Proton therapy for prostate cancer: current state and future perspectives

Abstract

Objective:

Localized prostate cancer can be treated with several radiotherapeutic approaches. Proton therapy (PT) can precisely target tumors, thus sparing normal tissues and reducing side-effects without sacrificing cancer control. However, PT is a costly treatment compared with conventional photon radiotherapy, which may undermine its overall efficacy. In this review, we summarize current data on the dosimetric rationale, clinical benefits, and cost of PT for prostate cancer.

Methods:

An extensive literature review of PT for prostate cancer was performed with emphasis on studies investigating dosimetric advantage, clinical outcomes, cost-effective strategies, and novel technology trends.

Results:

PT is safe, and its efficacy is comparable to that of standard photon-based therapy or brachytherapy. Data on gastrointestinal, genitourinary, and sexual function toxicity profiles are conflicting; however, PT is associated with a low risk of second cancer and has no effects on testosterone levels. Regarding cost-effectiveness, PT is suboptimal, although evolving trends in radiation delivery and construction of PT centers may help reduce the cost.

Conclusion:

PT has several advantages over conventional photon radiotherapy, and novel approaches may increase its efficacy and safety. Large prospective randomized trials comparing photon therapy with proton-based treatments are ongoing and may provide data on the differences in efficacy, toxicity profile, and quality of life between proton- and photon-based treatments for prostate cancer in the modern era.

Advances in knowledge:

PT provides excellent physical advantages and has a superior dose profile compared with X-ray radiotherapy. Further evidence from clinical trials and research studies will clarify the role of PT in the treatment of prostate cancer, and facilitate the implementation of PT in a more accessible, affordable, efficient, and safe way.

Introduction

Prostate cancer is one of the most common cancers among males in developed countries, and most patients are diagnosed with localized prostate cancer. ¹ Several curative treatment options are available for localized prostate cancer, including radical prostatectomy, radiation therapy (RT), ² and other ablative procedures. ³ RT can be classified according to the delivery technique (brachytherapy and X-ray external beam radiotherapy [EBRT]) ⁴ or according to the type of radiation used (photons, protons, ^5,6 or other charged particles). ⁷

Brachytherapy was initially the primary method for the treatment of prostate cancer. However, advances in linear accelerators and EBRT techniques have resulted in the widespread use of EBRT in the treatment of prostate cancer. Intensity-modulated radiation therapy (IMRT) has replaced three-dimensional conformal radiation therapy (3DCRT) as the standard of care. ⁸ IMRT optimizes radiation dose deposition within the target (i.e. the prostate) while sparing the adjacent normal tissues with high accuracy, ⁹ thereby increasing the therapeutic ratio. Proton therapy (PT) is another radiotherapeutic technique that increases the therapeutic ratio and minimizes normal tissue exposure to radiation by exploiting the physical properties of the proton beam itself. Several studies have demonstrated the advantages of PT in liver cancers, ^10–12 pediatric cancers, ^13–15 and tumors of the central nervous system. ^16–18 However, in prostate cancer, the use of PT remains controversial largely because of the high treatment costs involved and because of uncertainty about its true clinical benefit. ¹⁹ In this article, we review the theoretical rationale, clinical evidence, and future directions of PT for localized prostate cancer.

Characteristics of protons and theoretical benefit

EBRT typically delivers a radiation dose via high-energy photons to the treatment area. The energy deposition of photons is characterized by an exponential decrease as the beam travels through the tissue. This slow decrease in the radiation dose causes a significant dose distribution in normal tissues. By contrast, protons and heavy ions, which are relatively large and have a positive charge, have different physical properties; they release nearly all their energy at the end of their path through tissues, a characteristic called the “Bragg peak.” Therefore, the proper design of the proton beam path can maximize delivery to the target area, with practically no dose delivered beyond the target at the end of the beam path (Figure 1). This promotes dose reduction and sparing of normal tissues. ²⁰

Figure 1.

Radiation dose distribution of a single beam. When the proton beam enters the body from the right side of the patient, the proton beam will stop at the designated depth, and nearly no radiation dose is delivered to other parts of the body.

There are two main approaches to the delivery of proton beams for cancer treatment. One approach is the passive scattering technique, which delivers and shapes the beam using a series of physical scatterers, apertures, energy selection systems, range modulators, and compensators to spread the beam over the target volume. ²¹ The use of a compensator conforms the dose to the distal end of the target volume but not to the proximal end, which results in suboptimal conformality. Another approach is the active pencil beam scanning technique, which uses magnets to deflect the beam laterally and alters the proton energy to direct the beam longitudinally, thereby delivering the dose three-dimensionally over the target volume. The active scanning technique uses a dose optimization algorithm to perform intensity-modulated proton therapy (IMPT), which has better target conformality than the passive scattering technique. ²²

The distinct benefits of PT in terms of dose distribution for prostate cancer have been demonstrated in several studies. ^23–32 Although these dosimetric studies are heterogeneous, especially with regard to delivery techniques (e.g. 3D PT, IMPT) and the different treatment volumes used (with or without prophylactic pelvic irradiation), PT can reduce the dose to the urinary bladder and rectum (Table 1). However, its ability to protect the femoral head remains controversial. Studies have failed to demonstrate the advantages of PT in regions receiving a high radiation dose and have suggested that PT can be a disadvantageous approach regarding the femoral head. ^23,28,30 However, the dose delivered to the femoral head depends on the PT technique. The beam angle can be adjusted to avoid the femoral head, thus reducing the radiation dose deposited in this area. ³³ Arc PT can also reduce the delivery of radiation to the femoral head. ³⁴ Advances in PT techniques improved the dose distribution compared with that of conventional EBRT, thereby reducing the risk of acute adverse events, chronic complications, and even second primary cancer.

Table 1.

Summary of dosimetric modeling studies comparing photon vs proton-based prostate radiation plans regarding the rectum and bladder

	Mean dose to rectum		Mean dose to bladder		V70 of the rectum		V70 of the bladder
	Proton	Photon	Proton	Photon	Proton	Photon	Proton	Photon
Trofimove et al. 23	29.2 CGE	39.4 Gy	24.1 CGE	29.9 Gy	14%	15%	17%	11%
Vargas et al. 24	14.2 CGE	34.8 Gy	18.4 CGE	28.9 Gy	8%	14%	13%	15%
Chera et al. 26	16.6 CGE	40.9 Gy	21.2 CGE	42.1 Gy	12%	15%	14%	14%
Schwarz et al. 27	25 CGE	36.5 Gy	22.2 CGE	40.4 Gy	1%	1%	15%	17%
George et al. 28	19.5 CGE	28.2 Gy	12.4 CGE	16.0 Gy	4.5 ml	4.1 ml	3.4 ml	3.2 ml
Vees et al. 29	22.4 CGE	46.2 Gy	22.3 CGE	50.4 Gy	3%	15%	5%	25%
Scobioala et al. 30	9.0 CGE	17.3 Gy	13.3 CGE	17.4 Gy	1%	1%	5.3%	6%
Rana et al. 31	16.9 CGE	41.9 Gy	17.5 CGE	32.5 Gy	6.9%	12.8%	9.7%	10.5%
Dowdell et al. 25	31.7 CGE	Lower but NS	9.4 CGE	22.8 Gy	24%	19%	8%	7%
Tran et al. 32	25 CGE	24 Gy	18 CGE	22.0 Gy	15 ml	10 ml	19 ml	17 ml

CGE, cobalt gray equivalent; NS, not specified; Gy, gray; ml, milliliter.

The majority of patients with prostate cancer have excellent disease outcomes and long survival rates. ² Therefore, reducing the risk of potential complications and ensuring a good quality of life (QOL) are important objectives. Because patients with prostate cancer are expected to have a long survival, the development of a second primary malignancy after treatment for prostate cancer is an important factor affecting survival rates. PT has shown good results regarding dose distribution and sparing normal tissues from lower dose exposure. Radiotherapy is associated with high rates of second primary cancer after prostate cancer treatment. ^35,36 Therefore, reducing the total dose delivered to normal tissues, which may also reduce the risk of a second primary malignancy, is essential. A simulation study estimated that PT may reduce the risk of developing a second primary cancer by 26–39% compared with IMRT. ^37,38 If the dosimetric benefits are associated with good clinical outcomes, PT can improve the QOL of patients with prostate cancer after treatment.

Image guidance for PT

PT is dosimetrically superior to photon-based therapy because of the Bragg peak and the sharp dose falloff; however, these features are associated with increased sensitivity to changes in the water equivalent thickness (WET) in the beam path, and WET variance can cause inconsistent dose coverage by PT. ³⁹ In PT for prostate cancer, variation in WET can be caused by changes in the patient surface, displacement of dense tissues relative to the target (femoral heads), or variations in low density regions (rectum, bowels, bladder).

For accurate positioning during PT, most centers currently rely on implanted fiducial markers and 2D orthogonal X-ray imaging. Bony landmarks or fiducial markers on planar images are used as surrogates for defining positional variations. However, 2D- or fiducial marker-guided imaging does not provide sufficient information to prevent WET variance for prostate PT, which can lead to PT dose uncertainty. ⁴⁰

To monitor tissue anatomical changes during prostate cancer PT, image guidance is moving toward online volumetric cone beam CT (CBCT), which enables daily dose reconstruction, facilitates adaptation decisions, and increases the robustness of inter fractional PT dose distribution. ⁴¹ Although CBCT is already in use for traditional photon-based systems, its application to particle therapy is just beginning. ⁴⁰

CBCT is expected to reduce geometric uncertainties resulting from inter fractional anatomy changes and treatment setup; however, poor soft-tissue resolution has limited the accuracy of intrafractional real-time imaging. The development of next-generation image-guided systems of magnetic resonance integrated PT (MRiPT) is undergoing. ⁴² MRiPT combines excellent soft-tissue resolution and real-time imaging information with the most conformal dose distribution and best dose steering capability provided by modern PT. Although MRiPT is still in its infancy, its potential for improving the quality of PT is anticipated.

State-of-the-art PT

To provide highly conformal and robust dose distribution, the state-of-the-art PT treatment room would be equipped with IMPT delivery techniques to ensure dose coverage conformality, a CBCT image-guided system for monitoring tissue anatomical changes, and a 360° rotating gantry for flexible and precise beam angle selection (Figure 2).

Figure 2.

The beam delivery nozzle can rotate 360 degrees around the robotic patient couch and is equipped with IMPT beam delivery and a CBCT image guidance system. CBCT, cone beam CT; IMPT, intensity-modulated proton therapy.

Clinical evidence

Effective tumor control

Direct randomized controlled trials comparing the efficacy of tumor control between PT and EBRT in prostate cancer have not been performed to date. A randomized clinical trial performed in the 1980s compared the delivery of 50.4 Gy of conventional EBRT for T3–T4 tumors followed by a photon boost of 16.8 Gy vs a proton boost of 25.2 Gy (RBE). ⁴³ The study found that the dose-escalated PT failed to improve tumor control or the overall survival rate. However, the findings of this study are based on outdated techniques compared with those used in current standard practice.

Prospective or retrospective cohorts in Western ^6,44–46 and Japanese studies ^47–49 have shown that the patient outcomes are comparable between PT and EBRT. A case-matched comparative study demonstrated equivalent cancer control rates between high-dose PT and brachytherapy. ⁵⁰

In summary, there is no Level III evidence that PT is superior to EBRT for prostate cancer tumor control. Furthermore, current evidence supports that the efficacy of PT is comparable to that of standard EBRT or brachytherapy.

Mixed data for gastrointestinal (GI), genitourinary (GU), and sexual toxicities

Although there are no prospective randomized comparative trials available, several studies compared the side-effect profiles between PT and EBRT for patients with prostate cancer, including four large population-based studies and three prospective patient-reported outcome (PRO) comparative studies (Table 2).

Table 2.

Population-based studies and prospective PRO studies comparing proton and photon radiotherapy toxicities for prostate cancer

Author (year)	Trial type	Source	Period	Sample size		Proton vs photon toxicities
				Proton	Photon	Acute			Late
						GI	GU	Sexual	GI	GU	Sexual
Kim (2011)51 a	Population-based	SEER-Medicare	1992–2005	337	1,6415 b	NA	NA	NA	↑ b	NA	NA
Sheets (2012)52 c	Population-based	SEER-Medicare	2000–2009	684	684	NA	NA	NA	↑	=	=
Yu (2012)53 d	Population-based	Medicare	2008–2009	314 e	628 e	=	↓	NA	=	=	NA
Pan (2018)54 f	Population-based	MarketScan	2008–2015	693 g	3465 g	↓	↓	↓	↑	↓	↓
Gray (2013)56 h	Prospective PRO	MGH	2003–2008	95	276 i	↓	↓	NA	=	=	NA
Hoppe (2014)57 j	Prospective PRO	UF	2003–2010	1243	204	= k	=	=	= k	=	=
Fang (2015)58 l	Prospective PRO	UPENN	2010–2012	94	94	=	=	NA	=	=	NA

=, equivalent toxicity (no statistically significant difference).; ↑, increased toxicity with proton therapy compared with photon therapy; ↓, decreased toxicity with proton therapy compared with photon therapy; GI, Gastrointestinal; GU, Genitourinary, NA, not available; MGH, Massachusetts General Hospital;PRO, patient-reported outcomes; SEER, Surveillance, Epidemiology, and End Results; UF, University of Florida; UPENN, University of Pennsylvania.

^aLate toxicities defined as toxicity that developed >=6 months after diagnosis.

^bIntensity-modulated radiotherapy (IMRT), n = 4645; three-dimensional conformal radiotherapy (3DCRT), n = 11770 (total, n = 16415)

^cGastrointestinal morbidity, urinary incontinence, non-incontinence urinary morbidity, sexual dysfunction, >1 year after treatment.

^dAcute toxicities defined as toxicities at 6 months after start of treatment; late toxicities defined as toxicities at 12 months after start of treatment

^eSample size revealed: n = 421 (proton) for the analysis of late toxicity vs. n = 842 (photon) for the analysis of acute toxicity.

^fAcute toxicities defined as toxicities at 6 months after start of treatment; late toxicities defined as toxicities at 24 months after start of treatment.

^gSample size revealed: n = 341 (proton) for the analysis of 6 months of toxicity vs. n = 1718 (photon) for the analysis of 24 months of toxicity.

^hAcute toxicities defined at first post-treatment; late toxicities defined at 24 months after start of treatment.

ⁱIMRT, n = 153; 3DCRT, n = 123 (total, n = 276).

^jAcute toxicities defined as toxicities at 6 months after treatment; late toxicities defined as toxicities at 24 months after treatment.

^kPatients in the proton cohort are more likely to report better outcomes in the specific domains of rectal urgency and bowel frequency.

^lAcute toxicities defined as toxicities <90 days after start of treatment; late toxicities defined as toxicities >90 days after start of treatment.

A population-based study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database found that the GI toxicity at ≥6 months after the beginning of treatment was greater for PT than for EBRT ( vs IMRT: hazard ratio [HR], 3.32; 95% confidence interval [CI], 2.12–5.20; vs 3DCRT: HR, 2.13; 95% CI, 1.45–3.13). ⁵¹ The incidence of GI toxicity markedly decreased in patients treated with PT in later years, suggesting a substantial improvement in PT experience and technology. A second SEER-Medicare database study reported similar results for late GI toxicities, as data showed that IMRT had fewer adverse GI events (HR, 0.66; 95% CI, 0.55–0.79) than PT. ⁵² In addition, the study showed no significant differences in GU and sexual adverse events between the two modalities. A third database study including Medicare recipients showed that the 6 month GU toxicity was significantly lower in patients treated with PT than in those receiving IMRT (odds ratio [OR], 0.60; 95% CI, 0.38–0.96) ⁵³ ; however, this did not persist at 12 months post-treatment. In addition, there were no differences in GI toxicities between the two modalities. The most recent database study used the MarketScan Commercial Claims and Encounters database. ⁵⁴ The study found that male patients treated with PT had a lower risk of composite GU toxicity and erectile dysfunction at 6 months post-treatment. Bowel toxicity was lower at 6 months (1.6% vs 3.2%, p = 0.02) but higher at 2 years (19.5% vs 15.4%, p = 0.02) post-treatment. These database studies do not provide information on the radiation field or dose used, and they do not differentiate between passive scatter proton radiation and the more modern IMPT, which may have different toxicity profiles. ^32,55

Three PRO comparative studies were identified. The first study used the Massachusetts General Hospital (MGH) patient-reported QOL scores to compare post-treatment toxicity patterns in patients with localized prostate cancer who received 3DCRT (n = 123), IMRT (n = 153), or PT (n = 95). ⁵⁶ The authors observed that both 3DCRT and IMRT were associated with modest but clinically meaningful reductions in bowel and/or urinary QOL at the first follow-up after radiotherapy. However, the toxicity pattern was different in patients who received PT. At 24 months, patients who received all three radiation modalities reported modest but clinically meaningful changes in bowel QOL but not in GU QOL. A second study compared patient-reported QOL data between males who received PT (n = 1,243) and IMRT (n = 204) at the University of Florida. The authors did not find any statistically significant differences in GI, GU, or sexual summary scores at 6 months and 2 years post-treatment. ⁵⁷ However, patients who received PT were more likely to report better outcomes in the specific domains of rectal urgency and bowel frequency. The third comparative QOL study was published by the University of Pennsylvania. ⁵⁸ The authors performed a matched comparison of patients with localized prostate cancer treated with PT (n = 94) and IMRT (n = 94). This study indicated that there were no statistically significant differences in acute or late GI or GU grade ≥2 toxicities between IMRT and PT.

Because of the lack of Level I evidence to directly compare modalities, these billing code-based database studies have inherent limitations, and the design of the studies is based on comparison of old proton technologies (passive scattering proton) with advanced photon technologies (IMRT). Therefore, the superiority of PT in terms of toxicity reduction remains debatable. Performing randomized trials is thus essential to further investigate the efficacy of PT for the treatment of prostate cancer.

In summary, although existing studies present mixed data regarding the safety of PT, they support the potential early GI and GU toxicity benefits of PT over EBRT (3DCRT or IMRT). However, these early benefits are not consistent with long-term follow-up data, which suggest a deteriorating performance regarding late GI toxicity. With respect to the sexual function domain, data suggest that PT can improve function with at least an equivalent toxicity profile.

Preserving serum testosterone levels

Studies have demonstrated that low testosterone levels have a significant impact on health-related QOL in patients with prostate cancer. ^59,60 More specifically, it is suggested that EBRT monotherapy reduces testosterone levels in patients with localized prostate cancer. ^61–63 A study performed by Pickles et al ⁶² monitored the serum testosterone levels of 666 men treated with EBRT without hormonal therapy for localized prostate cancer. At 6 months after completing RT, the mean serum testosterone levels had decreased to 17% from baseline pretreatment levels. The study hypothesized that the post-EBRT hormonal changes resulted from Leydig cell injury due to scattered radiation dose to the testes. Zagars et al ⁶³ found a mean 9% reduction in serum testosterone in 85 men at 3 months after completing EBRT for prostate cancer. However, the authors suggested that the decrease in testosterone was induced by stress rather than by scattered radiation to the testes. A recent study conducted by Pompe et al ⁶¹ showed that EBRT monotherapy induces an average 30% decrease in testosterone levels. Although most patients eventually recover, approximately 45% experience biochemical hypogonadism.

In contrast to these EBRT-based studies demonstrating decreased testosterone levels after prostate radiotherapy, several studies have demonstrated the benefits of PT in terms of preserving post-treatment testosterone levels. ^64,65 For example, Nichols et al ^64,65 reported that serum testosterone did not decrease significantly within 5 years after treatment in patients with low to intermediate risk of prostate cancer who received PT. Although no PROs were available, these promising data indicate that testosterone levels remain unaffected in patients treated with PT, suggesting its positive QOL implications.

Reduction of second cancer risk

The development of a radiation-induced second cancer is one of the most serious long-term consequences of cancer treatment. The long life expectancy of patients with prostate cancer exposes them to the possibility of developing second primary malignancies. Murray et al ³⁷ conducted a systemic review of the development of second cancers after EBRT and/or brachytherapy in patients with prostate cancer. The results indicated that the risk of second malignancy was in the range of 1 in 220 to 1 in 290 (0.3–0.5%) and may increase to 1 in 70 (1.4%) in patients who were followed-up for >10 years. Another SEER-based population study indicated that EBRT for prostate cancer may induce a long-term increase (1.42-fold) in the risk of developing bladder and rectal cancer (1.70-fold) compared with the standardized general population rates. ⁶⁶

Dosimetry studies show that PT can reduce the extra radiation exposure to organs at risk compared with EBRT. ^38,67–69

Studies providing clinical evidence include a study by Christine et al, ⁷⁰ who compared the incidence of second cancers between 558 patients treated with proton radiation and a matched SEER cohort of 558 EBRT-treated patients. In this study, 33% of the patients with prostate cancer had a lower risk of developing a second cancer (adjusted HR, 0.52; 95% CI, 0.32–0.85; p = 0.009). A larger National Cancer Database study that included 450,373 patients with 9 types of primary cancer (33.5% received 3DCRT, 65.2% received IMRT, and 1.3% received PT) performed a matched comparison to evaluate potential differences in the rates of second cancer induced by different radiation modalities. ⁷¹ The authors found that PT was associated with a significantly lower risk of second cancer than IMRT in patients with prostate cancer (adjusted OR, 0.18; 95% CI, 0.14–0.24; p < 0.0001).

Although further randomized studies are needed to confirm these findings because the existing evidence may be hypothesis-generating, the clinical results presented are consistent with the dosimetry studies for PT, which show a reduced risk of second cancer.

Cost-effectiveness aspect

After reviewing the theoretical and clinical aspects of PT compared with photon therapy, we must evaluate the cost aspect, which is a source of controversy regarding PT for prostate cancer. Building a traditional proton center (with three to four gantry sites) may cost $100–250 million, which substantially exceeds the capital cost of setting up a state-of-the-art photon radiation center. ⁷² From a payer’s perspective, Pan et al designed a simplified model of the relative costs of PT and IMRT. This model suggested that, considering both the radiation delivery cost and the cost of complications, the relative cost of PT is approximately 1.5–2-fold higher than that of IMRT. ⁷³ Regarding the effect of PT on improving QOL, a cost utility analysis per quality-adjusted life year (QALY) from a literature review between 2002 and 2011 showed that PT is not cost-effective. ⁷⁴

The cost of PT and photon-based treatment should be analyzed in a dynamic manner. PT centers are being developed at a lower cost and with a smaller size; a single treatment room costs $15–25 million. The treatment fractions for prostate cancer are decreasing because evidence suggests comparable efficacy of hypofractionated radiation vs conventional fractionated radiation, which would further decrease the cost discrepancy between PT and IMRT. ^73,75

Solving the controversy

Randomized trials comparing PT and photon-based RT for localized prostate cancer using modern techniques are necessary to solve the debate regarding efficacy, QoL, and cost-effectiveness issues.

A randomized trial comparing PT with IMRT called Prostate Advanced Radiation Technologies Investigating Quality of Life (PARTIQoL; NCT01617161) is underway. This study is randomizing low- to intermediate-risk prostate cancer patients to receive dose-escalated prostate irradiation delivered with either PT or IMRT. The primary end point is related to QOL, and the reduction in mean EPIC bowel scores at 24 months after radiation will be compared between the two arms. Secondary outcomes include disease-specific QOL, cost-effectiveness, dosimetry analyses, biomarker response, and long-term survival.

A larger, prospective, pragmatic controlled comparison study called A Prospective Comparative Study of Outcomes with Proton and Photon Radiation in Prostate Cancer (COMPPARE; NCT03561220) aims to enroll 1500 patients receiving PT and 1500 IMRT patients to determine whether PT or IMRT is more effective in terms of cure rates, side-effects, and QoL for patients with localized prostate cancer. An embedded randomized trial comparing standard fractionated PT [78.0 Gy (RBE) in 39 fractions] with hypofractionated PT [60.0 Gy (RBE) in 20 fractions] may also help determine the optimal fractionation schedule for localized prostate cancer patients.

The results of these studies are expected to shed light on the controversy over the efficacy, QoL, and cost-effectiveness of PT vs photon-based RT in the treatment of localized prostate cancer.

Future directions

Proton stereotactic body radiation therapy (SBRT)

Over the past two decades, improvements in imaging and computation methods have led to advances in the planning and delivery of prostate RT. These technical advances have permitted a more precise and conformal delivery of escalated doses of radiation to the prostate with a concurrent shortening of the treatment course. Evidence-based hypofractionated RT guidelines for localized prostate cancer were recently published by American Society for Radiation Oncology (ASTRO), American Society of Clinical Oncology (ASCO), and American Urological Association consensus. The guidelines recommend the use of moderate hypofractionation (defined as a lower number of total treatment fractions compared with standard fractionation, but with a higher dose per fraction of 240–340 cGy) or ultra-hypofractionation/SBRT (defined as treatment fraction ≤5 and fraction size ≥500 cGy). ⁷⁶ There are distinct benefits regarding convenience and cost if patients with prostate cancer receive a shorter than conventional course of radiation treatment. However, most of the Level I evidence derived from EBRT-based trials ^77–81 does not clearly define or elucidate the role of PT and hypofractionated treatment in patients with prostate cancer.

Recent evidence suggests that proton SBRT in patients with low to intermediate risk of prostate cancer facilitates effective tumor control with minimal long-term GI and GU toxicities. ^82,83 One study prospectively analyzed 279 patients with low to intermediate risk of prostate cancer who received SBRT (36.25 GyE in 5 fractions) with the IMPT technique. ⁸² The 5 year biochemical disease-free survival rate was 96.9%, 91.7%, and 83.5% for the low, favorable, and unfavorable intermediate-risk groups, respectively. Favorable long-term toxicity results were also obtained, with rates of 7.8% for Grade 2 + GI toxicity and 5.7% for Grade 2 + GU toxicity. Another small, randomized trial including 82 patients with low-risk prostate cancer treated with proton SBRT (38 GyE in 5 fractions) vs standard fractionated PT (79.2 GyE in 44 fractions) assessed the differences in the QoL of patients. ⁸³ The authors did not observe any differences between the two arms with respect to urinary, bowel, or sexual function scores at 3, 6, 12, 18, or 24 months after treatment, and there were no Grade 3 or higher toxicities on either arm.

In summary, although proton SBRT evidence is incomplete, available data are promising and demonstrate comparable efficacy and toxicity profiles between EBRT and conventional fractionation programs. The SBRT schedule has potential for reducing the cost of PT, thus rendering this treatment more accessible and cost-effective.

Image-guided intraprostatic tumor boost

A dose–response relationship has been established between radiation and prostate cancer. A whole-prostate dose that escalates to 80 Gy is considered the care standard in modern practice. ^45,84–87 Further dose escalation to the entire prostate area results in higher toxicity rates. ⁸⁸ With advanced radiation technologies, focal boost to the macroscopic visible tumor using multiple parametric magnetic resonance imaging (mpMRI) is feasible without increasing the underlying toxicity risk. Recently, a randomized Phase III trial enrolled 571 patients with intermediate- to high-risk prostate cancer, who were treated with standard 77 Gy EBRT (fractions of 2.2 Gy) to the entire prostate or with an additional simultaneously integrated focal boost up to 95 Gy (fractions up to 2.7 Gy) to the MRI-visible intraprostatic lesion. ⁸⁹ The authors found that the addition of a focal boost to the intraprostatic lesion improved bDFS (HR, 0.45; 95% CI, 0.28–0.71; p < 0.001) without impacting the toxicity levels and QoL of patients.

Two studies evaluated the feasibility and differences between advanced PT (IMPT) and advanced EBRT (VMAT) for intraprostatic boost treatment planning. ^90,91 Both studies demonstrated the feasibility of IMPT to avoid organ at risk (OAR) constraint violations and the superiority of IMPT planning compared with VMAT in terms of OAR sparing. Efficient identification of the intraprostatic lesion is an important issue. Novel molecular positron emission tomography (PET), using radiotracers that are directed against prostate-specific membrane antigen (PSMA-PET), is a novel emerging technique. The highest degree of accuracy is achieved when combining PSMA-PET with mpMRI data. ^92–95 A new study on dosimetric evaluation of PSMA-PET-delineated intraprostatic lesion boost planning ⁹⁶ provides a new approach to facilitate more accurate and biologic intraprostatic lesion delineation. In turn, this can lay the foundation for future focal boost research that can further increase tumor control efficacy.

Flash PT

In contrast to conventional radiation, which delivers a radiation dose in minutes, FLASH radiotherapy instantaneously delivers the same radiation dose in milliseconds (ms). FLASH irradiation, a term first described by Favaudon et al, ⁹⁷ has tissue-sparing effects while maintaining the efficacy of tumor control compared with conventional radiotherapy, as demonstrated in several in vivo studies. ^98,99 The normal tissue-sparing phenomenon is called the “FLASH effect.” The clinical applications of FLASH radiotherapy remain scarce. The first patient treated with FLASH radiotherapy was a 75-year-old patient with CD30+ T cell cutaneous lymphoma disseminated throughout the skin surface, who was heavily treated with skin RT over 110 times in Switzerland. ¹⁰⁰ The patient received FLASH RT over a 3.5 cm tumor with 15 Gy in one shot delivered in 90 ms. After the treatment, the researchers observed a complete response of the irradiated tumor with only Grade I skin effects. However, most studies on FLASH radiotherapy have used electron beams, which have low tissue penetration and are clinically limited to superficial cancers. ^{97,98,100,101} A promising alternative FLASH delivery modality is PT. Because the respective dose can be distributed deeper within the body, this method could be applied to the treatment of deep-seated tumors (including prostate tumors). ^102–104 Although the FLASH effect appears to be a revolutionary and practice-changing approach, its clinical translation remains in its infancy; thus further research on FLASH PT is required.

Conclusion

PT provides excellent physical advantages and a superior dose profile compared with EBRT. Further evidence from clinical trials and research studies may help clarify the role of PT in the treatment of prostate cancer. Novel PT modalities, such as SBRT, image-guided intraprostatic tumor boost, and FLASH PT, may convert this treatment into a more accessible, affordable, efficient, and safe alternative.