University of Groningen
Towards an optimal clinical protocol for the treatment of moving targets with pencil beam scanned proton therapy
Ribeiro, Cássia O.
DOI:
10.33612/diss.126443635
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2020
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Ribeiro, C. O. (2020). Towards an optimal clinical protocol for the treatment of moving targets with pencil beam scanned proton therapy. University of Groningen. https://doi.org/10.33612/diss.126443635
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INTRODUCTION
In the 21
stcentury, cancer is estimated to rank as the leading cause of death globally [1]. Radiotherapy, next to surgery and chemotherapy, is one of the most common treatment mo- dalities for cancer [2]. The principle of radiotherapy is to use ionising radiation to kill the cancer cells, while minimising the dose exposure to healthy tissue adjacent to the tumour.
The focus in this thesis is on moving targets, such as tu- mours in the thorax (e.g. lung and oesophagus) and tumours in the abdomen region (e.g. liver) [3,4]. Small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) are the two main types of lung cancer. The most frequent histological type in NSCLC is adenocarcinoma [5]. SCLC encompasses only about 20 % of all lung cancer cases, and this type of lung cancer shows a decrease in the incidence rates over time [6]. Worldwide, lung cancer is the leading cause of cancer incidence and death, with 2.1 million new lung cancer cases in 2018 and representing 18.4 % of the cancer deaths [1]. According to global statistics from 2018, oesophageal cancer ranks seventh in terms of incidence (572 000 new cases) and sixth in mortality overall (509 000 deaths) [1].
Liver cancer is predicted to be the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide in 2018, with about 841 000 new cases and 782 000 deaths annually [1].
Within photon radiotherapy, intensity-modulated radia- tion therapy (IMRT) can deliver highly conformal dose dis- tributions, while sparing neighbouring critical organs-at-risk (OARs) [7]. Volumetric modulated arc therapy (VMAT) can be regarded as an extension of IMRT, which while providing at least similar target coverage and OARs dose sparing than IMRT, is capable of reducing the beam-on time and the required monitor units [8–12]. In terms of treatment related toxicities, even more clinical benefits are anticipated with proton radiotherapy for many cancer indications [13–16].
Treatment delivery strategies within proton therapy, such
as pencil beam scanned proton therapy (PBS-PT), with
General introduction
optimisation strategies such as intensity-modulated proton therapy (IMPT), are able to improve even more the dose conformity to the target, while reducing the dose to the OARs [17–20].
The continuous technological developments and emer- gence of highly conformal radiotherapy techniques are substantial for the improvement of thoracic and abdominal cancer treatments, due to their anatomic location and the critical OARs surrounding the tumour (lungs, heart, and liver). However, this increase in precision of radiotherapy techniques becomes a challenge due to the need of deal- ing with the inter- and intra- fractional motion for these patients (mainly due to respiration), and its associated potential disturbing effects on the planned dose distri- bution [21]. To guarantee target coverage for radiotherapy of moving targets, expansions in planning margins are then required, inevitably compromising healthy tissue dose sparing. Particularly for PBS-PT for moving targets, the current concern of plan robustness as a result of motion within the treatment delivery, hampers its wide clinical implementation worldwide.
The ultimate aim of this thesis is to overcome the current challenges and move forward to the development of an optimal clinical protocol, so that thoracic and abdominal indications would be able to benefit from the advantages of PBS-PT. For this purpose, an assessment of the possible dosimetric impacts of PBS-PT for an extended number of lung, oesophagus, and liver cancer patients is conducted.
PROTON THERAPY
Instead of using X-rays (photons) as in conventional radio- therapy, proton therapy uses charged particles (protons).
As can be seen by the shape of the beam depth-dose data
(Fig. 1), protons have a low entrance dose and release most
of their energy at the so-called Bragg peak (maximum dose
point), having then a finite range (sharp distal dose fall-off)
that depends on their initial energy and the density of the traversed material [22]. Due to these physical properties, the potential advantages of proton vs. photon dose distributions become clear. In proton therapy technique is possible to deliver a high tumour dose, and at the same time, superior healthy tissue sparing than with conventional radiotherapy can be achieved [23].
PBS-PT is the proton therapy modality we have available at our proton facility in the University Medical Center Gron- ingen (UMCG) (the UMCG Proton Therapy Center [GPTC]), which is a Proteus
®Plus (PPlus) machine (IBA, Louvain-la- Neuve, Belgium) (Fig. 2). In this technique, thin monoen- ergetic proton beams are deflected by scanning magnets to create individually weighted pencil beams with various energies to scan (or ‘paint’) the target volume in depth.
When prescribing and delivering dose, we rely on the dose distributions calculated and optimised by a treatment planning system (TPS) [23]. In order to combine fields in a PBS-PT treatment plan, two main approaches can be used:
single-field uniform dose (SFUD) and IMPT. In SFUD, since
Fig. 1. Photon vs. proton beam depth-dose profiles (adapted from Mohan et al. [24]). The green curve depicts a typical 15 MV photon beam. The red curve shows a monoenergetic proton beam. The blue curve is obtained by electromechanically spreading the monoener- getic proton beam laterally and longitudinally. The top flat portion of the blue curve is called the spread-out Bragg peak.General introduction Fig. 2. Schematic representation of the components of the beam delivery system equipment in the PBS-PT treatment mode for an IBA PPlus gantry based system (adapted from [25–27]).
each field is optimised independently, there is the assurance of homogeneous dose distributions delivered by the individ- ual fields. Conversely, in IMPT (proton equivalent of IMRT), all fields are simultaneously optimised [28]. For IMPT, the planning target volume (PTV) concept of photon therapy can be replaced by a clinical target volume (CTV) robust optimisation technique, which incorporates setup and range uncertainties into the planning (nominal) dose distribution (i.e. error-free dose distribution). This CTV based optimisa- tion process is known by 3D robust optimisation [29].
PBS-PT has the advantage, when compared to passively scattered proton therapy, of being able to deliver a more conformal dose distribution. However, this greater precision of PBS-PT (due to the sharp gradients of pencil beams), and especially IMPT, comes with the cost of higher sensitivity to any variations from the planning situation [30,31].
3D medical imaging for treatment preparation
As for photon therapy, the treatment preparation in proton therapy is based on acquired computed tomography (CT) images of each patient in treatment position. The CT is used to delineate the planning volumes and calculate the nominal dose distribution in the TPS. For patient alignment at the treatment table, on-board cone beam computed tomography (CBCT) systems are now integrated in many new proton therapy gantries [32]. While rotating around the patient, the CBCT acquires planar images, which can be reconstructed into volumetric images [33].
Deformable image registration (DIR)
DIR is required for several processes in radiotherapy [34,35].
DIR is the process of finding a point-to-point correspon-
dence map between positions in one medical scan and posi-
tions in another scan from the same patient. In other words,
DIR is used to estimate the patient’s deformable motion
present between two images. There is always a fixed image
and a moving image in a DIR process. To perform a DIR,
the fixed and the moving images are pre-defined and then
General introduction
the physical result is an estimated deformation vector field (DVF) containing vectors for each voxel, pointing from the fixed image towards the moving image. DIR is required for different purposes throughout the treatment planning work- flow, such as contour propagation, or dose warping, from the fixed (reference) image to the moving image.
It is well-known that DIR is an ill-posed problem intrinsi- cally. When applying DIR, the resulted estimated DVFs can be inaccurate. Additionally, another problem is that differ- ent DIR algorithms applied to the same image pair provide estimated DVFs that can remarkably differ from each other.
Therefore, the quality of different DIR algorithms needs to be carefully assessed [36].
3D dose evaluation
To ensure that the CTV receives adequate dose and to limit the dose to critical organs-at-risk (OARs) despite treatment uncertainties, robust optimisation [29] and robustness eval- uation [37] are used in this work. Both robust optimisation and robustness evaluation follow a probabilistic treatment planning approach (scenario based). In photon therapy in- stead, a PTV margin approach is standardly used [38,39].
In the PTV method, the treatment uncertainties for each indication are quantified to create margin sizes, ensuring that for 90 % of the patient population, the CTV receives at least 95 % of the prescribed dose [38]. The probabilistic approach used here incorporates the dosimetric uncertainties of a certain scenario into the dose, using directly the CTV for plan optimisation and evaluation purposes.
The PTV method is not adequate for proton therapy due to the need to consider range errors. The robustly opti- mised plans generated in our commercial TPS RayStation (RaySearch Laboratories, Stockholm, Sweden) are afterwards robustly evaluated. This is necessary to guarantee adequate target coverage and minimal OARs dose under all uncer- tainty scenarios [37].
The increased sensitivity of proton therapy to geomet-
ric accuracy requires, besides accurate patient positioning,
recurrent volumetric imaging throughout the course of treat- ment [32]. To take into account patient inter-fractional an- atomic changes, verification (repeated) CTs can be acquired during treatment. As an alternative to routine CT imaging, on-board CBCT images can also be used. In comparison with repeated CT, CBCT provides insufficient image quality for direct and accurate dose calculations [40,41]. However, CBCT has the advantage of enabling daily monitoring of the patient’s anatomy prior to the treatment fraction.
PROTON THERAPY FOR MOVING TARGETS
When using a highly precise treatment technique such as PBS-PT for moving targets, several disturbing effects can occur within the treatment delivery, deteriorating the actual delivered dose distribution. To be able to evaluate the possi- ble uncertainties in the PBS-PT planned dose distributions for moving targets, extensive 4D robustness evaluations, including 4D dose calculations, are compulsory.
4D medical imaging
For the treatment preparation of moving targets with PBS-PT, time-resolved 3D (4D) imaging is necessary for quantifying the motion characteristics. The 4DCT data set contains sev- eral 3DCTs (or phases), each giving information of the patient anatomy at a certain moment during an averaged breathing cycle. A 4DCT consists of snapshot representations of the breathing motion of the patient. For the reconstruction of a 4DCT, it is assumed that the breathing pattern is regular, which in reality is rarely true.
4DCBCT reconstruction [42,43] is used for 4D image guid-
ance for both thoracic and abdominal cancer patients treated
with photon therapy [44], and its feasibility has also been
investigated for proton therapy [45]. Furthermore, 4DMRI
arises as a viable non-additional imaging dose solution, since
it provides better soft tissue contrast, while limiting dose
to the patient [46].
General introduction
Interplay effects
When employing PBS-PT for the treatment of moving tar- gets, interplay effects can occur. Interplay effects happen due to the relative motion between the target and the scanned proton beam delivery. The CTV motion will result in a mis- positioning of the planned pencil beams. This will result in dose in-homogeneities, producing cold or hot spots within the target (Fig. 3). Although interplay effects may lead to pro- nounced deteriorations of the dose distribution for a single fraction, these are potentially smoothed out over a fraction- ated treatment course [47,48].
4D dose evaluation
For the treatment of moving targets in free breathing with PBS-PT, dosimetric disturbances caused by motion (target miss, dose blurring, and the interplay effects) need to be con- sidered by a 4D dose calculation (accumulation) algorithm [47–49]. A 4D dose calculation simulates the dynamics of the pencil beam scanning, thus being crucial to evaluate the deterioration of the delivered dose distribution due to the interplay effects. Both a 4DCT and DIR application in 4D images are necessary to perform a 4D dose calculation for a moving indication (Fig. 4).
There are at least two different ways of performing a 4D
dose calculation. The most standard one (and usually the
one available in most TPSs) consists in performing multiple
calculations of the corresponding dose on the particular
phase of the 4DCT in which was delivered [50–53]. Then
these doses are subsequently warped back to a reference
phase where they will be accumulated (or summed). Another
developed and experimentally validated 4D dose calculation
engine for PBS-PT involves deforming the dose grid (using
DIR) as a function of time [54]. After performing a 4D dose
calculation, we obtain a 4D dose distribution in a reference
CT, which represents the actual delivered dose considering
possible interplay effects. Within any 4D dose calculation,
the intrinsic inaccuracies of DIR can directly prompt dis-
tinguishable differences in dose distribution, which would
consequently influence any further dosimetric analysis and clinical decision [55].
Motion mitigation techniques
There are several ways to reduce the impact of motion effects in the delivered dose distributions: beam gating or tracking, rescanning, breath-hold, abdominal compression, increase in
Fig. 3. A: Nominal dose distribution and B: fraction dose distribu- tion affected by interplay effects for a sample lung cancer patient planned with PBS-PT.Fig. 4. Workflow for a 4D dose calculation algorithm.
General introduction
spot size, 4D robust optimisation, among others [56]. Motion mitigation techniques explored in this thesis are rescanning, breath-hold, and 4D robust optimisation.
Rescanning consists in delivering the planned proton spots multiple times within each field [57]. There are sev- eral flavours of rescanning. The rescanning type that can be applied in a PBS-PT PPlus machine, for instance, is called scaled (controlled) [58]. Scaled rescanning can be done using either a layered or a volumetric approach [59]. 4D robust optimisation has been introduced and suggested to moderate respiratory-induced dosimetric perturbations [60–63]. This IMPT treatment planning approach includes several 4DCT phases during the optimisation process. To mitigate inter- and intra-fractional motion for PBS-PT of moving targets within the treatment delivery, deep inspiration breath-hold (DIBH) gating is also currently clinically implemented [64].
THESIS OUTLINE
Towards an optimal clinical PBS-PT planning protocol for moving targets, the possible dosimetric uncertainties (with and without the application of motion mitigation techniques) are thoroughly investigated for thoracic and abdominal tu- mours in the six remaining chapters of this thesis.
Chapter 2 focuses on incorporating all the possible disturb- ing effects in a treatment course of PBS-PT for moving targets in a dedicated tool for 4D evaluation (the 4D robustness eval- uation method [4DREM]). The 4DREM was implemented using the scripting capabilities of our TPS (RayStation) and was applied to exemplary IMPT plans of two thoracic indi- cations to illustrate its capability.
Chapter 3 presents an exhaustive evaluation of uncertain-
ties occurring when using different DIR algorithms. The
geometric error as well as the dosimetric error (the latter
one provided by 4D dose calculations), were analysed and
quantified for a comprehensive 4DCT data set of liver cancer
patients treated with SFUD.
In Chapter 4, the 4DREM (Chapter 2) is used to evaluate thoroughly designed planning protocols (using 3D or 4D robust optimisation approaches and also the DIR error infor- mation from Chapter 3) for a representative number of lung and oesophagus indications. Extensive patient 4DCT images (data acquired as part of a clinical trial) and treatment plan delivery information were used in this chapter. As a result of this study, an optimal and efficient clinical protocol for the first thoracic patients treated at our proton facility was established.
In Chapter 5, the 4DREM (Chapter 2) assesses two dif- ferent beam delivery configurations, provided by different PBS-PT implementations at Proteus
®One and Proteus
®Plus, respectively. This chapter uses NSCLC patient information and machine specific data.
Chapter 6 arouse as a follow-up of Chapter 3. This chapter consists in an evaluation of the provided DIR ambiguity for inter-fractional variations (i.e. differences in dose warping and accumulation provided by several different DIR algo- rithms). NSCLC patients under DIBH conditions planned with IMPT are included in this study.
In the last chapter of this thesis (Chapter 7), all the findings
and conclusions are summarised and future perspectives
are discussed.
General introduction
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