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Protontherapy Versus Carbon Ion Therapy : Advantages, Disadvantages and Similarities

To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Help us improve our products. Sign up to take part. A Nature Research Journal. Protons, however, lack distinct radiobiological advantages over photons or electrons.

However, economic and radiobiological issues hamper 12 C-ion clinical amenability.

Thus, enhancing proton RBE is desirable. To maximize the reaction rate, we used sodium borocaptate BSH with natural boron content. We recorded significantly increased cellular lethality and chromosome aberration complexity. The urgent need for radical radiotherapy research to achieve improved tumour control in the context of reducing the risk of normal tissue toxicity and late-occurring sequelae, has driven the fast-growing development of cancer treatment by accelerated beams of charged particles hadrontherapy in recent decades 1.

This appears to be particularly true for protontherapy, which has emerged as the most-rapidly expanding hadrontherapy approach, totalling over , patients treated thus far worldwide 2. Wilson first proposed the use of energetic protons for cancer radiotherapy in 3. This in principle enables the delivery of very high-dose gradients close to organs at risk, confining the high-dose area to the tumour volume. Cancer treatment by protons also remains the most attractive solution in the case of paediatric patients due to the significant reduction in the integral dose delivered to the patient 8 , even compared to newer photon techniques such as intensity modulated radiation therapy However, protons have been traditionally regarded as only slightly more biologically effective than photons The combination of ballistic precision with an increased ability to kill cells is the radiobiological rationale currently supporting the clinical exploitation of heavier particles such as fully stripped 12 C-ions 18 , which present some advantages over protons 6 , Not only do they ensure a better physical dose distribution, due to less lateral scattering 19 , but they also result more biologically effective both in vitro and in vivo as a result of their higher Linear Energy Transfer LET 11 , 20 , In fact, densely ionizing radiation tracks cause more spatio-temporally contiguous and complex lesions at the DNA level, comprising DNA double-strand breaks and damaged bases, which are highly clustered in nature 22 , 23 , This impairs cellular ability for correct repair 25 and decreases the dependence of radiosensitization upon the presence of oxygen, desirable features for eradication of resilient, hypoxic tumors 5 , Further potential radiobiological advantages include greater RBE for killing putatively radioresistant cancer stem cells 27 and counteracting cancer invasiveness 28 , 29 , albeit the latter remains controversial Finally, low doses of high-LET radiation appear to elicit stronger immunological responses compared to low-LET radiation On the other hand, complications related to nuclear fragmentation from the primary beam, along with a partial understanding of the consequences of the exposure of normal cells to high-LET radiation, and also considering the complexity and high costs associated with a 12 C treatment facility, fueled research into exploring novel strategies with the aim to achieve alternative solutions for a localized increase of proton RBE.

One of such recently proposed approaches foresees the use of gold nanoparticles as protontherapy radiosensitizers The ability of particle radiation to stimulate favourable immunological responses represents another attractive solution as it has become increasingly evident that proton and photon irradiation differentially modulate systemic biological responses 8 , In this work, we experimentally test for the first time the idea theoretically proposed by Do-Kun Y et al. BNCT requires thermal neutrons to trigger the reaction where two charged particles one alpha of 1.

We observed a significant increase in proton-induced cytogenetic effects, both in terms of cell death, assessed as loss of proliferative potential by the clonogenic assay, and of induction of DNA damage.


Specifically, the markedly higher frequency of complex-type chromosome exchanges a typical cytogenetic signature of high-LET ionizing radiation, see ref. These findings, therefore, yield important implications for an enhanced cancer protontherapy. It has a positive Q-value 8. This reaction has garnered interest since the s 33 , 34 because of the process ability to produce copious numbers of alpha particles in an exothermic reaction.

A more detailed description of the reaction is reported in Methods. Such a reaction has been considered very attractive for the generation of fusion energy without producing neutron-induced radioactivity 41 , Such a nuclear reaction may be even more useful as it could play a strategic role in medical applications improving the effectiveness of protontherapy. The potential clinical use of the p- 11 B reaction has been thus far only investigated and validated by means of Monte Carlo simulations 32 , 43 , with preliminary experimental work on its imaging potentialities 44 , 45 being also performed.

In this paper, we experimentally implement for the first time this innovative approach in a clinical scenario by measuring the biological effects as a direct consequence of the p- 11 B reaction. As schematically depicted in Fig. Thus, most of its energy dose is delivered to the tumour cells. Under the assumption that a given concentration of 11 B nuclei is present preferentially, but not exclusively, in the tumour, the arrival of slow protons could trigger a series of fusion events generating several alpha particles that are localized in the tumour region. Hence, even if such particles are mainly produced outside the cell cytoplasm due to sub-optimal boron uptake, the probability that they would reach the nucleus and damage the DNA remains very high.

Moreover, even if a non-negligible concentration of 11 B nuclei is present in the healthy tissues surrounding the tumour, the number of fusion events i. This would lead to a more biologically effective particle dose localization, higher than the one currently achievable with conventional protontherapy, thus to a more efficient treatment in terms of an enhancement in cancer cell lethality, especially because of the clustered nature of the DNA damage, which is caused by the high-LET alpha particles emitted in the tumour region. Hence, protontherapy could acquire the benefits of an enhanced efficiency in cancer cell killing, moving close to 12 C ion hadrontherapy but without the above-mentioned complications of the latter.

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Whereas in A the incident proton beam mainly results in isolated, mostly repairable DNA breaks, the extremely localized emission of high-LET radiation produced by the proton-boron fusion in the Bragg peak region causes irreparable clustered DNA damage, similar in nature to that induced by 12 C ions, hence the expected increase in effectiveness at tumor cell killing. The ballistic advantage granted by the inverted dose-depth profile of charged particles is such that in protontherapy most of the dose is released mainly in the tumor region upper panel , cancer cells being represented here by purple circles and damaging events by black dots A : proton-induced damage is similar to that imparted to DNA by photons, consisting mainly of isolated lesions middle and lower panels.

If cancer cells are loaded with 11 B-delivering agents middle panel, B , as is the case with 10 B-enriched compounds in BNCT, unrepairable DNA clustered lesions will be also produced by the high-LET alpha particles generated by the p- 11 B nuclear fusion reaction lower panel. This in turn leads to a Dose Modifying Factor DMF for cancer cell killing while maintaining beneficial sparing of surrounding healthy tissues middle panel. Furthermore, for a given clinical case, such higher DMF can potentially allow to reduce the overall dose delivered to the patient lower total number of protons used in the number of fractions compared to a standard treatment without the presence of 11 B-delivering agents in the tumor.

Irradiations were performed in the presence of two concentrations of BSH see Methods for details on the irradiation set-up and BSH pre-treatment. The considered BSH concentrations were equivalent to 40 ppm parts per million and 80 ppm of 11 B.

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These were chosen based on values from the literature on the 10 B-enriched BSH analogue used in BNCT in order to achieve the optimal intracellular 10 B concentration 35 , 46 , In particular, similar boron-equivalent concentration ranges of another BNCT compound, BPA, had been previously used with the same cell line in vitro Boron treatment enhanced proton biological effectiveness resulting in a significant increase in the induction of cell death in DU cells as measured by loss of colony-forming ability.

Cells that were irradiated after pre-treatment with, and in the presence of, boron-containing BSH exhibited a greater radiosensitivity in comparison with cells exposed to radiation alone: BSH-treated cells yielded a much steeper clonogenic dose-response curve than that obtained for cells grown and irradiated in BSH-free medium Fig. The clonogenic survival fraction SF following irradiation with protons alone was best fitted to a linear-quadratic function of dose, i. Boron-mediated increase in proton irradiation-induced cell death.

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Data are weighted mean values plus standard error from four independent experiments in the case of proton irradiation in the absence of BSH open circles and in the presence of the compound at the highest concentration used 80 ppm, open triangles. Two experiments were performed with cells irradiated in the presence of 40 ppm of 11 B.

X ray-irradiation survival data are also shown for comparison. A slight yet not statistically significant effect due to boron concentration was observed. Based upon the measured survival dose-responses, a calculated DMF of 1. This indicated that the presence of the boron compound conferred a radiobiological advantage at reducing cell survival compared to proton irradiation alone. This means that the measured enhancement of proton effectiveness at cell killing was not contributed to by cytotoxicity caused by the boron-containing compound per se. Such a reaction critically depends on the incident proton energy; hence, its radiobiological effectiveness can be expected to vary along the clinical proton SOBP.

To verify this hypothesis, the induction of cell killing in the presence of the boron compound at the concentration of 80 ppm 11 B Fig. Cell irradiation along the proton SOBP. Dose profiles as obtained by direct measurement by Markus chamber and by Monte-Carlo simulation. The panel in Fig. In line with the expected variation in cell radiosensitivity along a clinical SOBP 14 , proton irradiation alone resulted in a progressive increase in cell killing from P1 to P3. Interestingly, data clearly show no effect of BSH at the beam entrance.

A DMF of about 1. These experimental results, particularly the lack of a measurable effect due to the presence of 11 B at beam entrance where the incident proton energy is the highest, confirm that the enhancement of biological effectiveness is caused by the occurrence of p-B nuclear fusion events, which have a higher probability i. Clonogenic survival along the proton SOBP. Data shown here refer to dose-response curves obtained at positions P1, P2 and P3 as indicated in Fig.

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Enhancement of cell killing due to the presence of the boron compound black circles is null at beam entrance highest proton mean energy while reaching its maximum at the distal end of the SOBP lowest mean proton energies. Ionizing radiation can give rise to a wide spectrum of structural chromosome aberrations or CAs It is long-known that CAs are closely linked to clonogenic cell death 50 , hence an increase in cell killing due to the alpha particles produced by the p-B reaction ought to reflect in an increase in the yield of CAs.

Furthermore, complex-type exchanges, defined as those rearrangements involving at least two chromosomes and generated by at least three breaks, are an archetypical feature of high-LET exposure 37 , To this end, in addition to conventional FISH labelling which is limited to painting two pairs of homolog chromosomes a more comprehensive investigation was also carried out employing the multicolour m -FISH technique, which represents the method of choice when an accurate scoring of CAs, particularly of those of complex type, is required since it allows analysis of the whole karyotype.

This is exemplified by Fig. One cell is conventionally FISH-painted, presenting with chromosome rearrangements of complex nature as several portions of the painted chromosomes are aberrantly joined with aspecifically stained chromosomes appearing blue and with themselves. The other cell has been subjected to mFISH analysis revealing a number of aberrations that would have gone undetected confining analyses to conventional FISH scoring.

Analysis of proton irradiation-induced structural chromosome damage. Representative pictures of chromosome spreads from 4 Gy-proton irradiated cells treated with 80 ppm of 11 B scored by conventional left and mFISH analysis right , respectively. Both exhibit complex-type CAs. However, conventional FISH would, have detected neither the complex exchanges shown on the right that involves chromosomes 1, 10 e 19, nor the two translocations between chromosome 1 and 4 and between 14 e 20, as it paints just chromosomes 1 and 2.

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Cancer cells are known to be genetically unstable; hence, they do not lend themselves to reliable assessment of radiation-induced DNA damage. Radiation-induced chromosome rearrangements would superimpose onto an elevated confounding frequency of baseline damage. Conversely, proton irradiation resulted in a higher yield of all CA types in cells treated with BSH compared to cells irradiated with protons in the absence of BSH Fig.

As expected, the overall measured frequency of CAs raised for all irradiation conditions when using mFISH because of its greater sensitivity. The yield of CAs following x-rays was identical to that measured after exposure to protons in the absence of BSH, in line with the observed lack of a significant difference in cell killing between x-rays and protons alone also seen in DU cancer cells Fig.

BSH-induced increased induction of chromosome aberrations following proton irradiation. The dose-dependent frequency of all chromosome exchanges scored by either conventional FISH painting left or m-FISH karyotyping right is shown for proton irradiation alone black circles and for proton irradiation in the presence of 11 B at concentrations of 40 ppm open circles and 80 ppm down triangles.

X-ray data are also shown for comparison. In the interest of clarity, fitted curves are shown only for the highest boron concentration used 80 ppm, dashed line and for irradiation with no boron compound solid line. Data points correspond to the mean value measured in at least two independent experiments with standard errors of counts. Because of the purely quadratic nature of the dose-response curve for proton irradiation in the absence of BSH, no estimate for DMF max could be derived as this is defined as the ratio of the linear components of the linear-quadratic dose-response curve by analogy with the concept of RBE DMF values were calculated for two levels of damage instead, that is 20 and 40 aberrations per cells.

In the case of 20 aberrations per cells, the calculated DMF was about 2. The most interesting result, however, came from the analysis of complex-type aberration exchanges. A markedly pronounced occurrence of complex-type exchanges was found in samples treated with BSH compared to cells that had been irradiated with protons in the absence of BSH Fig.

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After 0. These values dramatically increased with dose and remained consistently higher in the case of BSH-treated cells, reaching about 0. Occurrence of complex-type exchanges following x-rays is also shown for comparison Fig.