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Proton Therapy for Prostate Cancer: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Darren M. C. Poon.

Proton therapy (PT) was first proposed by Robert R Wilson in 1946 because of the unique dosimetric property of proton beams known as the Bragg peak. In theory, a proton beam traversing a medium deposits a relatively small amount of radiation before it reaches the Bragg peak, and no radiation beyond it. The depth of the Bragg peak in the medium is determined by the energy of the protons. The dosimetric advantages of proton therapy (PT) treatment plans are demonstrably superior to photon-based external beam radiotherapy (EBRT) for localized prostate cancer, but the reported clinical outcomes are similar.

  • prostate
  • proton therapy
  • magnetic resonance imaging

1. Introduction

Proton therapy (PT) was first proposed by Robert R Wilson in 1946 [1] because of the unique dosimetric property of proton beams known as the Bragg peak. In theory, a proton beam traversing a medium deposits a relatively small amount of radiation before it reaches the Bragg peak, and no radiation beyond it. The depth of the Bragg peak in the medium is determined by the energy of the protons. By irradiating the medium with proton beams of different energies, a range of spread-out Bragg peaks (SOBPs) can be positioned at a pre-defined depth of the medium, as determined by the range of the beam energies. PT takes advantage of this dosimetric property to deliver a conformal therapeutic dose of radiation to the patient by positioning the SOBP of a proton beam, of appropriate field size and range of beam energies, to precisely cover the tumor volume without damaging the normal surrounding tissue. Treatment planning studies have demonstrated superior dosimetric benefits of PT plans compared with plans for conventional external beam radiotherapy (EBRT), such as intensity-modulated radiotherapy (IMRT) and volumetric modulated RapidArc therapy (VMAT) [2,3][2][3].

Treatment of patients with PT began around 1954 [4], but progress in the development of this modality has been slow due to numerous technical hurdles. Challenges for PT pioneers included the immaturity of the PT accelerator and dose-delivery systems in handling complex treatments, lack of knowledge on dosimetric properties such as the relative biological effectiveness (RBE) of proton beams, and lack of interest and incentive in the manufacturing industry to invest in developments of PT equipment [5]. This situation changed when the US Food and Drug Administration approved the clinical use of PT in 1988 [6], and the world’s first hospital-based PT system was established, at Loma Linda University Medical Center in California, in 1990. Since then, the number of hospital-based PT facilities has increased exponentially, with 104 PT treatment facilities operating globally by the end of 2021 and many more under construction and planning [7]. By the end of 2020, over 250,000 patients had been treated with PT worldwide [7]. Although prostate cancer has been one of the main treatment sites in PT, the practice has been controversial because of a lack of clinical evidence to justify the treatment cost [8]. Reported clinical outcomes in both local control and toxicity of PT for prostate cancer are similar to those for EBRT. The theoretical dosimetric benefits of PT have not translated to greater clinical benefits than EBRT for the prostate, as they have in other diseases sites, including pediatric malignancies of the central nervous system, large liver cancers, ocular melanomas, chordomas and chondrosarcomas [9,10][9][10]. The far-below-expected performance of PT in treatment outcomes in prostate cancer has been attributed to two main causes. First, the results of the randomized controlled Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) trial [11] point to inadequate dose prescription, particularly in patients with high-risk disease, indicative of a dose–response characteristic of radiotherapy (RT) of the prostate. Second, improper dose delivery due to large uncertainties associated with the individual processes involved in PT and pre-treatment workflow may compromise the dose conformity of PT treatment, as demonstrated by robust planning [12]. The objectives of this review are twofold: (1) examine the underlying reasons behind the disappointing clinical outcomes in PT treatment of prostate cancer; and (2) investigate new PT technologies and innovative work procedures that are being implemented, how they may improve the accuracy and quality of PT treatment and facilitate a reduction in treatment margins, and the possibility of dose escalation to the appropriate level.

2. Potential Benefits of PT and Reported Clinical Outcomes of Prostate Treatments

Given the different beam characteristics of protons and photons, a modulated proton beam confines dose deposition to the target region, with a rapid depth- and lateral-dose fall-off favoring normal tissue sparing and target dose escalation. Both passive scattering [13,14][13][14] and pencil beam scanning [2,15][2][15] PT reduced the mean dose and percentage of volume receiving low dose in the rectum and bladder compared with IMRT. In the prostate, PT maintained dose coverage, demonstrating superior dose conformity over IMRT. In most circumstances, a simple bilateral proton beam is employed for localized prostate cancer. Other arrangements, such as anterior–posterior or anterior–oblique beams may be used in patients with a hip prosthesis or previously irradiated hip [16,17,18][16][17][18]. Nevertheless, PT has consistently been shown to have a smaller irradiated volume of normal tissue and lower integral non-target dose [14[14][15],15], as illustrated in Figure 1. A systematic review showed that the risk of radiation-induced second primary cancer appears to be small (range, 1 in 290 to 1 in 220 over all durations of follow-up), but does increase over time [19]. As prostate cancer survival improves, the risk of radiation-induced second malignancies becomes more relevant [20].
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Figure 1. Integral dose comparison of volumetric modulated RapidArc therapy (VMAT)-full rotation (A) and photon therapy (PT)-bilateral (B) in prostate treatment plans. The most significant differences were in the 10% and 30% isodose distributions of the 78-Gy prescription.
The theoretical dosimetric advantages of PT have not borne fruit clinically. Dose prescription might be a factor in the suboptimal clinical outcomes of PT. Numerous randomized trials have compared various dose prescriptions (range, 64 to 86.4 Gy) of 3D-conformal RT or IMRT, in which higher dose prescription demonstrated superior biochemical tumor control and decreased the risk of distant metastases for prostate cancer in different risk groups [30,31,32,33,34,35,36][21][22][23][24][25][26][27]. In the ASCENDE-RT trial, the low-dose rate brachytherapy (LDR-PB) boost arm received an iodine-125 implant prescribed at the minimum peripheral dose of 115 Gy, while the dose-escalation external beam (DE-EBRT) boost arm received an additional 32 Gy (total, 78 Gy) in 16 fractions. The LDR-PB boost patients were twice as likely to be free of biochemical failure at a median follow-up of 6.5 years [37][28].
Another factor limiting the potential of PT could be discrepancies between planned doses and actual doses delivered to patients. Major contributors to such discrepancies include uncertainties involved in the treatment planning and delivery processes, as well as technological limitations in PT treatment systems. Proton beams manifest an intrinsic range uncertainty due to range straggling, in which the absolute straggling width increases with energy. Water equivalent thickness is a one-dimensional range estimate in a heterogeneous medium. Monte Carlo (MC)-based studies have demonstrated that not only is the range related to water equivalent thickness, but it is also sensitive to the geometry and position of tissue density variation relative to the depth of the Bragg peak [38,39,40,41,42,43][29][30][31][32][33][34].
The RBE of PT has typically been taken as a spatially invariant value of 1.1, regardless of clinical endpoint [38][29]. However, dose- and depth-dependence of RBE has been demonstrated in which the RBE values in the distal edge rose to 1.21 [53,54][35][36]. A wide RBE range was reported in low α/β biological systems, with RBE values often above 1.1 within the SOBP linear energy transfer (LET) range, compared with the lower RBE values of high α/β systems (below 1.1). Dose per fraction was also reported to have an impact on RBE for low α/β biological systems [55][37]. Based on existing in vitro and in vivo studies, the RBE uncertainty in normal tissue is higher (compared to the nominal value of 1.1), potentially causing unexpected complications and toxicity.

3. Opportunities for Improvement with New Technologies and Innovative Techniques

For decades, PT treatment systems with double scattering or a wobbling beam with brass aperture collimation and compensator have been used to treat prostate cancer. Large treatment margins of up to 10 mm or more were used in “large field” conventional PT techniques [50[38][39],56], and contributed to critical organ toxicity [57][40]. Most of the reported clinical data were based on treatments delivered with this large field technique. With the recent commercial availability of the latest generation of PT technologies, clinical implementation of new techniques such as intensity modulated proton therapy (IMPT) can now be realized. IMPT is capable of delivering treatment with superior dose conformity, which can potentially provide better protection of critical organs, as illustrated by the dose displays of two treatment plans shown in Figure 2. In principle, a reduction in the regions of critical organs that are exposed to high radiation doses will help reduce related toxicity [15]. In reality, dose conformity of IMPT treatment plans may not always be reproducible in a patient’s course of treatment because of the various uncertainties involved in treatment and pre-treatment processes.
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Figure 2. Isodose distribution comparison of two different proton therapy techniques: conventional passive scattering (A) and modern intensity-modulated proton therapy (IMPT) (B). IMPT shows improved dose conformity near critical organs.
Proton range uncertainties are mainly caused by uncertainties arising from: (1) errors introduced when deriving the mass density or SPR for PT dose calculation in treatment planning; and (2) patient positioning errors introduced during treatment setup. There is a minor dosimetric effect for range uncertainty because of the bilateral delivered beam in prostate treatment. The non-target tissue was defined as body tissue that excludes the clinical target volume (CTV) and limits the region between 1 cm superior and inferior from the CTV. Such uncertainties should be minimized before the dosimetric benefits of PT can be realized as clinical benefits in prostate treatment.
In traditional PT of prostate cancer, large margins are used to account for the two major sources of uncertainties mentioned above. Such planning strategies may compromise the dose conformity of the treatment, thereby affecting the clinical outcome. These uncertainties can now be minimized using new technologies and innovative techniques in the PT workflow, as discussed below.
  • The large uncertainties in CT HU values, and CT conversion to mass density or SPR [45,50][41][38], can now be overcome by modern CT, which can acquire mass density maps or SPR directly [59][42] from CT image reconstruction data. Mass density and SPR are less sensitive to patient scan conditions than HU [60][43], and thus have less uncertainty. With this approach, the range uncertainty could be decreased from 3.5% to 2–2.5%. There is also an increasing interest in dual energy CT (DECT) as an alternative imaging modality for PT treatment planning because of its ability to discriminate between changes in patient density and chemical composition [61][44]. SPR calculation accuracy was found to be superior, on average, for DECT relative to single energy CT (SECT). Maximum errors of 12.8% and 2.2% were found in SPR data derived from SECT imaging and DECT imaging, respectively [61][44]. Quantitatively, the maximum dose calculation error in the SECT plan was 7.8%, compared to a value of 1.4% in the DECT plan [62][45]. Additionally, a novel spectral CT imaging technique based on a dual-layer detector-based approach has been used to demonstrate improvement in SPR prediction for particle therapy treatment planning, and would minimize the beam range uncertainty, allowing for the use of reduced safety margins in patient plans [63][46].
  • Because of the inferior soft tissue contrast, orthogonal X-ray imaging systems rely on bony structures for verification of treatment position during patient setup. This type of setup technique can result in large positioning errors due to daily movement of the target and organs at risk (OARs) relative to the bony structures in the former technique. With fiducial markers implanted inside the prostate, many studies concluded that image registration by fiducial markers would reduce matching error. However, some patients may not accept marker implantation. Migration of markers with time may introduce registration errors. Such problems can now be minimized using on-board cone beam CT (CBCT). The better image quality of CBCT can provide 3D images and more information on the anatomic relationships between organs [64,65][47][48], which can be used to improve the accuracy of patient setup. Besides patient positioning, CBCT images can also provide information about inter-fractional changes in patient anatomy. In a recent study, an image-based correction method to generate pseudo-CT images from CBCT images was investigated for possible application in proton dose calculations [66][49] in adaptive PT. MRI, which has the ability to offer fast real-time imaging with high soft tissue contrast in the absence of ionizing radiation exposure [67][50], is being investigated for use in patient setup in RT. Our study using an external MRI setup room [68][51] and studies by others [69][52] indicated that patient positioning accuracy on the order of 1 mm is feasible, and is a significant reduction from that of conventional setup systems.
Improving the levels of accuracy in determining the penetration ranges of proton beams and positioning patients for treatment can facilitate better organ sparing, as illustrated in Table 1. Reduction in PT range and patient positioning uncertainties can also help improve dose conformity in PT treatment, leading to better protection of normal tissues and reduced toxicity, and facilitating the possibility of dose escalation to improve local control. The concept of in-room or integrated MRI-guided PT, although still investigational, is gaining momentum [70,71,72][53][54][55]. Integrated PT with MR gantry systems have created many engineering problems that must be overcome. Deflection of complex charge particles observed in magnetic fields changed the direction vectors, depending on the energy and heterogeneity. Optimized IMPT plans should account for the scanning beam in the complex fringe field. Compared with integrated MRI-guided PT, there is less uncertainty in a PT system combined with in-room MRI equipment. With in-room or on-line MRI-guided patient positioning, as illustrated in Figure 3 (upper panel), further improvements in accuracy and dose conformity in PT treatment are possible, and we should remember that MRI delivers superior soft-tissue contrast compared with CT (lower panel). Development of such a treatment modality will be technologically and economically challenging, and is unlikely to be accomplished in the near future.
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Figure 3. (A) Diagram of a proton therapy system with in-room magnetic resonance (MR). MR images are acquired first, with the patient lying on a robotic couch in position A, followed by relocation to position B for proton delivery, directly after image registration. (B) Comparison of computed tomography and MR images of prostate cancer.
Table 1. Comparative effects of simulated robust optimization uncertainties in proton beam range and setup on dosimetry in a prostate intensity-modulated proton therapy (IMPT) planning system.
Clinical Scenarios
Range uncertainty3.5%3.0%2.5%2.0%1.5%1.0%
Setup error5 mm3 mm2 mm1 mm1 mm
CTV, V78Gy99.9%99.6%99.1%98.4%98.8%98.5%98.8%99.3%99.6%
Rectum, V70Gy30.8%25.9%24.5%20.1%19.7%20.1%18.2%19.5%19.5%
Bladder, V70Gy35.2%30.6%29.1%25.3%24.7%24.7%24.5%23.6%23.5%
Rectum, Dmean (Gy)37.133.332.428.828.528.927.128.428.5
Bladder, Dmean (Gy)40.437.036.132.832.332.532.231.831.7
Non-target tissue, Dmean (Gy)14.613.613.312.312.112.111.711.811.7
Non-target tissue describes body tissue that excludes the clinical target volume (CTV) and limits the region between 1 cm superior and inferior from the CTV.
Significant advancements in treatment planning system (TPS) technology have also been made in recent years. The MC-based TPS dose calculation algorithm is considered to be the most accurate method, and it has been demonstrated that it could lead to a significant reduction in treatment planning margins [50,73][38][56]. However, the lengthy time required for MC-based dose calculations in the past was impractical for routine clinical treatment planning. In recent years, computer graphic processing units (GPUs) have drawn great attention due to their tremendous ability to accelerate a variety of computationally intensive tasks. A TPS running on a GPU computer makes the MC-based dose calculation algorithm in RT treatment planning feasible. TPS options based on simplified MC algorithms and GPU computers are now commercially available for routine clinical use. Because of these efforts, the calculation time of MC-based proton dose calculation has been significantly shortened. MC-based dose planning and calculation in PT is now becoming routine, helping to reduce treatment uncertainties.

4. Conclusions

Despite its dosimetric advantage, the use of PT for the treatment of prostate cancer has been limited, mainly by inadequate dose prescription and improper dose delivery. Advanced high-precision PT technologies, dose planning and beam delivery techniques have been developed and commercially available for implementation and are expected to optimize the dose conformity of PT in prostate treatment. Improvement in dose conformity can enhance local disease control, patient throughput and cost-effectiveness by allowing for implementation of dose escalation and hypofractionation treatment schemes.

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