The relative biological effectiveness of antiprotons.

BACKGROUND AND PURPOSE: Aside from the enhancement of physical dose deposited by antiprotons annihilating in tissue-like material compared to protons of the same range a further increase of biological effective dose has been demonstrated. This enhancement can be expressed in an increase of the relative biological effectiveness (RBE) of antiprotons near the end of range. We have performed the first-ever direct measurement of the RBE of antiprotons both at rest and in flight. MATERIALS AND METHODS: Experimental data were generated on the RBE of an antiproton beam entering a tissue-like target consisting of V79 cells embedded in gelatin with an energy providing a range of approximately 10cm. RESULTS: The RBE in the entrance channel (the "plateau") is only slightly above the value for a comparable proton beam, and remains low until the proximal edge of the spread-out Bragg peak (SOBP). A steep increase of RBE is seen starting from the onset of the SOBP. CONCLUSIONS: This paper reports the final results of the experiment AD-4/ACE at CERN on the first-ever direct measurement of RBE of antiprotons and constitutes the first step toward developing treatment plans.

Dose determination using alanine detectors in a mixed neutron and gamma field for boron neutron capture therapy of liver malignancies.

UNLABELLED: Boron Neutron Capture Therapy for liver malignancies is being investigated at the University of Mainz. One important aim is the set-up of a reliable dosimetry system. Alanine dosimeters have previously been applied for dosimetry of mixed radiation fields in antiproton therapy, and may be suitable for measurements in mixed neutron and gamma fields. MATERIAL AND METHODS: Two experiments have been carried out in the thermal column of the TRIGA Mark II reactor at the University of Mainz. Alanine dosimeters have been irradiated in a phantom and in liver tissue. RESULTS: For the interpretation and prediction of the dose for each pellet, beside the results of the measurements, calculations with the Monte Carlo code FLUKA are presented here. For the phantom, as well as for the liver tissue, the measured and calculated dose and flux values are in good agreement. DISCUSSION: Alanine dosimeters, in combination with flux measurements and Monte Carlo calculations with FLUKA, suggest that it is possible to establish a system for monitoring the dose in a mixed neutron and gamma field for BNCT and other applications in radiotherapy.

Neutron fluence in antiproton radiotherapy, measurements and simulations.

INTRODUCTION: A significant part of the secondary particle spectrum from antiproton annihilation consists of fast neutrons, which may contribute to a significant dose background found outside the primary beam. MATERIALS AND METHODS: Using a polystyrene phantom as a moderator, we have performed absolute fluence measurements of the thermalized part of the fast neutron spectrum using Lithium-6 and -7 Fluoride TLD pairs. The results were compared with the Monte Carlo particle transport code FLUKA. RESULTS: The experimental results are found to be in good agreement with simulations. The thermal neutron kerma resulting from the measured thermal neutron fluence is insignificant compared to the contribution from fast neutrons. DISCUSSION: The secondary neutron fluences encountered in antiproton therapy are found to be similar to values calculated for pion treatment, however exact modeling under more realistic treatment scenarios is still required to quantitatively compare these treatment modalities.

Dose calculation in biological samples in a mixed neutron-gamma field at the TRIGA reactor of the University of Mainz.

To establish Boron Neutron Capture Therapy (BNCT) for non-resectable liver metastases and for in vitro experiments at the TRIGA Mark II reactor at the University of Mainz, Germany, it is necessary to have a reliable dose monitoring system. The in vitro experiments are used to determine the relative biological effectiveness (RBE) of liver and cancer cells in our mixed neutron and gamma field. We work with alanine detectors in combination with Monte Carlo simulations, where we can measure and characterize the dose. To verify our calculations we perform neutron flux measurements using gold foil activation and pin-diodes. Material and methods. When L-α-alanine is irradiated with ionizing radiation, it forms a stable radical which can be detected by electron spin resonance (ESR) spectroscopy. The value of the ESR signal correlates to the amount of absorbed dose. The dose for each pellet is calculated using FLUKA, a multipurpose Monte Carlo transport code. The pin-diode is augmented by a lithium fluoride foil. This foil converts the neutrons into alpha and tritium particles which are products of the (7)Li(n,α)(3)H-reaction. These particles are detected by the diode and their amount correlates to the neutron fluence directly. Results and discussion. Gold foil activation and the pin-diode are reliable fluence measurement systems for the TRIGA reactor, Mainz. Alanine dosimetry of the photon field and charged particle field from secondary reactions can in principle be carried out in combination with MC-calculations for mixed radiation fields and the Hansen & Olsen alanine detector response model. With the acquired data about the background dose and charged particle spectrum, and with the acquired information of the neutron flux, we are capable of calculating the dose to the tissue. Conclusion. Monte Carlo simulation of the mixed neutron and gamma field of the TRIGA Mainz is possible in order to characterize the neutron behavior in the thermal column. Currently we also speculate on sensitizing alanine to thermal neutrons by adding boron compounds.

Comparison of optimized single and multifield irradiation plans of antiproton, proton and carbon ion beams.

BACKGROUND AND PURPOSE: Antiprotons have been suggested as a possibly superior modality for radiotherapy, due to the energy released when antiprotons annihilate, which enhances the Bragg peak and introduces a high-LET component to the dose. However, concerns are expressed about the inferior lateral dose distribution caused by the annihilation products. METHODS: We use the Monte Carlo code FLUKA to generate depth-dose kernels for protons, antiprotons, and carbon ions. Using these we then build virtual treatment plans optimized according to ICRU recommendations for the different beam modalities, which then are recalculated with FLUKA. Dose-volume histograms generated from these plans can be used to compare the different irradiations. RESULTS: The enhancement in physical and possibly biological dose from annihilating antiprotons can significantly lower the dose in the entrance channel; but only at the expense of a diffuse low dose background from long-range secondary particles. Lateral dose distributions are improved using active beam delivery methods, instead of flat fields. CONCLUSIONS: Dose-volume histograms for different treatment scenarios show that antiprotons have the potential to reduce the volume of normal tissue receiving medium to high dose, however, in the low dose region antiprotons are inferior to both protons and carbon ions. This limits the potential usage to situations where dose to normal tissue must be reduced as much as possible.

V-79 Chinese hamster cells irradiated with antiprotons, a study of peripheral damage due to medium and long range components of the annihilation radiation.

PURPOSE: Radiotherapy of cancer carries a perceived risk of inducing secondary cancer and other damage due to dose delivered to normal tissue. While expectedly small, this risk must be carefully analysed for all modalities. Especially in the use of exotic particles like pions and antiprotons, which annihilate and produce a mixed radiation field when interacting with normal matter nuclei, the biological effective dose far out of field needs to be considered in evaluating this approach. We describe first biological measurements to address the concern that medium and long range annihilation products may produce a significant background dose and reverse any benefits of higher biological dose in the target area. MATERIALS AND METHODS: Using the Antiproton Decelerator (AD) at CERN (Conseil Européen pour la Recherche Nucléaire) we irradiated V-79 Chinese Hamster cells embedded in gelatine using an antiproton beam with fluence ranging from 4.5 x 10(8) to 4.5 x 10(9) particles, and evaluated the biological effect on cells located distal to the Bragg peak using clonogenic survival and the COMET assay. RESULTS: Both methods show a substantial biological effect on the cells in the entrance channel and the Bragg Peak area, but any damage is reduced to levels well below the effect in the entrance channel 15 mm distal to the Bragg peak for even the highest particle fluence used. CONCLUSIONS: The annihilation radiation generated by antiprotons stopping in biological targets causes an increase of the penumbra of the beam but the effect rapidly decreases with distance from the target volume. No major increase in the biological effect is found in the far field outside of the primary beam.

Calculated LET spectrum from antiproton beams stopping in water.

INTRODUCTION: Antiprotons have been proposed as a potential modality for radiotherapy because the annihilation at the end of range leads to roughly a doubling of physical dose in the Bragg peak region. So far it has been anticipated that the radiobiology of antiproton beams is similar to that of protons in the entry region of the beam, but very different in the annihilation region, due to the expected high-LET components resulting from the annihilation. On closer inspection we find that calculations of dose averaged LET in the entry region may suggest that the RBE of antiprotons in the plateau region could significantly differ from unity, which seems to warrant closer inspection of the radiobiology in this region. MATERIALS AND METHODS: Monte Carlo simulations using FLUKA were performed for calculating the entire particle spectrum of a beam of 126 MeV antiprotons hitting a water phantom. RESULTS AND DISCUSSION: In the plateau region of the simulated antiproton beam we observe a dose-averaged unrestricted LET of about 4 keV/microm, which is very different from the expected 0.6 keV/microm of an equivalent primary proton beam. Even though the fluence of secondaries is a magnitude less than the fluence of primary particles, the increased stopping power of the secondary particles causes an increase in the dose averaged LET which is expected to result in a RBE different from unity.

Antiproton radiotherapy.

Antiprotons are interesting as a possible future modality in radiation therapy for the following reasons: When fast antiprotons penetrate matter, protons and antiprotons have near identical stopping powers and exhibit equal radiobiology well before the Bragg-peak. But when the antiprotons come to rest at the Bragg-peak, they annihilate, releasing almost 2 GeV per antiproton-proton annihilation. Most of this energy is carried away by energetic pions, but the Bragg-peak of the antiprotons is still locally augmented with approximately 20-30 MeV per antiproton. Apart from the gain in physical dose, an increased relative biological effect also has been observed, which can be explained by the fact that some of the secondary particles from the antiproton annihilation exhibit high-LET properties. Finally, the weakly interacting energetic pions, which are leaving the target volume, may provide a real time feedback on the exact location of the annihilation peak. We have performed dosimetry experiments and investigated the radiobiological properties using the antiproton beam available at CERN, Geneva. Dosimetry experiments were carried out with ionization chambers, alanine pellets and radiochromic film. Radiobiological experiments were done with V79 WNRE Chinese hamster cells. The radiobiological experiments were repeated with protons and carbon ions at TRIUMF and GSI, respectively, for comparison. Several Monte Carlo particle transport codes were investigated and compared with our experimental data obtained at CERN. The code that matched our data best was used to generate a set of depth dose data at several energies, including secondary particle-energy spectra. This can be used as base data for a treatment planning software such as TRiP. Our findings from the CERN experiments indicate that the biological effect of antiprotons in the plateau region may be reduced by a factor of 4 for the same biological target dose in a spread-out Bragg-peak, when comparing with protons. The extension of TRiP to handle antiproton beams is currently in progress. This will enable us to perform planning studies, where the potential clinical consequences can be examined, and compared to those of other beam modalities such as protons, carbon ions, or IMRT photons.

The biological effectiveness of antiproton irradiation.

BACKGROUND AND PURPOSE: Antiprotons travel through tissue in a manner similar to that for protons until they reach the end of their range where they annihilate and deposit additional energy. This makes them potentially interesting for radiotherapy. The aim of this study was to conduct the first ever measurements of the biological effectiveness of antiprotons. MATERIALS AND METHODS: V79 cells were suspended in a semi-solid matrix and irradiated with 46.7MeV antiprotons, 48MeV protons, or (60)Co gamma-rays. Clonogenic survival was determined as a function of depth along the particle beams. Dose and particle fluence response relationships were constructed from data in the plateau and Bragg peak regions of the beams and used to assess the biological effectiveness. RESULTS: Due to uncertainties in antiproton dosimetry we defined a new term, called the biologically effective dose ratio (BEDR), which compares the response in a minimally spread out Bragg peak (SOBP) to that in the plateau as a function of particle fluence. This value was approximately 3.75 times larger for antiprotons than for protons. This increase arises due to the increased dose deposited in the Bragg peak by annihilation and because this dose has a higher relative biological effectiveness (RBE). CONCLUSION: We have produced the first measurements of the biological consequences of antiproton irradiation. These data substantiate theoretical predictions of the biological effects of antiproton annihilation within the Bragg peak, and suggest antiprotons warrant further investigation.