University of Groningen
Real-time positron emission tomography for range verification of particle radiotherapy
Ozoemelam, Ikechi
DOI:
10.33612/diss.133158935
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Publication date: 2020
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Ozoemelam, I. (2020). Real-time positron emission tomography for range verification of particle radiotherapy. University of Groningen. https://doi.org/10.33612/diss.133158935
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1
Chapter 1
Introduction
1.1 Rationale for particle therapy
Cancer is a leading cause of death worldwide and poses considerable public health concerns. In Europe, the change in population composition is expected to result in an increase in the cancer burden from the 3.4 million diagnosed cases recorded in 2012 to 4 million new cancer cases by 2025 (Borras et al 2016). Radiotherapy plays a role in the multidisciplinary approaches for treating cancers. It is estimated that, regardless of the region in the world, approximately 50% of cancer patients have indications for which treatment with radiation in either stand-alone treatment regimen or as a combinational therapy with surgery and/or chemotherapy is recommended (Delaney et al 2005, Barton et
al 2014, Atun et al 2015).
The application of radiation for treating cancers quickly followed the discovery of X-rays by Wilhelm Roentgen in 1895 and the discovery of radium by Marie and Pierre Curie in 1898 (Connell and Hellman, 2009). Although the nascent era of radiotherapy witnessed the cure of some superficial tumours using the external beam delivery technique, treatment of deep-seated tumours was largely unsuccessful owing to limitations attributed to the low energies delivered by the available X-ray tubes and the realization that applying higher radiation doses, to achieve cure, results in damage to normal tissues. The recognition of the potential of radiation to damage normal tissues has since been captured in the principles of curative radiotherapy, whereby a tumoricidal dose of radiation is accurately conformed to the tumour volume while ensuring that there is maximal sparing of normal tissue.
Over the years, weighty advancements in treatment techniques and technology, guided by the principles of increased conformity and maximum sparing of co-irradiated tissues, have paved the road towards contemporary radiotherapy (Thariat et al 2013). Some of these advancements include technological advancements in photon (X-ray and γ-rays) production and delivery, improvements in imaging and computer-based treatment planning (Connell and Hellman, 2009). These advancements are incorporated into modern treatment techniques such as three-dimensional conformal radiation therapy (3D-CRT), intensity modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), helical tomotherapy and image guided radiotherapy (IGRT). They have also contributed to improved experiences for patients. The use of an IMRT technique in treating prostate cancer, for example, allows the delivery of a high dose (> 80 Gy), yielding high local control rates with minimal treatment toxicities (Spratt et al 2017). The reduction in treatment toxicities as seen in this example is attributed to a careful adherence to the dose constraints in the treatment plan and the enhanced dose conformity which limits the volumes of normal tissues exposed to high radiation dose.
1.1 Rationale for particle therapy Despite the application of these modern treatment techniques and the ensuing conformal high dose distributions, there is still a substantial volume of healthy tissue exposed to low and intermediate radiation doses, leading to the exposure of the patient to a high integral dose. The high integral dose stems from the limitations imposed by the physics of the interaction of photons, neutrons and electrons with matter. Figure 1.1 shows the dose distribution of different radiotherapy beams as a function of depth in water. The differences in the dose distribution of the particles shown highlight the various interaction mechanisms of charged particles (heavy charged particles (for e.g. protons and carbon ions) and electrons) and neutral particles (photons and neutrons). Charged particles interact via closely spaced ionization and excitation of atoms, losing energy steadily till they are brought to rest at a finite range. As the energy loss is inversely proportional to the velocity of the particles, the depth dose distribution of charged particles is characterized by a low dose in the entrance channel with a prominent dose peak, known as the Bragg peak, at a precise, energy dependent depth and almost no dose beyond the range of the particles. In contrast to heavy charged particles, the lower energy electron beams (4 – 20 MeV) typically used in radiotherapy, are brought to rest relatively close to the entrance (1 – 5 cm). Furthermore, due to the large angle scattering, no Bragg peak is seen in their depth dose distribution. Thus electrons are more suited for treatment of superficial tumours. Photons and other neutral particles such as neutrons, on the other hand, do not steadily lose energy. They travel substantial distances in between their interactions with the atoms in the materials. Single interactions with the atoms can, depending on the energy and the materials traversed, lead to complete absorption or scatter with or without significant energy loss in the medium. As the attenuation of these particles follows an exponential fall-off with depth, the depth-dose distribution features an increase in dose before a peak dose close to the entrance, where secondary electron equilibrium is established, followed by an exponential reduction of dose with depth.
For clinical therapeutic applications in deeply seated tumours, for e.g. that shown in figure 1.1 with a thickness of about 5 cm in the beam direction and located 20 cm from the entrance, charged particles offer a clear advantage. Their finite range and the Bragg peak ensures that healthy tissues along the beam path, in front and behind the tumour, are spared from a significant fraction of the total dose. Thus, charged particles offer the highest degree of conformity and enable the realization of a lower integral dose distribution (Paganetti, 2012). In addition to the Bragg peak, protons, down to a certain energy within the clinically useful energy range, and other heavier charged particles show less lateral scattering with depth in comparison to photons. Thus, heavy charged particles offer improved spatial dose selectivity which enhances the sparing of co-irradiated organs at risk (OAR). An additional boost in therapeutic effect, through a higher biological effectiveness, is observed with heavy ion (Z > 1) treatment. Particularly, there is an enhancement of the relative biological effectiveness (RBE) (Barendsen et al, 1963; Kraft, 1987 as cited in Krämer et al, 2003) and a reduction of the oxygen enhancement ratio (ratio of dose producing similar biological effect in hypoxic and oxic conditions) (Furusawa et al, 2000). The additional therapeutic enhancement due to the RBE is relevant to the extent that the RBE vs energy is peaked within the tumour volume.
1 Introduction
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Figure 1.1: Depth dose distribution of different radiation beams in water. The tumour volume considered is indicated in colour. Figure is adapted from Amaldi and Kraft (2005). Reprinted with permission.
1.2 Emerging interest in helium therapy
The first proposal to use heavy charged particles in radiation therapy dates back to 1946 and is described in Robert Wilson’s seminal paper on “Radiological use of fast protons” (Wilson, 1946). The next few years after this proposal were dedicated to understanding the biological effects of charged particles on rodents (Tobias et al, 1952 and 1954) and an upgrade of the 184-inch synchrocyclotron (Reimers et al, 1989), paving the way for the first treatments with protons in 1954 (Tobias et al 1958) and helium ions in 1955 (Cleveland et al, 1960) at the Lawrence Berkeley Laboratory (LBL). Developments in accelerator designs, resulting in the merging of LBL’s Heavy Ion Linear Accelerator (HILAC) and the Bevatron proton accelerator to form the BEVALAC, lead to the use of carbon, neon, silicon, and argon beams in clinical trials between 1975 and 1992 (Lillis-Hearne and Castro, 1995). Towards present-day treatment facilities, the history of particle therapy witnessed a transition from nuclear physics laboratories to the first dedicated therapy center at the Harvard Cyclotron laboratory in 1961 and following resolution of the technical challenges and cost, to hospital-based centers starting with the Clatterbridge Cancer center, United Kingdom in 1989 and the Loma Linda center in the United States in 1990 (PTCOG, 2020a).
Today, patients are treated with protons and carbon ion beams in 90 and 11 dedicated treatment facilities worldwide respectively (PTCOG, 2020b). In the Netherlands, three facilities are currently treating patients with protons. These facilities are the UMCG Proton Therapy Center in Groningen, HollandPTC in Delft and ZON-PTC in Maastricht. However, protons and carbon are not optimal for treatment in all circumstances, especially when there are concerns about risks to normal tissue. Protons, on the one hand, show a higher lateral scattering than heavier ions of the same range, which also exceeds that of photon beams beyond a penetration depth of 7 cm (Kraft, 2000). Carbon ions, on the other hand, despite showing reduced lateral scattering as well
1.2 Emerging interest in helium therapy as higher biological effectiveness than protons, may not represent an ideal ion for all treatments (Remmes et al, 2011). The spatially variable RBE of carbon and its associated dependencies results in an increased uncertainty in the parameters for biological optimization of therapy (Tommasino et al, 2015). In addition to the RBE related problems of carbon ions, the fragmentation tail beyond the Bragg peak distorts the much desired steep distal dose gradients. Therefore, concerns about the suitability of both protons and carbon ions have triggered a search for the optimum ion for treating cancer with enhanced capability of high dose conformation to the tumour target and sparing of OAR (Grün et al, 2015; Tommasino et al, 2015; Durante and Paganetti, 2016; Kempe et al, 2007).
This search may not result in an all-purpose optimum ion considering that the quality of particle therapy relies on the interplay of physical and biological properties of the ions as well as the configuration of the treatment field (Grün et al, 2015). This means that a particular ion with ideal physical properties may show deficiencies when considered in the light of its biological effectiveness and suitability to the treatment field configuration. The appeal of helium ions is based on a “middle-ground” advantage over the commonly used proton and carbon ion beams. From a physical perspective, helium ion beams show a smaller penumbra and less range straggling than proton beams (See e.g. Ströbele et al 2012 and Durante and Paganetti 2016). Thus, compared to proton beams, the physical properties of helium ions ensure higher conformity of dose distributions to the target (Ströbele et al 2012 and Kaplan et al 1994). Although carbon ions, due to their heavier mass, allow a still smaller penumbra than helium beams, the presence of a fragmentation tail in their depth-dose profile deteriorates the distal dose gradient of the Bragg peak (Sihver et al 1998). Since helium ions undergo less fragmentation than carbon ions (Rovituso et al 2017), they provide a good alternative for preservation of a sharp distal fall-off to negligible dose. When compared with carbon ions under biological consideration, they show a low linear energy transfer (LET) in the entrance channel and a reduced sensitivity to RBE uncertainty.
Historically, treatment with helium beams was performed only at Lawrence Berkeley Laboratory (LBL) just after the first treatments with proton beams and during the BEVALAC era (1975-1992) (Raju, 1996). In these periods, around 2000 patients were treated with helium beams for diseases including systemic disorders - controlled via pituitary irradiation, uveal melanoma, arteriovenous malformations (AVM), and large-field radiotherapy. Local control rates greater than 60%, depending on the treatment sites, were obtained for large-field radiotherapy with helium beams. Despite the impressive results obtained within this period, treatment with helium beams and other heavy ions was discontinued after the withdrawal of operational funding for the nuclear physics program at the Berkeley laboratory. Given the attractive dosimetric properties of helium ions, the interest in the utilization of helium ions in hadron therapy has recently increased again (Durante and Paganetti 2016, Tommasino et al 2015, Kempe et al 2006, Knäusl et al 2016, Grün et al 2015), with implementation planned for centres such as the Heidelberg Ion Beam Therapy Center (HIT) (Krämer et al 2016, Mairani et al 2016 and Tessonnier et
al 2018). Considering the enhanced reduction of low and intermediate dose exposure of
surrounding normal tissues, in silico treatment planning studies have demonstrated potential benefits from helium therapy for paediatric patients (Knäusl et al, 2016). A further in silico study using a dedicated treatment planning system by Tessonnier et al (2018) compared the dose distributions obtained for irradiations with protons and helium ions on 4 patients with brain and ocular meningiomas. The treatment plans were optimized taking into account a phenomenologically determined variable RBE approach for both ions (Mairani et al 2016 and 2017) as well as an RBE of 1.1 for protons. An evaluation of the dose volume histograms (DVH), which illustrates the volume of target structures receiving a given dose level, shows that although an almost similar planning
1 Introduction
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target volume (PTV) coverage can be obtained with both beams, helium ions, in almost all evaluated cases, show a smaller dose exposure to critical structures (Figure 1.2). Indeed, these results underscore the superior capability of helium ions to spare surrounding normal tissues.
Figure 1.2: Dose volume histograms (DVH) of the treatment plans for two patients. The DVH of the planning target volumes (PTV) and critical structures as indicated in the legend are shown. H and H(RBE=1.1) refer to the dose from protons with variable and fixed RBE respectively. The helium dose is represented by solid lines. The figure is adapted from Tessonnier et al (2018).
1.3 Aim and Outline of the Thesis
In practice, realization of the superior spatial dose selectivity of charged particles is hampered by uncertainties in the prediction of the particle range. Because these particles stop in the body, dose delivery verification techniques used in photon therapy are not applicable in particle radiotherapy. Secondary emissions resulting from the interactions of these charged particles with the tissues traversed provide surrogate signals of the particle trajectory and thus can be used to monitor the accuracy of dose delivery. One type of secondary emission is the annihilation photons. These photons are emitted during the decay of beam-induced positron emitters.
A number of investigations to assess the feasibility and in some cases clinical implementation of dose delivery verification using PET in treatments with protons (For e.g. Maccabee et al, 1969, Paans and Schippers 1993, Ferrero et al 2018), lithium (Priegnitz
1.3 Aim and Outline of the Thesis
et al, 2008), carbon (For e,g. Enghardt et al 2004) and oxygen (For e.g. Bennett et al 1975,
Sommerer et al, 2009) ions have been performed. Considering the growing interest in helium beam therapy and the fact that, like other ions, helium beams are also subject to range uncertainty, the monitoring of helium beam therapy can provide additional information on the accuracy of dose delivery. In contrast to other ions, there is a paucity of studies on PET monitoring of helium beam therapy. Early investigations into verification of a helium beam (Maccabee et al, 1969) show that positron emitting isotopes (for e.g. 11C (T1/2 =20.3 m), 15O (T1/2 =2.05 m)) are produced on carbon-rich materials
and soft tissues, and could potentially indicate the range of the beams, provided that technical limitations of the prevalent imaging hardware could be resolved. The limitations experienced at that time were related to the unavailability of on-line detection systems which allow the detection of short-lived nuclides and reduce biological washout of the nuclides; signal deterioration by background radiation; poor detector resolution and sensitivity; absence of computing power for image reconstruction and Monte Carlo simulations; absence of cross section measurements; absence of CT imaging and absence of treatment planning systems. Several decades after this investigation, most of these limitations have received significant attention and detection systems for on-line monitoring with improved detector resolution and sensitivity (see section 2.2.1.1) and methods for suppressing background radiation (Crespo et al, 2005) have been developed. A more recent investigation into the feasibility of in-beam PET for therapeutic 3He
beams (Fiedler et al, 2005) provides a quantitative estimation of the production rates of the relevant radionuclides mentioned in (Maccabee et al, 1969), and highlights significant reduction in measured activity levels, especially in oxygen-rich materials, when changing from an in-beam detection to an off-line method.
Though these studies, including those with protons, identified short-lived nuclides, for example 15O, Dendooven et al (2015 and 2019) show that positron emitting
nuclides with short half-lives are produced during proton irradiation. One such short-lived positron emitter is 12N with a half-life of 11 ms. By imaging this positron emitter
and other short-lived positron emitters, faster feedback on the accuracy of the treatment can be realized. The provision of feedback at a timescale comparable to about five times
12N half-lives will provide a trigger for implementation of corrective actions such as daily
adaptive therapy (Albertini et al 2019) when deviations from the treatment plan are observed during imaging. This thesis is therefore aimed at investigating the production of these short-lived positron emitters during helium radiotherapy and also providing information on the feasibility of near real-time feedback on dose delivery for proton and helium beam irradiations when imaging these nuclides. Through a collaboration with Siemens, a scanner suitable for imaging of short-lived positron emitters has been realized and thus allows studies in clinical conditions.
In chapter 2, the rationale and the principles of currently investigated in vivo range verification techniques are discussed. Furthermore, the practical implementation of PET-based techniques including the imaging of short-lived positron emitters are reviewed.
In chapter 3, the yields of relevant short-lived positron emitters produced in 3He
and 4He irradiations are presented to provide a first line assessment of the feasibility of
imaging short-lived positron emitters for monitoring helium beam radiotherapy. In chapter 4 and 5, the performance of near real-time range verification on the basis of imaging very short-lived positron emitters for monitoring helium and proton therapy is presented respectively. A more comprehensive description of the scanner system is provided in chapter 5.
A summary of the results and an outlook to future improvements and implementation strategies are given in chapter 6.
1 Introduction
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