinically significant enhancement of the absorbed dose for contrast-enhanced radiotherapy. The antitumor effect of 6 MV photons in the presence of dose-enhancing agents in the tumor is likely to be a case of radiosensitization and is not caused by increased absorption of radiation by the tumor. A question remains whether the use of flattening filters for orthovoltage and kilovoltage energies can be avoided during 6 MV CERT.
Values of dose enhancement factor measured at different iodine concentrations
Iodine concentration, mg/ml DEF
2.50 ± 0.08 1.00 ± 0.05
5.0 ± 0.1 0.90 ± 0.08
10.0 ± 0.3 1.00 ± 0.05
20.0 ± 0.6 1.00 ± 0.05
50.0 ± 1.5 1.13 ± 0.05*
Note. * — difference Is statistically significant (p < 0.05).
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Литература
1. Kulakov VN, Lipengol'ts AA, Grigor'eva EY, Shimanovskii NL. Pharmaceuticals for Binary Radiotherapy and Their Use for Treatment of Malignancies (A Review). Pharm Chem J. 2016; 50 (6): 388-93.
2. Hainfeld JF, Smilowitz HM, O'Connor MJ, Dilmanian FA, Slatkin DN. Gold nanoparticle imaging and radiotherapy of brain tumors in mice. Nanomedicine. 2013; 8 (10): 1601-9. DOI: 10.2217/nnm.12.165.
3. Butterworth KT, Nicol JR, Ghita M, Rosa S, Chaudhary P, McGarry CK et al. Preclinical evaluation of gold-DTDTPA nanoparticles as theranostic agents in prostate cancer radiotherapy. Nanomedicine. 2016; 11 (16): 2035-47. DOI: 10.2217/nnm-2016-0062.
4. Lipengolts AA, Cherepanov AA, Kulakov VN, Grigorieva EY, Sheino IN, Klimanov VA. Antitumor efficacy of extracellular complexes with gadolinium in Binary Radiotherapy. Appl Radiat Isot. 2015 Dec 1; 106: 233-6. DOI: 10.1016/j. apradiso.2015.07.051.
5. Rose JH, Norman A, Ingram M, Aoki C, Solberg T, Mesa A. First radiotherapy of human metastatic brain tumors delivered by a computerized tomography scanner (CTRx). Int J Radiat Oncol Biol Phys. 1999; 45 (5): 1127-32.
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13. Detappe A, Kunjachan S, Rottmann J, Robar J, Tsiamas P, Korideck H, et al. AGuIX nanoparticles as a promising platform for image-guided radiation therapy. Cancer Nanotechnol. 2015; 6 (1): 4. DOI: 10.1186/s12645-015-0012-3.
14. McMahon SJ, Hyland WB, Muir MF, Coulter JA, Jain S, Butterworth KT, et al. Nanodosimetric effects of gold nanoparticles in megavoltage radiation therapy. Radiother Oncol. 2011 Sep; 100 (3): 412-6. DOI: 10.1016/j.radonc.2011.08.027.
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16. Tsiamas P, Liu B, Cifter F, Ngwa WF, Berbeco RI, Kappas C, et al. Impact of beam quality on megavoltage radiotherapy treatment techniques utilizing gold nanoparticles for dose enhancement. Phys Med Biol. 2013 Feb 7; 58 (3): 451-64. DOI: 10.1088/00319155/58/3/451.
17. Kakade NR, Sharma SD. Dose enhancement in gold nanoparticle-aided radiotherapy for the therapeutic photon beams using Monte Carlo technique. J Cancer Res Ther. 2015 Jan-Mar; 11 (1): 94-7. DOI: 10.4103/0973-1482.147691.
18. Smith CL, Ackerly T, Best SP, Gagliardi F, Kie K, Little PJ, et al. Determination of dose enhancement caused by gold-nanoparticles irradiated with proton, X-rays (kV and MV) and electron beams, using alanine/EPR dosimeters. Radiat Meas. 2015; 82: 122-8.
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20. Obeid L, Deman P, Tessier A, Balosso J, Esteve F, Adam J-F. Absolute perfusion measurements and associated iodinated contrast agent time course in brain metastasis: a study for contrast-enhanced radiotherapy. J Cereb Blood Flow Metab. 2014 Apr; 34 (4) :638-45. DOI: 10.1038/jcbfm.2013.239.
7. Bobyk L, Edouard M, Deman P, Vautrin M, Pernet-Gallay K, Delaroche J et al. Photoactivation of gold nanoparticles for glioma treatment. Nanomedicine. 2013 Oct; 9 (7): 1089-97. DOI: 10.1016/j.nano.2013.04.007.
8. Wolfe T, Chatterjee D, Lee J, Grant JD, Bhattarai S, Tailor R et al. Targeted gold nanoparticles enhance sensitization of prostate tumors to megavoltage radiation therapy in vivo. Nanomedicine. 2015 Jul; 11 (5): 1277-83. DOI: 10.1016/j.nano.2014.12.016.
9. Detappe A, Kunjachan S, Drané P, Kotb S, Myronakis M, Biancur DE, et al. Key clinical beam parameters for nanoparticle-mediated radiation dose amplification. Sci Rep. 2016 Sep 23; 6 (1): 34040. DOI: 10.1038/srep34040.
10. Rahman WN, Bishara N, Ackerly T, He CF, Jackson P, Wong C et al. Enhancement of radiation effects by gold nanoparticles for superficial radiation therapy. Nanomedicine. 2009 Jun; 5 (2) : 136-42.
11. Chang MY, Shiau AL, Chen YH, Chang CJ, Chen HHW, Wu CL. Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice. Cancer Sci. 2008 Jul; 99 (7): 1479-84. DOI: 10.1111/j.1349-7006.2008.00827.x.
12. Rousseau J, Boudou C, Barth RF, Balosso J, Estève F, Elleaume H. Enhanced survival and cure of F98 glioma-bearing rats following intracerebral delivery of carboplatin in combination with photon irradiation. Clin Cancer Res. 2007 Sep; 13 (17): 5195-201. DOI: 10.1158/1078-0432.CCR-07-1002.
13. Detappe A, Kunjachan S, Rottmann J, Robar J, Tsiamas P, Korideck H, et al. AGuIX nanoparticles as a promising platform for
image-guided radiation therapy. Cancer Nanotechnol. 2015; 6 (1): 4. DOI: 10.1186/s12645-015-0012-3.
14. McMahon SJ, Hyland WB, Muir MF, Coulter JA, Jain S, Butterworth KT, et al. Nanodosimetric effects of gold nanoparticles in megavoltage radiation therapy. Radiother Oncol. 2011 Sep; 100 (3): 412-6. DOI: 10.1016/j.radonc.2011.08.027.
15. Lin Y, McMahon SJ, Scarpelli M, Paganetti H, Schuemann J. Comparing gold nano-particle enhanced radiotherapy with protons, megavoltage photons and kilovoltage photons: a Monte Carlo simulation. Phys Med Biol. 2014 Dec 21; 59 (24): 7675-89. DOI: 10.1088/0031-9155/59/24/7675.
16. Tsiamas P, Liu B, Cifter F, Ngwa WF, Berbeco RI, Kappas C, et al. Impact of beam quality on megavoltage radiotherapy treatment techniques utilizing gold nanoparticles for dose enhancement. Phys Med Biol. 2013 Feb 7; 58 (3): 451-64. DOI: 10.1088/00319155/58/3/451.
17. Kakade NR, Sharma SD. Dose enhancement in gold nanoparticle-aided radiotherapy for the therapeutic photon beams using Monte
Carlo technique. J Cancer Res Ther. 2015 Jan-Mar; 11 (1): 94-7. DOI: 10.4103/0973-1482.147691.
18. Smith CL, Ackerly T, Best SP, Gagliardi F, Kie K, Little PJ, et al. Determination of dose enhancement caused by gold-nanoparticles irradiated with proton, X-rays (kV and MV) and electron beams, using alanine/EPR dosimeters. Radiat Meas. 2015; 82: 122-8.
19. Черепанов А. А., Липенгольц А. А., Воробьева Е. С., Кулаков В. Н., Климанов В. А., Григорьева Е. Ю. Исследование увеличения энерговыделения в среде за счет присутствия тяжелого элемента с использованием дозиметра Фрике. Медицинская физика. 2016; 72 (4): 38-41.
20. Obeid L, Deman P, Tessier A, Balosso J, Esteve F, Adam J-F. Absolute perfusion measurements and associated iodinated contrast agent time course in brain metastasis: a study for contrast-enhanced radiotherapy. J Cereb Blood Flow Metab. 2014 Apr; 34 (4) :638-45. DOI: 10.1038/jcbfm.2013.239.
