Consequences for treatment planning and treatment

One consequence is that the beam direction is never chosen so that a critical structure is placed just distal to the Bragg peak, for fear of over-shooting and damaging the critical structure. Beam directions are chosen so that the lateral penumbra, which is rather well-known, is used to spare critical organs. This means that the sharpness of the peak and the advantage of the no-dose behind it are not fully exploited.

Another consequence is the increase of the ‘safety margins’ and thus the irradiated volume, also called planning target volume (PTV). Typically, the PTV is defined in the following way: the Gross Tumour Volume (GTV) seen on X-ray CT, MRI, PET or SPECT (Single-Photon Emission Computed Tomography) images is delineated. This GTV is contained in a larger volume, the Clinical Target Volume (CTV), that aims at taking into account the potential microscopic spread of the disease that could not be seen on the images. The PTV encapsulates the last volumes adding margins accounting for uncertainties in planning or treatment delivery.

In order to take the range uncertainty into account, the margins added when establishing the PTV in particle therapy are rather large. Here are examples of margins used for proton therapy [Paganetti,2012]:

– Massachusetts General Hospital (Boston): 3.5% of range + 1 mm

– MD Anderson Proton Therapy Center (Huston), Loma Linda University Medical Center, Roberts Proton Therapy Center at the University of Pennsylvania: 3.5%

+ 3 mm

– University of Florida Proton Therapy Institute: 2.5% + 1.5 mm

The need for these margins somehow reduces the attractiveness of ion beam therapy.

While a precision weapon is available, allowing for better a sparing of the normal tissues, we are limited by the range uncertainty, causing the voluntary irradiation of a portion of normal tissue.

Quality control for ion beam therapy

The question of the precision in the irradiation has produced the need to worry more about quality control in ion beam therapy than previously for conventional radiotherapy.

Means to verify the conformity of the irradiation to the treatment plan were investigated, and different methods have been proposed [Knopf and Lomax, 2013]. Amongst these methods, some are real-time measurements during the irradiations, others are pre- or post- irradiation controls; some methods are invasive, others not. Here is a brief summary of the potential solutions that have been investigated:

– Range probes and particle radiography (pre-irradiation control):

The idea of a range probe is the following: before treatment, a particle pencil beam of energy sufficient to pass completely through the patient is sent and the residual range is measured upon exit. This makes it possible to check the expected range [Romero et al.,1995;Watts et al.,2009;Mumot et al.,2010]. This

approach has been implemented in many proton therapy centres. It was shown on Monte Carlo simulations performed using real X-ray CT data that in vivo range estimates at the level of 0.5% could be achieved [Mumot et al.,2010]. The dose delivered is low – in the plateau region – and the method is fast. Based on the same principle of measuring the residual range of the particles, the proton radiography concept makes use of a two-dimensional fluence of protons. In order to increase spatial resolution, a proton radiography system measuring the entrance and exit coordinates with the range measurements has been proposed [Schneider and Pedroni,1995].

These concepts, first developed with protons, work the same way for ions, like carbon [Ohno et al.,2004;Shinoda et al.,2006;Parodi,2014].

– Point dose measurements (real-time control, direct, invasive):

It has been proposed to control the dose deposit in vivo using implantable dosimeters and using the time-dependence of the distribution delivered by range modulated passive scattering fields, using ionization chambers [Lu,2008b] or semi-conductor diodes [Gottschalk et al.,2011]. This proposition was later generalized to measuring SOBPs generated by complementary field pairs [Lu,2008a] and for intensity modulated proton therapy (IMPT) plans [Lu, 2009]. The advantage of this method is that it provides a real-time and precise measurement of the dose deposit. The potential sub-millimetric precision has yet to be confirmed in clinical studies on patients. Nevertheless, this technique presents the major drawback of being invasive and provides information on a limited number of points that have to be carefully chosen.

– Positron emission tomography (real-time or post-irradiation, indirect):

Nuclear interactions of protons or ions in the matter can generate the activation of the materials [Graffman and Jung,1975;Bennett et al.,1978]. The production ofβ⁺ emitters, of half life between 2 and 20 minutes in particular, is appropriate for PET. Proton beams generate mostly ¹¹C, ¹³N, ¹⁵O [Litzenberg and Bajema, 1992], while carbon beams produce¹⁰C,¹¹C,¹⁵O [Enghardt,2004a]. The detection in coincidence of the photon pairs resulting from the annihilation of the emitted positrons with electrons in the medium then allows forin vivo range verification.

The activity profile obtained depends on the nature of the beam but is, both for proton and carbon therapy, strongly correlated to the dose distribution [Enghardt, 2004b].

It has been shown that this technique makes it possible to detect deviations in the patient positioning or local changes in the patient anatomy in the course of a fractionated treatment [Enghardt,2004b;Schardt et al.,2010].

PET monitoring can be performed either in-beam (during the irradiation) or off-line (just after the irradiation). Off-off-line PET imaging has the obvious advantage that commercially available scanners can be used. In contrast, in-beam PET requires the inclusion of the PET system around the treatment bed, generating

1.2. TREATMENT PLANNING AND UNCERTAINTIES IN PARTICLE BEAM THERAPY

higher costs and challenges in image reconstruction due to the limited angle.

Nevertheless, downsides of off-line PET are the diminished activity due to the waiting time between the irradiation and the imaging, and a degraded spatial correlation between the activity map and the dose distribution due to the biological washout processes [Parodi,2012].

– Prompt gamma imaging (real-time control, indirect):

The de-excitation process of nuclear interactions occurring as the protons or ions pass into the matter generates the prompt emission of photons. The presence of these gammas was first considered in the context of PET imaging for dose monitoring of therapy, as background noise [Parodi et al.,2005]. The idea to use them as actual information was proposed soon thereafter for proton beams [Min et al.,2006;Polf et al.,2009] and for carbon beams [Testa et al.,2008]. The prompt gamma emission profile is correlated to the Bragg peak position and could thus be used in order to verify its position. However, the falloff of the gamma profile does not correspond to the dose falloff. As a consequence, only a consistent and predictable falloff difference enables range verification [Moteabbed et al., 2011].

Prompt gamma imaging can be performed in a similar fashion to SPECT imaging, using a collimated gamma-camera [Bom et al.,2012;Smeets et al.,2012], or using a Compton camera [Kormoll et al.,2011;Roellinghoff et al.,2011].

– Interaction vertex imaging (real-time control for ion beam therapy, indirect):

Interaction vertex imaging (IVI) is based on the detection of secondary charged particles exiting from the patient during the irradiation with ions (not with protons) [Amaldi et al.,2010;Henriquet et al.,2012]. The advantage of IVI over prompt gamma and PET monitoring is the potentially greater number of particles to detect. However, the difficulty resides in the fact that the charged particles detected undergo multiple Coulomb scattering before their exit from the patient, challenging the spatial resolution achievable with such a technique [Rescigno et al., 2014].

– Magnetic resonance imaging (post-irradiation verification):

MRI can not be used to verify the treatment delivered during or just after the delivery, but makes it possible to see changes in the tissues as a consequence of the irradiation, one or two weeks after. MRI-visible changes in the tissues enable the observation of the delivered dose in vivo. However, it was shown that visual analysis of MRI images only was not sufficient to detect the distal dose edge after proton therapy treatment of the spine [Gensheimer et al.,2010]. Different methods are still being investigated.

The use of range probes or particle radiography makes it possible to check before irradiation if the energy loss of the particles used as probes corresponds to that predicted by the image of the treatment plan. Range prediction inaccuracies and potential

patient mis-alignment or anatomical changes could be detected, thus reducing the range uncertainty. This technique does not, however, enable verification of the delivered treatment.

To be able to check in real time if the dose delivered during irradiation corresponds to that planned would be ideal. However, the point dose measurement is the only method currently available that can give this information before the treatment is complete. The major drawback is that it is invasive, and limited in the number of measurement points. As far as the non-invasive methods are concerned, prompt gamma imaging has the advantage that the time-scale of the emission is small enough not to be affected by biological washout processes. The production rate is higher than for PET.

However, the potentially lower detection efficiency or resolution of a SPECT imager or Compton camera compared to a PET imager may result in an unfavourable trade-off.

Moreover, prompt gamma monitoring is, like interaction vertex imaging, still in an rather early stage of research and development, whereas off-line PET has already been used extensively in routine [Parodi,2012].