Practical Radiation Oncology (2013) 3, e87–e94
www.practicalradonc.org
Review Article
Proton beam therapy for the treatment of prostate cancer Thomas J. Pugh MDa,⁎, Seungtaek Choi MDa , Quyhn Nhu Nguyen MDa , Michael T. Gillin PhDb , X. Ron Zhu PhDb , Matthew B. Palmer MBA, CMDb , Andrew K. Lee MD, MPHa a
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
b
Received 2 January 2012; revised 1 May 2012; accepted 30 May 2012
Abstract Proton beam therapy (PBT) offers the potential of dose escalation to target tissue while decreasing toxicity through unique physical dose deposition characteristics. PBT has been used to treat prostate cancer for several decades; however, recent enhancements in availability and treatment delivery have peaked interest in this technology among radiation oncologists, industry experts, and prostate cancer patients. As a result, the importance of understanding the collective experience and technical aspects of PBT delivery has become increasingly important in radiation medicine. This review article is intended to critically review the literature on PBT for localized prostate cancer, discuss the fundamentals of PBT treatment planning, and describe the continued development of proton beam technology for the treatment of prostate cancer. © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction External beam radiation therapy (EBRT) is commonly used to deliver curative treatment for localized prostate cancer. Well-conducted research over the past several decades have validated the importance of radiation dose in the treatment of localized prostate cancer. 1-3 The conclusion from these studies can be summarized succinctly: higher radiation dose leads to greater likelihood of biochemical control. However, escalation of radiation dose to the prostate brings increased risk of toxicity to adjacent normal tissue. The volume of normal rectum exposed during a course of EBRT correlates with treatment complications, most notably rectal bleeding. 4,5
Conflicts of interest: None. ⁎ Corresponding author. The University of Texas M. D. Anderson Cancer Center, 1840 Old Spanish Trail, Unit 1150, Houston, TX 77030. E-mail address: [email protected] (T.J. Pugh).
The volume of rectum receiving high doses of radiation (≥60 Gy) appears to be the most relevant predictor of rectal toxicity; while the association of low dose (≤45 Gy) and intermediate dose radiation with rectal toxicity is less clear. 6 Therefore, the glass ceiling of dose escalation for prostate cancer is where the therapeutic ratio of cure rateto-toxicity risk is no longer acceptable. As a result, many of the technologic advancements in radiation medicine for prostate cancer over the past several years have focused on delivering dose-escalation to target tissue while minimizing radiation dose to the rectum. Due to unique dose deposition characteristics, proton beam therapy (PBT) was an original method of prostate cancer dose-escalation. 7 Although PBT has been used to treat prostate cancer for over 4 decades, the small number of facilities where such treatments were available has historically limited the application of this technology in the United States. Within the past several years, the number of operational proton therapy centers in the United States has more than quadrupled with several additional proton
1879-8500/$ – see front matter © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.05.010
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centers planned for development within the next several years. Men with prostate cancer comprise a substantial percentage of patients treated at proton therapy centers due in part to the prevalence of the disease combined with the established safety and efficacy of PBT for localized prostate cancer. In anticipation of increased PBT application, the purposes of this review are the following: (1) critically review the literature on PBT for localized prostate cancer; (2) discuss the fundamentals of PBT treatment planning and delivery; (3) describe the continued development of proton beam technology for the treatment of prostate cancer.
Methods and materials A Medline search identified relevant articles with key words “proton” and “prostate cancer.” The search strategy was intentionally sensitive in order to ensure capture of all relevant material. Review articles, editorials, and articles on proton-based imaging were immediately excluded from consideration. The remaining articles were evaluated for quality using the following prioritization (highest to lowest priority for inclusion): randomized controlled trial, prospective clinical trial, prospectively obtained observation series, retrospective clinical outcome study, and dosimetry studies.
Discussion Fundamentals of proton beam therapy treatment planning Treatment planning for PBT must consider potential sources of error inherent in all forms of EBRT (ie, daily patient positioning reproducibility, interfractional anatomic changes, intrafractional organ motion) as well as proton specific uncertainties such as intrinsic proton range uncertainty, Hounsfield unit stopping power conversions,
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range degradation, and the impact of tissue inhomogeneity along the beam path. In addition to these factors, proton incident energies, production systems, delivery systems, and treatment planning systems vary among proton therapy centers. Therefore, a comprehensive review of treatment planning across all clinically active proton centers is beyond the scope of this review. This article will illustrate the technical elements of PBT for localized prostate cancer at the University of Texas MD Anderson Proton Therapy Center in Houston (PTC-H), acknowledging that subtle discordances between the procedures described here and those of other operational proton centers exist. There currently exist 2 distinct systems of PBT delivery: passive scattering and pencil beam scanning. The vast majority of patients represented in the published series of PBT for prostate cancer were treated with a passive scattering technique. Both passive scattering and pencil beam scanning are utilized at PTC-H. 8 Passive scattering Proton beams possess the unique physical property of depositing the majority of their energy over a narrow range at a fixed depth in tissue, with very little dose deposited beyond that depth. This property contrasts to photon beams where the beam is exponentially attenuated in tissue with a significant portion of the energy deposited as the beam exits the patient. The ability to precisely deliver high-dose radiation to a target while limiting collateral damage to surrounding normal tissue underscores the promise of PBT. The depth of penetration is defined by the incident energy of the proton beam, such that higher incident energy protons allow for greater penetration into tissue. In order to uniformly irradiate a target, the proton beam's energy must be modulated between predefined minimum and maximum energies, creating a “spread out Bragg peak.” In passive scattering PBT, range modulation of a monoenergetic proton beam is provided by the mounted range modulation wheel (Fig 1A). The narrow proton beam is then spread out laterally via a double scattering system.
Figure 1 Beam modification in passive scattering proton beam therapy. (A) Range modulation wheel used to create a spread out Bragg peak (SOBP). (B) Metal aperture designed to shape the proton beam to the intended target. (C) Tissue compensator provides a dose “smearing” effect to account for range uncertainty.
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Customized brass apertures are then used to shape the proton beam to the desired target (Fig 1B). Dense tissues (ie, bone) scatter protons to a greater extent than less dense tissues. 9 This sensitivity to tissue inhomogeneity creates uncertainty about the actual point of dose falloff at the distal edge of a proton beam. Given the potential consequences of range uncertainty in the anterior or posterior direction, an opposed lateral or slight lateral oblique beam arrangement is currently preferred for the treatment of prostate cancer. Beam attenuation from the pelvic bones and femoral heads must be accounted for in order to adequately cover the target and obtain a homogenous dose distribution. Therefore, customized tissue compensators are required for each lateral field in order to “smear” the dose from the proton beam (Fig 1C). Smearing ensures adequate target coverage and accounts for variations in dose distribution from potential patient misalignment. Sejpal et al 10 evaluated the robustness of this treatment delivery technique in a comparative dosimetry study using 70 prostate cancer plans. Each plan used parallel opposed proton beams designed to deliver a total dose of 76-Gy relative biologic equivalents
Figure 2
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(RBE) over 38 fractions. Rotational setup errors were simulated by adjusting the gantry and couch angle plus or minus 3°-5°. The mean clinical target volume (CTV) coverage change was ≤2 Gy (RBE) (range, 77.2-78.4 Gy [RBE]) and the dose change to critical structures (anterior rectal wall, bladder, and rectum) was b5% for all rotational errors. Pencil beam scanning Due to the capability of delivering intensity modulated proton therapy (IMPT), pencil beam scanning has become an area of great technologic interest. Scanning protons offer better dose conformation without the need for custom collimation or tissue compensators. There are 2 clinically applied methods of pencil beam therapy delivery: dynamic spot scanning and discrete spot scanning. A “spot” may best be described as a burst of monoenergetic protons over a short period of time or individually placed Bragg peaks within a target. Discrete spot scanning allows for dose delivery spot by spot along a 3-dimensional grid representing the clinical target. The dose grid is populated at depth by changing the energy of the incident proton
Dose wash comparison between passive scattering and pencil beam scanning proton beam therapy for prostate cancer treatment.
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beam. The beam path is adjusted to isolate each independent spot via a magnetic field. In pencil beam scanning PBT, the CTV and normal structures are contoured in an identical process to passive scattering PBT or modern photon based treatments. A small expansion of the CTV creates a scanning target volume (STV). The STV margin accounts for range uncertainty along the beam path and for organ motion or patient setup error. Meyer et al 11 studied the robustness of this treatment technique in a comparative dosimetry study. Errors in patient alignment in 2 axes (rotational and yaw), as well as translational errors in the anterior-posterior direction, were simulated and compared with control cases. Dose perturbations were minimal despite extreme rotational and yaw shifts. As would be expected when using an opposed lateral beam approach, translational errors resulted in much larger dose perturbations. Pencil beam scanning PBT appears to reduce neutron contamination, 12 reduce treatment time, 13 and confer dosimetric advantages in both the low-dose and high-dose regions compared with passive-scattering PBT 14 (Fig 2). These potential advantages have created widespread interest in pencil beam scanning PBT for the treatment of prostate cancer and other disease sites. Computed tomography simulation Prior to computed tomography (CT) simulation, fiducial markers are placed within the prostate under ultrasound guidance to allow for daily kilovoltage (kV) xray target verification. Two markers are placed: 1 cranially (approximating the base) and 1 caudally (approximating the apex). Fiducial markers made of higher density material may have an unintended shielding effect within the target when an opposed lateral beam approach is employed. 15 Therefore, fiducials markers manufactured from low-density material may be preferable to gold fiducials. At the time of simulation, the patient is positioned supine in a leg and foot cradle. A bladder scan is performed to quantify bladder filling. An endorectal balloon with a gas-release system is inserted to standardize rectal filling volume and immobilize the prostate. Initial scout films are obtained in the anteriorposterior and lateral directions to confirm symmetric alignment of the pelvic bones. Once optimal positioning has been verified, CT images are obtained from L4 through the mid femurs. Skin marks corresponding to the physician-placed isocenter in the mid prostate are placed. The intersection of the cranial edge of the leg-foot cradle and the patient's thigh is also marked. The process is then repeated to confirm reproducibility. The acquired study sets are then uploaded to the treatment planning system. Treatment planning The CTV, organs at risk, and fiducial markers are contoured in the treatment planning system by the treating physician. Conventional CTVs are customized according
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to National Comprehensive Cancer Network (NCCN) risk stratification as follows: low-risk (prostate only); intermediate-risk (prostate + proximal seminal vesicle); and highrisk (prostate + full seminal vesicle). When using a passive scattering approach, an evaluation target volume representing a marginal expansion of the CTV is applied in synonymous fashion to conventional CTV to planning target volume expansions. The current expansion from CTV to evaluation target volume is 6 millimeters (mm) radially except in the posterior direction, where the margin is limited to 4 mm. When a scanning beam approach is utilized, the STV is produced as described above using a differential margin of 12 mm laterally, 6 mm anteriorly, 5 mm superiorly-inferiorly, and 4 mm posteriorly to the CTV. The treatment is prescribed to deliver a total dose of 78 Gy (RBE) in 2 Gy (RBE) daily fractions with treatment delivered 5 days per week. The intended total dose is prescribed to an isodose line above 95% for optimal homogeneity. Treatment delivery Prior to treatment delivery, a bladder scan is performed to ensure bladder filling is within 20% of the volume achieved at the time of simulation. The patient is then positioned on the treatment table according to skin markings, with the endorectal balloon in place. Anteriorposterior and lateral kV images are obtained for comparison with digitally reconstructed radiographs derived from the planning CT. If needed, the treatment table is adjusted to optimize alignment utilizing the fiducial markers, bony anatomy, and the radiopaque endorectal balloon tip as reference points. Treatment is initiated once positioning has been optimized and verified.
Clinical investigation of proton beam therapy for prostate cancer: Review of the literature Early clinical trials Investigators at the Massachusetts General Hospital and Loma Linda University pioneered the use of PBT as a method of dose escalation. Shipley et al 7 reported the sentinel pilot study of PBT for prostate cancer in 1979. This report described a cohort of 17 patients who received an initial course of 48-50 Gy via megavoltage x-rays followed by a perineal proton boost to a total dose of 70-76.5 Gy (RBE). The initial results were encouraging; there was no rectal toxicity, 2 patients developed urinary strictures, and 1 patient experienced a local failure. The treatment paradigm from this pilot study (photon plus proton boost to total dose of 75.6 Gy (RBE) was subsequently evaluated in a randomized trial versus conventional photon therapy alone to a total dose of 67.2 Gy in men with locally advanced (T3-T4) or lymph node positive prostate cancer. 16 At a median follow-up of 5 years, there were no significant differences in overall survival, disease-specific survival, recurrence-free survival, or
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local control between the 2 treatment groups. Local control was improved with higher radiation dose (92% vs 80%; P = .089); however, grade 1 or 2 rectal bleeding was also more common in the high-dose group (32% vs 12%; P = .002). In the early 1990s, Loma Linda University opened the first proton beam facility designed specifically for clinical application. An opposed lateral beam approach was used with a delivery system that included rotating gantries. Yonemoto et al 17 reported the preliminary results of 106 patients with localized prostate cancer treated with combined photons and PBT. All patients received photons to 45 Gy followed by a 30 Gy (RBE) proton boost. At 2-year median follow-up, the incidence of grade 1 or 2 rectal and urinary toxicity were 8% and 4%, respectively. There was no grade 3 or greater toxicity. The culmination of these early studies combining photon therapy and PBT was a randomized trial with joint participation by both centers. The Proton Radiation Oncology Group (PROG) 95-09 trial randomized 393 men with clinical stage T1b-T2b prostate cancer and baseline prostate-specific antigen b15 ng/mL to low-dose (70.2 Gy [RBE]) or high-dose (79.2 Gy [RBE]) radiation. 3,18 All patients received photon therapy to a dose of 50.4 Gy, with the randomization occurring between either a 19.8 Gy (RBE) or 28.8 Gy (RBE) proton beam boost. A total of 393 men were enrolled in the trial. At median 8.9-year followup, high-dose radiation therapy demonstrated superior cancer control as evidenced by improved rates of local control, biochemical failure, and androgen deprivation therapy requirement when compared with lower dose radiation. There was no difference in overall survival. The incidence of grade 3 or greater toxicity was low (b3%) and not significantly different between the 2 groups. An ad hoc quality of life comparison between the low-dose and highdose groups failed to show a significant difference in patient reported quality of life outcomes. 19 In this landmark study, men who were treated with PBT to escalate radiation dose showed improved disease control without significant increase in toxicity or adverse impact on patient reported quality of life.
Contemporary results The long-term results of PBT yield comparable diseasefree survival to alternative treatments for localized prostate cancer with minimal morbidity. The Loma Linda experience provides the most mature insight on PBT for localized prostate cancer, including the first reported experience using PBT as a single modality (without supplemental photons). 20 The most recent update of the Loma Linda experience included 1255 men with clinically localized prostate cancer. All patients were treated to a total prostate dose of 74-75 Gy (RBE) using either a combination of photons and protons (n = 731) or protons alone (n = 524). Patients with an estimated risk of lymph node micro-
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metastases N15% according to the Partin tables received an initial course of 45 Gy to the whole pelvis followed by a PBT boost to the prostate and seminal vesicle. At median follow-up of 63 months, the biochemical failure-free survival was 75% and grade ≥3 gastrointestinal (GI) or genitourinary (GU) toxicity was b1%. Several proton therapy centers in Japan have published their early experiences with PBT for localized prostate cancer. The National Cancer Center Hospital East in Kashiwa, Japan began clinical operations in the late 1990s. Nihei et al 21 confirmed the feasibility of combined photons and protons for dose-escalated prostate cancer treatment in a phase 2 feasibility study. A subsequent multi-institutional series included patients enrolled at 2 additional proton centers in Japan between 2004 and 2007. 22 A total of 151 men with clinical stage T1T2N0M0, Gleason score ≤7, and prostate-specific antigen ≤20 received a total prostate dose of 74 Gy (RBE) in 37 fractions. At a median follow-up of 42 months, acute grade 2 GI and GU toxicity was appreciated in 0.7% and 12% of patients, respectively. Of the 147 patients who had been followed for N2 years, the incidence of late grade 2 or greater GI and GU toxicity was 2.0% and 4.1%, respectively, at 2 years. One of the participating institutions in this multi-institutional trial recently reported on the acute morbidity using PBT for localized prostate cancer. The Hyogo Ion Beam Medical Center reviewed acute morbidity in 287 men with localized prostate cancer treated with PBT. All patients received a total prostate dose of 74 Gy (RBE) in 37 fractions. 23 No patient experienced grade 2 or higher acute GI toxicity; however, 39% and 1% of patients experienced acute grade 2 and grade 3 GU toxicity, respectively. Most of the patients (87%) experiencing grade 2 or 3 GU toxicity were successfully managed with selective alpha-blocker therapy. Larger CTV and the use of androgen deprivation therapy were significant predictors of acute grade 2 or 3 GU morbidity on multivariate analysis. Following PROG 95-09, investigation of PBT in the United States continued to focus primarily on doseescalation. Investigators at Loma Linda University and the Massachusetts General Hospital once again collaborated on a phase 2 trial sponsored by the American College of Radiology (ACR). The ACR 03-12 trial evaluated the safety and efficacy of delivering 82 Gy (RBE) in 41 fractions without androgen deprivation for men with localized prostate cancer. 24 All patients received conformal PBT to the prostate and caudal seminal vesicle to a total dose of 50 Gy (RBE) followed by a 32 Gy (RBE) prostate boost at 2 Gy (RBE) per treatment. Treatments were delivered via passive scattering PBT using opposed lateral beam arrangements with either transabdominal ultrasound or orthogonal radiographs for daily localization. A total of 85 patients were accrued from May 2003 through March 2006. At a median follow-up of 31.6 months, the rate of acute grade
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Summary of published clinical results using proton beam therapy for prostate cancer
Study
Patient selection
Shipley et al 16 T3-T4; N0-N +
Zeitman et al 18 Low- or intermediaterisk Slater et al 20
Nonmetastatic
Nihei et al 22
T1-T2 Gleason score ≤ 7 PSA ≤20 Nonmetastatic
Mayahara et al 23 Coen et al 24
Intermediaterisk High-risk
No.
Total dose
1982-1992 99
75.6 Gy (RBE) 103 67.2 Gy (RBE) 1996-1999 196 79.2 Gy (RBE) 197 70.2 Gy (RBE) 1991-1997 1255 74-75 Gy (RBE) 2004-2007 151 74 Gy (RBE) 2003-2004 287 2003-2006 85
2006-2007 89 82 40
74 Gy (RBE) 82 Gy (RBE)
Median FFBF follow-up (mo)
Acute toxicity Genitourinary
Late toxicity Gastrointestinal
Genitourinary
Gastrointestinal
≤ Grade 2 ≥ Grade 3 ≤ Grade 2 ≥ Grade 3 ≤ Grade 2 ≥ Grade 3 ≤ Grade 2 ≥ Grade 3
80% (5-y) a NR
0%
NR
0%
11% b
3% c
9% d
2% e
92% (5-y) a NR
0%
NR
0%
36% b
6% c
27% d
9% e
83% (10-y) 60% f
2% f
63% f
1% f
27% f
2% f
24% f
1% f
69% (10-y) 51% f
3% f
44% f
1% f
22% f
2% f
13% f
0% f
62
73% (8-y)
NR
b 1% f
NR
b 1% f
NR
b 1% f
NR
b 1% f
43
94% (3-y)
12% g
0% g
1% g
0% g
8% g
0% g
13% g
0% g
NR
NR
39% g
1% g
0% g
0% g
NR
NR
NR
NR
32
NR
69% g
2% g
17% g
0% g
76% g
8% g
43% f
2% f
NR
NR
NR
24% g
2% g
4% g
b 1% g
61
107
78 Gy NR (RBE) 78-82 Gy (RBE) 78 Gy (RBE)
100% (2-y) NR 99% (2-y) 94% (2-y)
Gy, Gray; FFBF, freedom from biochemical failure; NR, not reported; PSA, prostate-specific antigen; RBE, relative biologic equivalents. a Local control defined as no palpable recurrence and negative biopsy in patients completing treatment. b Incidence of hematuria or urinary stricture. c Persistence of hematuria or urinary stricture. d Incidence of rectal bleeding. e Persistence of rectal bleeding. f Radiation Therapy Oncology Group (RTOG) toxicity grading. g Common Terminology Criteria for Adverse Events grading.
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Mendenhall et al 25
T1c-T2b Gleason score ≤ 7 PSA ≤15 Low-risk
Accrual period
T.J. Pugh et al
Table 1
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3 GU or GI toxicity was 2%. The rate of late grade 3 GU or GI toxicity was 7%. As expected, rectal bleeding was the predominant late GI toxicity. The University of Florida presented their early results of 212 patients treated according to 1 of 3 prospective trials from August 2006 thru September 2007 with all patients having a minimum follow-up of 2 years. 25 Treatments were prescribed as follows: 78 Gy (RBE) (low-risk); 78-82 Gy (RBE) (intermediate-risk); and 78 Gy (RBE) with concomitant docetaxel (Taxotere) followed by androgen deprivation (high-risk). All treatments were delivered using conventional treatment schedules of 2 Gy (RBE) per fraction delivered 5 days per week. The incidence of ≥grade 3 GU toxicity was 1.9% and the incidence of ≥grade 3 GI toxicity was b0.5%. All grade 3 GU events were transient. The lone grade 3 GI event was attributed in part to a post-treatment rectal mucosal biopsy in the high-dose region. The rates of ≥grade 2 GU and GI toxicity were 24% and 4%, respectively. The need for pretreatment symptom management predicted grade ≥2 GU events. Surprisingly, the use of concomitant chemotherapy did not appear to significantly effect toxicity. These contemporary studies of dose-escalated PBT for localized prostate cancer confirm the safety and efficacy of this treatment paradigm. Table 1 summarizes both the historic and contemporary results of PBT in patients with prostate cancer. These series report low rates of late toxicity and high rates of biochemical control, the mature results of these series are needed to affirm these assumptions.
Future development of proton beam therapy for prostate cancer The field of radiation oncology continues to pioneer innovative treatments for cancer patients through new technology and improvements in well-established therapies. Technologic advances in PBT delivery, combined with a rapid increase in the availability of this technology, will likely provide the framework for further development of PBT for the treatment of prostate cancer and other diseases. The following are areas of active investigation using PBT for prostate cancer. Hypofractionation The optimal radiation dose and fractionation schedule for prostate cancer treatment is not known. Dose-escalated radiation treatment using conventional fraction sizes and schedules requires a 2-month time commitment from patients and often includes geographic relocation for treatment. There is a growing body of evidence suggesting noninferiority of hypofractionated regimens compared with conventional fractionation for the treatment of prostate cancer. 26,27 Exploration of hypofractionated regimens using PBT is currently underway at several institutions, including PTC-H.
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Intensity modulated proton therapy As described above, IMPT is an area of great technologic interest and is currently implemented clinically for select patients at PTC-H. The favorable dose conformality and modulation using IMPT may allow for further dose escalation while avoiding normal structures.
Comparative effectiveness research There is a paucity of high quality data comparing commonly implemented therapies for localized prostate cancer. 28 There has never been a randomized trial directly comparing external beam radiation treatment delivery techniques. Sheets et al 29 recently interrogated the SEERMedicare database using billing code surrogates for recurrence and treatment morbidity. Paradoxically, PBT was associated with a greater risk of subsequent diagnoses or procedures surrogating GI morbidity compared with intensity modulated radiation therapy (relative risk 0.66). Interpretation of these data is challenging due to the multiple limitations of the analysis, including use of potentially unreliable surrogate endpoints, reporting bias, the absence of specific radiation treatment information regarding dose or technique, and the inherit restriction of data within the Surveillance, Epidemiology and End Results-Medicare database allowing for a single proton therapy center to be represented in the analysis. Furthermore, during the time period analyzed the combination of photon and proton therapy was a common practice as detailed above, clouding the comparison across modalities. Analyses such as these should be considered hypotheses generating. In the absence of high-quality comparative effectiveness research, several agencies have called for randomized evidence to assess the relative clinical benefit of PBT for prostate cancer. 30,31 Efforts for a multiinstitutional collaborative trial comparing intensity modulated radiation therapy and PBT are ongoing. 32
Conclusions The experience to date clearly demonstrates PBT to be a safe and effective method of delivering dose-escalated radiation therapy for localized prostate cancer. The interest in PBT from practitioners, industry leaders, and prostate cancer patients has grown exponentially over the past several years. As a result, the practicing radiation oncologist is increasingly presented with the challenges of reviewing, applying, comparing, and contrasting PBT to other management options for localized prostate cancer. Future work should focus on optimizing this technology, including additional dose escalation strategies, hypofractionation, IMPT applications, and treatment verification techniques, in order to optimize the advantages of this modality. Of particular relevance for prostate cancer
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patients, high-quality comparative-effectiveness research using both biochemical and patient-reported quality of life endpoints is desirable.
References 1. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys. 2002;53:1097-1105. 2. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys. 1998;41:491-500. 3. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294:1233-1239. 4. Nguyen PL, Chen RC, Hoffman KE, et al. Rectal dose-volume histogram parameters are associated with long-term patient-reported gastrointestinal quality of life after conventional and high-dose radiation for prostate cancer: a subgroup analysis of a randomized trial. Int J Radiat Oncol Biol Phys. 2010;78:1081-1085. 5. Skwarchuk MW, Jackson A, Zelefsky MJ, et al. Late rectal toxicity after conformal radiotherapy of prostate cancer (I): multivariate analysis and dose-response. Int J Radiat Oncol Biol Phys. 2000;47:103-113. 6. Michalski JM, Gay H, Jackson A, Tucker SL, Deasy JO. Radiation Dose–Volume Effects in Radiation-Induced Rectal Injury. Int J Radiat Oncol Biol Phys. 2010;76:S123-S129. 7. Shipley WU, Tepper JE, Prout Jr GR, et al. Proton radiation as boost therapy for localized prostatic carcinoma. JAMA. 1979;241: 1912-1915. 8. Smith A, Gillin M, Bues M, et al. The M. D. Anderson proton therapy system. Med Phys. 2009;36:4068-4083. 9. Weber U, Kraft G. Comparison of carbon ions versus protons. Cancer J. 2009;15:325-332. 10. Sejpal SV, Amos RA, Bluett JB, et al. Dosimetric changes resulting from patient rotational setup errors in proton therapy prostate plans. Int J Radiat Oncol Biol Phys. 2009;75:40-48. 11. Meyer J, Bluett J, Amos R, et al. Spot scanning proton beam therapy for prostate cancer: treatment planning technique and analysis of consequences of rotational and translational alignment errors. Int J Radiat Oncol Biol Phys. 2010;78:428-434. 12. Lomax AJ, Boehringer T, Coray A, et al. Intensity modulated proton therapy: a clinical example. Med Phys. 2001;28:317-324. 13. Gillin MT, Sahoo N, Bues M, et al. Commissioning of the discrete spot scanning proton beam delivery system at the University of Texas M.D. Anderson Cancer Center, Proton Therapy Center, Houston. Med Phys. 2010;37:154-163. 14. Choi S, Amin M, Palmer M, et al. Comparison of intensity modulated proton therapy (IMPT) to passively scattered proton therapy (PSPT) in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys. 2011;81:S154-S155. 15. Newhauser W, Fontenot J, Koch N, et al. Monte Carlo simulations of the dosimetric impact of radiopaque fiducial markers for proton radiotherapy of the prostate. Phys Med Biol. 2007;52:2937-2952. 16. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys. 1995;32:3-12.
Practical Radiation Oncology: April-June 2013 17. Yonemoto LT, Slater JD, Rossi Jr CJ, et al. Combined proton and photon conformal radiation therapy for locally advanced carcinoma of the prostate: preliminary results of a phase I/II study. Int J Radiat Oncol Biol Phys. 1997;37:21-29. 18. Zietman AL, Bae K, Slater JD, et al. Randomized trial comparing conventional-dose with high-dose conformal radiation therapy in early-stage adenocarcinoma of the prostate: long-term results from Proton Radiation Oncology Group/American College of Radiology 95-09. J Clin Oncol. 2010;28:1106-1111. 19. Talcott JA, Rossi C, Shipley WU, et al. Patient-reported longterm outcomes after conventional and high-dose combined proton and photon radiation for early prostate cancer. JAMA. 2010;303: 1046-1053. 20. Slater JD, Rossi Jr CJ, Yonemoto LT, et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int J Radiat Oncol Biol Phys. 2004;59:348-352. 21. Nihei K, Ogino T, Ishikura S, et al. Phase II feasibility study of highdose radiotherapy for prostate cancer using proton boost therapy: first clinical trial of proton beam therapy for prostate cancer in Japan. Jpn J Clin Oncol. 2005;35:745-752. 22. Nihei K, Ogino T, Onozawa M, et al. Multi-institutional phase II study of proton beam therapy for organ-confined prostate cancer focusing on the incidence of late rectal toxicities. Int J Radiat Oncol Biol Phys. 2011;81:390-396. 23. Mayahara H, Murakami M, Kagawa K, et al. Acute morbidity of proton therapy for prostate cancer: the Hyogo Ion Beam Medical Center experience. Int J Radiat Oncol Biol Phys. 2007;69:434-443. 24. Coen JJ, Bae K, Zietman AL, et al. Acute and late toxicity after dose escalation to 82 GyE using conformal proton radiation for localized prostate cancer: initial report of American College of Radiology phase II study 03-12. Int J Radiat Oncol Biol Phys. 2011;81:1005-1009. 25. Mendenhall NP, Li Z, Hoppe BS, et al. Early outcomes from three prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2012;82:213-221. 26. Kuban DA, Nogueras-Gonzalez GM, Hamblin L, et al. Preliminary report of a randomized dose escalation trial for prostate cancer using hypofractionation. Int J Radiat Oncol Biol Phys. 2010;78:S58-S59. 27. Pollack A, Walker G, Buyyounouski MK, et al. Five year results of a randomized external beam radiotherapy hypofractionation trial for prostate cancer. Int J Radiat Oncol Biol Phys. 2011;81:S1. 28. Wilt TJ, MacDonald R, Rutks I, Shamliyan TA, Taylor BC, Kane RL. Systematic review: comparative effectiveness and harms of treatments for clinically localized prostate cancer. Ann Intern Med. 2008;148:435-448. 29. Sheets NC, Goldin GH, Meyer A-M, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. JAMA. 2012;307:1611-1620. 30. Anon. Institute of Medicine. Available at: http://www.iom.edu/ Global/Search.aspx?q=Proton+PROSTATE&output=xml_no_dtd& client=default_frontend&site=default_collection&proxyreload=1. Accessed April 30, 2012. 31. Wilt TJ, Shamliyan TT, Taylor BB, et al. Comparative effectiveness of therapies for clinically localized prostate cancer. Rockville, MD: Agency for Healthcare Research and Quality (US). 2008. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20704036. Accessed April 30, 2012. 32. Shah A, Efstathiou JA, Paly JJ, et al. Prospective preference assessment of patients' willingness to participate in a randomized controlled trial of intensity-modulated radiotherapy versus proton therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2012;83:e13-e19.
www.practicalradonc.org
Review Article
Proton beam therapy for the treatment of prostate cancer Thomas J. Pugh MDa,⁎, Seungtaek Choi MDa , Quyhn Nhu Nguyen MDa , Michael T. Gillin PhDb , X. Ron Zhu PhDb , Matthew B. Palmer MBA, CMDb , Andrew K. Lee MD, MPHa a
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
b
Received 2 January 2012; revised 1 May 2012; accepted 30 May 2012
Abstract Proton beam therapy (PBT) offers the potential of dose escalation to target tissue while decreasing toxicity through unique physical dose deposition characteristics. PBT has been used to treat prostate cancer for several decades; however, recent enhancements in availability and treatment delivery have peaked interest in this technology among radiation oncologists, industry experts, and prostate cancer patients. As a result, the importance of understanding the collective experience and technical aspects of PBT delivery has become increasingly important in radiation medicine. This review article is intended to critically review the literature on PBT for localized prostate cancer, discuss the fundamentals of PBT treatment planning, and describe the continued development of proton beam technology for the treatment of prostate cancer. © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Introduction External beam radiation therapy (EBRT) is commonly used to deliver curative treatment for localized prostate cancer. Well-conducted research over the past several decades have validated the importance of radiation dose in the treatment of localized prostate cancer. 1-3 The conclusion from these studies can be summarized succinctly: higher radiation dose leads to greater likelihood of biochemical control. However, escalation of radiation dose to the prostate brings increased risk of toxicity to adjacent normal tissue. The volume of normal rectum exposed during a course of EBRT correlates with treatment complications, most notably rectal bleeding. 4,5
Conflicts of interest: None. ⁎ Corresponding author. The University of Texas M. D. Anderson Cancer Center, 1840 Old Spanish Trail, Unit 1150, Houston, TX 77030. E-mail address: [email protected] (T.J. Pugh).
The volume of rectum receiving high doses of radiation (≥60 Gy) appears to be the most relevant predictor of rectal toxicity; while the association of low dose (≤45 Gy) and intermediate dose radiation with rectal toxicity is less clear. 6 Therefore, the glass ceiling of dose escalation for prostate cancer is where the therapeutic ratio of cure rateto-toxicity risk is no longer acceptable. As a result, many of the technologic advancements in radiation medicine for prostate cancer over the past several years have focused on delivering dose-escalation to target tissue while minimizing radiation dose to the rectum. Due to unique dose deposition characteristics, proton beam therapy (PBT) was an original method of prostate cancer dose-escalation. 7 Although PBT has been used to treat prostate cancer for over 4 decades, the small number of facilities where such treatments were available has historically limited the application of this technology in the United States. Within the past several years, the number of operational proton therapy centers in the United States has more than quadrupled with several additional proton
1879-8500/$ – see front matter © 2013 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.prro.2012.05.010
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centers planned for development within the next several years. Men with prostate cancer comprise a substantial percentage of patients treated at proton therapy centers due in part to the prevalence of the disease combined with the established safety and efficacy of PBT for localized prostate cancer. In anticipation of increased PBT application, the purposes of this review are the following: (1) critically review the literature on PBT for localized prostate cancer; (2) discuss the fundamentals of PBT treatment planning and delivery; (3) describe the continued development of proton beam technology for the treatment of prostate cancer.
Methods and materials A Medline search identified relevant articles with key words “proton” and “prostate cancer.” The search strategy was intentionally sensitive in order to ensure capture of all relevant material. Review articles, editorials, and articles on proton-based imaging were immediately excluded from consideration. The remaining articles were evaluated for quality using the following prioritization (highest to lowest priority for inclusion): randomized controlled trial, prospective clinical trial, prospectively obtained observation series, retrospective clinical outcome study, and dosimetry studies.
Discussion Fundamentals of proton beam therapy treatment planning Treatment planning for PBT must consider potential sources of error inherent in all forms of EBRT (ie, daily patient positioning reproducibility, interfractional anatomic changes, intrafractional organ motion) as well as proton specific uncertainties such as intrinsic proton range uncertainty, Hounsfield unit stopping power conversions,
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range degradation, and the impact of tissue inhomogeneity along the beam path. In addition to these factors, proton incident energies, production systems, delivery systems, and treatment planning systems vary among proton therapy centers. Therefore, a comprehensive review of treatment planning across all clinically active proton centers is beyond the scope of this review. This article will illustrate the technical elements of PBT for localized prostate cancer at the University of Texas MD Anderson Proton Therapy Center in Houston (PTC-H), acknowledging that subtle discordances between the procedures described here and those of other operational proton centers exist. There currently exist 2 distinct systems of PBT delivery: passive scattering and pencil beam scanning. The vast majority of patients represented in the published series of PBT for prostate cancer were treated with a passive scattering technique. Both passive scattering and pencil beam scanning are utilized at PTC-H. 8 Passive scattering Proton beams possess the unique physical property of depositing the majority of their energy over a narrow range at a fixed depth in tissue, with very little dose deposited beyond that depth. This property contrasts to photon beams where the beam is exponentially attenuated in tissue with a significant portion of the energy deposited as the beam exits the patient. The ability to precisely deliver high-dose radiation to a target while limiting collateral damage to surrounding normal tissue underscores the promise of PBT. The depth of penetration is defined by the incident energy of the proton beam, such that higher incident energy protons allow for greater penetration into tissue. In order to uniformly irradiate a target, the proton beam's energy must be modulated between predefined minimum and maximum energies, creating a “spread out Bragg peak.” In passive scattering PBT, range modulation of a monoenergetic proton beam is provided by the mounted range modulation wheel (Fig 1A). The narrow proton beam is then spread out laterally via a double scattering system.
Figure 1 Beam modification in passive scattering proton beam therapy. (A) Range modulation wheel used to create a spread out Bragg peak (SOBP). (B) Metal aperture designed to shape the proton beam to the intended target. (C) Tissue compensator provides a dose “smearing” effect to account for range uncertainty.
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Customized brass apertures are then used to shape the proton beam to the desired target (Fig 1B). Dense tissues (ie, bone) scatter protons to a greater extent than less dense tissues. 9 This sensitivity to tissue inhomogeneity creates uncertainty about the actual point of dose falloff at the distal edge of a proton beam. Given the potential consequences of range uncertainty in the anterior or posterior direction, an opposed lateral or slight lateral oblique beam arrangement is currently preferred for the treatment of prostate cancer. Beam attenuation from the pelvic bones and femoral heads must be accounted for in order to adequately cover the target and obtain a homogenous dose distribution. Therefore, customized tissue compensators are required for each lateral field in order to “smear” the dose from the proton beam (Fig 1C). Smearing ensures adequate target coverage and accounts for variations in dose distribution from potential patient misalignment. Sejpal et al 10 evaluated the robustness of this treatment delivery technique in a comparative dosimetry study using 70 prostate cancer plans. Each plan used parallel opposed proton beams designed to deliver a total dose of 76-Gy relative biologic equivalents
Figure 2
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(RBE) over 38 fractions. Rotational setup errors were simulated by adjusting the gantry and couch angle plus or minus 3°-5°. The mean clinical target volume (CTV) coverage change was ≤2 Gy (RBE) (range, 77.2-78.4 Gy [RBE]) and the dose change to critical structures (anterior rectal wall, bladder, and rectum) was b5% for all rotational errors. Pencil beam scanning Due to the capability of delivering intensity modulated proton therapy (IMPT), pencil beam scanning has become an area of great technologic interest. Scanning protons offer better dose conformation without the need for custom collimation or tissue compensators. There are 2 clinically applied methods of pencil beam therapy delivery: dynamic spot scanning and discrete spot scanning. A “spot” may best be described as a burst of monoenergetic protons over a short period of time or individually placed Bragg peaks within a target. Discrete spot scanning allows for dose delivery spot by spot along a 3-dimensional grid representing the clinical target. The dose grid is populated at depth by changing the energy of the incident proton
Dose wash comparison between passive scattering and pencil beam scanning proton beam therapy for prostate cancer treatment.
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beam. The beam path is adjusted to isolate each independent spot via a magnetic field. In pencil beam scanning PBT, the CTV and normal structures are contoured in an identical process to passive scattering PBT or modern photon based treatments. A small expansion of the CTV creates a scanning target volume (STV). The STV margin accounts for range uncertainty along the beam path and for organ motion or patient setup error. Meyer et al 11 studied the robustness of this treatment technique in a comparative dosimetry study. Errors in patient alignment in 2 axes (rotational and yaw), as well as translational errors in the anterior-posterior direction, were simulated and compared with control cases. Dose perturbations were minimal despite extreme rotational and yaw shifts. As would be expected when using an opposed lateral beam approach, translational errors resulted in much larger dose perturbations. Pencil beam scanning PBT appears to reduce neutron contamination, 12 reduce treatment time, 13 and confer dosimetric advantages in both the low-dose and high-dose regions compared with passive-scattering PBT 14 (Fig 2). These potential advantages have created widespread interest in pencil beam scanning PBT for the treatment of prostate cancer and other disease sites. Computed tomography simulation Prior to computed tomography (CT) simulation, fiducial markers are placed within the prostate under ultrasound guidance to allow for daily kilovoltage (kV) xray target verification. Two markers are placed: 1 cranially (approximating the base) and 1 caudally (approximating the apex). Fiducial markers made of higher density material may have an unintended shielding effect within the target when an opposed lateral beam approach is employed. 15 Therefore, fiducials markers manufactured from low-density material may be preferable to gold fiducials. At the time of simulation, the patient is positioned supine in a leg and foot cradle. A bladder scan is performed to quantify bladder filling. An endorectal balloon with a gas-release system is inserted to standardize rectal filling volume and immobilize the prostate. Initial scout films are obtained in the anteriorposterior and lateral directions to confirm symmetric alignment of the pelvic bones. Once optimal positioning has been verified, CT images are obtained from L4 through the mid femurs. Skin marks corresponding to the physician-placed isocenter in the mid prostate are placed. The intersection of the cranial edge of the leg-foot cradle and the patient's thigh is also marked. The process is then repeated to confirm reproducibility. The acquired study sets are then uploaded to the treatment planning system. Treatment planning The CTV, organs at risk, and fiducial markers are contoured in the treatment planning system by the treating physician. Conventional CTVs are customized according
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to National Comprehensive Cancer Network (NCCN) risk stratification as follows: low-risk (prostate only); intermediate-risk (prostate + proximal seminal vesicle); and highrisk (prostate + full seminal vesicle). When using a passive scattering approach, an evaluation target volume representing a marginal expansion of the CTV is applied in synonymous fashion to conventional CTV to planning target volume expansions. The current expansion from CTV to evaluation target volume is 6 millimeters (mm) radially except in the posterior direction, where the margin is limited to 4 mm. When a scanning beam approach is utilized, the STV is produced as described above using a differential margin of 12 mm laterally, 6 mm anteriorly, 5 mm superiorly-inferiorly, and 4 mm posteriorly to the CTV. The treatment is prescribed to deliver a total dose of 78 Gy (RBE) in 2 Gy (RBE) daily fractions with treatment delivered 5 days per week. The intended total dose is prescribed to an isodose line above 95% for optimal homogeneity. Treatment delivery Prior to treatment delivery, a bladder scan is performed to ensure bladder filling is within 20% of the volume achieved at the time of simulation. The patient is then positioned on the treatment table according to skin markings, with the endorectal balloon in place. Anteriorposterior and lateral kV images are obtained for comparison with digitally reconstructed radiographs derived from the planning CT. If needed, the treatment table is adjusted to optimize alignment utilizing the fiducial markers, bony anatomy, and the radiopaque endorectal balloon tip as reference points. Treatment is initiated once positioning has been optimized and verified.
Clinical investigation of proton beam therapy for prostate cancer: Review of the literature Early clinical trials Investigators at the Massachusetts General Hospital and Loma Linda University pioneered the use of PBT as a method of dose escalation. Shipley et al 7 reported the sentinel pilot study of PBT for prostate cancer in 1979. This report described a cohort of 17 patients who received an initial course of 48-50 Gy via megavoltage x-rays followed by a perineal proton boost to a total dose of 70-76.5 Gy (RBE). The initial results were encouraging; there was no rectal toxicity, 2 patients developed urinary strictures, and 1 patient experienced a local failure. The treatment paradigm from this pilot study (photon plus proton boost to total dose of 75.6 Gy (RBE) was subsequently evaluated in a randomized trial versus conventional photon therapy alone to a total dose of 67.2 Gy in men with locally advanced (T3-T4) or lymph node positive prostate cancer. 16 At a median follow-up of 5 years, there were no significant differences in overall survival, disease-specific survival, recurrence-free survival, or
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local control between the 2 treatment groups. Local control was improved with higher radiation dose (92% vs 80%; P = .089); however, grade 1 or 2 rectal bleeding was also more common in the high-dose group (32% vs 12%; P = .002). In the early 1990s, Loma Linda University opened the first proton beam facility designed specifically for clinical application. An opposed lateral beam approach was used with a delivery system that included rotating gantries. Yonemoto et al 17 reported the preliminary results of 106 patients with localized prostate cancer treated with combined photons and PBT. All patients received photons to 45 Gy followed by a 30 Gy (RBE) proton boost. At 2-year median follow-up, the incidence of grade 1 or 2 rectal and urinary toxicity were 8% and 4%, respectively. There was no grade 3 or greater toxicity. The culmination of these early studies combining photon therapy and PBT was a randomized trial with joint participation by both centers. The Proton Radiation Oncology Group (PROG) 95-09 trial randomized 393 men with clinical stage T1b-T2b prostate cancer and baseline prostate-specific antigen b15 ng/mL to low-dose (70.2 Gy [RBE]) or high-dose (79.2 Gy [RBE]) radiation. 3,18 All patients received photon therapy to a dose of 50.4 Gy, with the randomization occurring between either a 19.8 Gy (RBE) or 28.8 Gy (RBE) proton beam boost. A total of 393 men were enrolled in the trial. At median 8.9-year followup, high-dose radiation therapy demonstrated superior cancer control as evidenced by improved rates of local control, biochemical failure, and androgen deprivation therapy requirement when compared with lower dose radiation. There was no difference in overall survival. The incidence of grade 3 or greater toxicity was low (b3%) and not significantly different between the 2 groups. An ad hoc quality of life comparison between the low-dose and highdose groups failed to show a significant difference in patient reported quality of life outcomes. 19 In this landmark study, men who were treated with PBT to escalate radiation dose showed improved disease control without significant increase in toxicity or adverse impact on patient reported quality of life.
Contemporary results The long-term results of PBT yield comparable diseasefree survival to alternative treatments for localized prostate cancer with minimal morbidity. The Loma Linda experience provides the most mature insight on PBT for localized prostate cancer, including the first reported experience using PBT as a single modality (without supplemental photons). 20 The most recent update of the Loma Linda experience included 1255 men with clinically localized prostate cancer. All patients were treated to a total prostate dose of 74-75 Gy (RBE) using either a combination of photons and protons (n = 731) or protons alone (n = 524). Patients with an estimated risk of lymph node micro-
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metastases N15% according to the Partin tables received an initial course of 45 Gy to the whole pelvis followed by a PBT boost to the prostate and seminal vesicle. At median follow-up of 63 months, the biochemical failure-free survival was 75% and grade ≥3 gastrointestinal (GI) or genitourinary (GU) toxicity was b1%. Several proton therapy centers in Japan have published their early experiences with PBT for localized prostate cancer. The National Cancer Center Hospital East in Kashiwa, Japan began clinical operations in the late 1990s. Nihei et al 21 confirmed the feasibility of combined photons and protons for dose-escalated prostate cancer treatment in a phase 2 feasibility study. A subsequent multi-institutional series included patients enrolled at 2 additional proton centers in Japan between 2004 and 2007. 22 A total of 151 men with clinical stage T1T2N0M0, Gleason score ≤7, and prostate-specific antigen ≤20 received a total prostate dose of 74 Gy (RBE) in 37 fractions. At a median follow-up of 42 months, acute grade 2 GI and GU toxicity was appreciated in 0.7% and 12% of patients, respectively. Of the 147 patients who had been followed for N2 years, the incidence of late grade 2 or greater GI and GU toxicity was 2.0% and 4.1%, respectively, at 2 years. One of the participating institutions in this multi-institutional trial recently reported on the acute morbidity using PBT for localized prostate cancer. The Hyogo Ion Beam Medical Center reviewed acute morbidity in 287 men with localized prostate cancer treated with PBT. All patients received a total prostate dose of 74 Gy (RBE) in 37 fractions. 23 No patient experienced grade 2 or higher acute GI toxicity; however, 39% and 1% of patients experienced acute grade 2 and grade 3 GU toxicity, respectively. Most of the patients (87%) experiencing grade 2 or 3 GU toxicity were successfully managed with selective alpha-blocker therapy. Larger CTV and the use of androgen deprivation therapy were significant predictors of acute grade 2 or 3 GU morbidity on multivariate analysis. Following PROG 95-09, investigation of PBT in the United States continued to focus primarily on doseescalation. Investigators at Loma Linda University and the Massachusetts General Hospital once again collaborated on a phase 2 trial sponsored by the American College of Radiology (ACR). The ACR 03-12 trial evaluated the safety and efficacy of delivering 82 Gy (RBE) in 41 fractions without androgen deprivation for men with localized prostate cancer. 24 All patients received conformal PBT to the prostate and caudal seminal vesicle to a total dose of 50 Gy (RBE) followed by a 32 Gy (RBE) prostate boost at 2 Gy (RBE) per treatment. Treatments were delivered via passive scattering PBT using opposed lateral beam arrangements with either transabdominal ultrasound or orthogonal radiographs for daily localization. A total of 85 patients were accrued from May 2003 through March 2006. At a median follow-up of 31.6 months, the rate of acute grade
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Summary of published clinical results using proton beam therapy for prostate cancer
Study
Patient selection
Shipley et al 16 T3-T4; N0-N +
Zeitman et al 18 Low- or intermediaterisk Slater et al 20
Nonmetastatic
Nihei et al 22
T1-T2 Gleason score ≤ 7 PSA ≤20 Nonmetastatic
Mayahara et al 23 Coen et al 24
Intermediaterisk High-risk
No.
Total dose
1982-1992 99
75.6 Gy (RBE) 103 67.2 Gy (RBE) 1996-1999 196 79.2 Gy (RBE) 197 70.2 Gy (RBE) 1991-1997 1255 74-75 Gy (RBE) 2004-2007 151 74 Gy (RBE) 2003-2004 287 2003-2006 85
2006-2007 89 82 40
74 Gy (RBE) 82 Gy (RBE)
Median FFBF follow-up (mo)
Acute toxicity Genitourinary
Late toxicity Gastrointestinal
Genitourinary
Gastrointestinal
≤ Grade 2 ≥ Grade 3 ≤ Grade 2 ≥ Grade 3 ≤ Grade 2 ≥ Grade 3 ≤ Grade 2 ≥ Grade 3
80% (5-y) a NR
0%
NR
0%
11% b
3% c
9% d
2% e
92% (5-y) a NR
0%
NR
0%
36% b
6% c
27% d
9% e
83% (10-y) 60% f
2% f
63% f
1% f
27% f
2% f
24% f
1% f
69% (10-y) 51% f
3% f
44% f
1% f
22% f
2% f
13% f
0% f
62
73% (8-y)
NR
b 1% f
NR
b 1% f
NR
b 1% f
NR
b 1% f
43
94% (3-y)
12% g
0% g
1% g
0% g
8% g
0% g
13% g
0% g
NR
NR
39% g
1% g
0% g
0% g
NR
NR
NR
NR
32
NR
69% g
2% g
17% g
0% g
76% g
8% g
43% f
2% f
NR
NR
NR
24% g
2% g
4% g
b 1% g
61
107
78 Gy NR (RBE) 78-82 Gy (RBE) 78 Gy (RBE)
100% (2-y) NR 99% (2-y) 94% (2-y)
Gy, Gray; FFBF, freedom from biochemical failure; NR, not reported; PSA, prostate-specific antigen; RBE, relative biologic equivalents. a Local control defined as no palpable recurrence and negative biopsy in patients completing treatment. b Incidence of hematuria or urinary stricture. c Persistence of hematuria or urinary stricture. d Incidence of rectal bleeding. e Persistence of rectal bleeding. f Radiation Therapy Oncology Group (RTOG) toxicity grading. g Common Terminology Criteria for Adverse Events grading.
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Mendenhall et al 25
T1c-T2b Gleason score ≤ 7 PSA ≤15 Low-risk
Accrual period
T.J. Pugh et al
Table 1
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3 GU or GI toxicity was 2%. The rate of late grade 3 GU or GI toxicity was 7%. As expected, rectal bleeding was the predominant late GI toxicity. The University of Florida presented their early results of 212 patients treated according to 1 of 3 prospective trials from August 2006 thru September 2007 with all patients having a minimum follow-up of 2 years. 25 Treatments were prescribed as follows: 78 Gy (RBE) (low-risk); 78-82 Gy (RBE) (intermediate-risk); and 78 Gy (RBE) with concomitant docetaxel (Taxotere) followed by androgen deprivation (high-risk). All treatments were delivered using conventional treatment schedules of 2 Gy (RBE) per fraction delivered 5 days per week. The incidence of ≥grade 3 GU toxicity was 1.9% and the incidence of ≥grade 3 GI toxicity was b0.5%. All grade 3 GU events were transient. The lone grade 3 GI event was attributed in part to a post-treatment rectal mucosal biopsy in the high-dose region. The rates of ≥grade 2 GU and GI toxicity were 24% and 4%, respectively. The need for pretreatment symptom management predicted grade ≥2 GU events. Surprisingly, the use of concomitant chemotherapy did not appear to significantly effect toxicity. These contemporary studies of dose-escalated PBT for localized prostate cancer confirm the safety and efficacy of this treatment paradigm. Table 1 summarizes both the historic and contemporary results of PBT in patients with prostate cancer. These series report low rates of late toxicity and high rates of biochemical control, the mature results of these series are needed to affirm these assumptions.
Future development of proton beam therapy for prostate cancer The field of radiation oncology continues to pioneer innovative treatments for cancer patients through new technology and improvements in well-established therapies. Technologic advances in PBT delivery, combined with a rapid increase in the availability of this technology, will likely provide the framework for further development of PBT for the treatment of prostate cancer and other diseases. The following are areas of active investigation using PBT for prostate cancer. Hypofractionation The optimal radiation dose and fractionation schedule for prostate cancer treatment is not known. Dose-escalated radiation treatment using conventional fraction sizes and schedules requires a 2-month time commitment from patients and often includes geographic relocation for treatment. There is a growing body of evidence suggesting noninferiority of hypofractionated regimens compared with conventional fractionation for the treatment of prostate cancer. 26,27 Exploration of hypofractionated regimens using PBT is currently underway at several institutions, including PTC-H.
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Intensity modulated proton therapy As described above, IMPT is an area of great technologic interest and is currently implemented clinically for select patients at PTC-H. The favorable dose conformality and modulation using IMPT may allow for further dose escalation while avoiding normal structures.
Comparative effectiveness research There is a paucity of high quality data comparing commonly implemented therapies for localized prostate cancer. 28 There has never been a randomized trial directly comparing external beam radiation treatment delivery techniques. Sheets et al 29 recently interrogated the SEERMedicare database using billing code surrogates for recurrence and treatment morbidity. Paradoxically, PBT was associated with a greater risk of subsequent diagnoses or procedures surrogating GI morbidity compared with intensity modulated radiation therapy (relative risk 0.66). Interpretation of these data is challenging due to the multiple limitations of the analysis, including use of potentially unreliable surrogate endpoints, reporting bias, the absence of specific radiation treatment information regarding dose or technique, and the inherit restriction of data within the Surveillance, Epidemiology and End Results-Medicare database allowing for a single proton therapy center to be represented in the analysis. Furthermore, during the time period analyzed the combination of photon and proton therapy was a common practice as detailed above, clouding the comparison across modalities. Analyses such as these should be considered hypotheses generating. In the absence of high-quality comparative effectiveness research, several agencies have called for randomized evidence to assess the relative clinical benefit of PBT for prostate cancer. 30,31 Efforts for a multiinstitutional collaborative trial comparing intensity modulated radiation therapy and PBT are ongoing. 32
Conclusions The experience to date clearly demonstrates PBT to be a safe and effective method of delivering dose-escalated radiation therapy for localized prostate cancer. The interest in PBT from practitioners, industry leaders, and prostate cancer patients has grown exponentially over the past several years. As a result, the practicing radiation oncologist is increasingly presented with the challenges of reviewing, applying, comparing, and contrasting PBT to other management options for localized prostate cancer. Future work should focus on optimizing this technology, including additional dose escalation strategies, hypofractionation, IMPT applications, and treatment verification techniques, in order to optimize the advantages of this modality. Of particular relevance for prostate cancer
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patients, high-quality comparative-effectiveness research using both biochemical and patient-reported quality of life endpoints is desirable.
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