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International Journal of Urology (2015) 22, 33–39
Review Article
Particle radiotherapy for prostate cancer Yoshiyuki Shioyama,1 Hiroshi Tsuji,2 Hiroaki Suefuji,1 Makoto Sinoto,1 Akira Matsunobu,1 Shingo Toyama,1 Katsumasa Nakamura3 and Sho Kudo1 1
Ion Beam Therapy Center, SAGA-HIMAT Foundation, Tosu, Sagan, 2National Institute of Radiological Sciences, Chiba, Chiba, and Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
3
Abbreviations & Acronyms 3DCRT = 3-dimensional conformal radiation therapy ADT = androgen deprivation therapy CGE = cobalt gray equivalent GI = gastrointestinal GU = genitourinary IMRT = intensity-modulated radiation therapy LBNL = Lawrence Berkeley National Laboratory LET = linear energy transfer NIRS = National Institute of Radiological Sciences RT = radiotherapy SBRT = stereotactic body radiotherapy Correspondence: Yoshiyuki Shioyama M.D., Ph.D., Ion Beam Therapy Center, SAGA-HIMAT Foundation, 415 Harakoga-machi, Tosu 841-0071, Japan. Email: shioyama-yoshiyuki@saga -himat.jp Received 16 July 2014; accepted 3 September 2014. Online publication 12 October 2014
© 2014 The Japanese Urological Association
Abstract: Recent advances in external beam radiotherapy have allowed us to deliver higher doses to the tumors while decreasing doses to the surrounding tissues. Dose escalation using high-precision radiotherapy has improved the treatment outcomes of prostate cancer. Intensity-modulated radiation therapy has been widely used throughout the world as the most advanced form of photon radiotherapy. In contrast, particle radiotherapy has also been under development, and has been used as an effective and non-invasive radiation modality for prostate and other cancers. Among the particles used in such treatments, protons and carbon ions have the physical advantage that the dose can be focused on the tumor with only minimal exposure of the surrounding normal tissues. Furthermore, carbon ions also have radiobiological advantages that include higher killing effects on intrinsic radioresistant tumors, hypoxic tumor cells and tumor cells in the G0 or S phase. However, the degree of clinical benefit derived from these theoretical advantages in the treatment of prostate cancer has not been adequately determined. The present article reviews the available literature on the use of particle radiotherapy for prostate cancer as well as the literature on the physical and radiobiological properties of this treatment, and discusses the role and the relative merits of particle radiotherapy compared with current photon-based radiotherapy, with a focus on proton beam therapy and carbon ion radiotherapy. Key words: carbon ion radiotherapy, intensity-modulated radiation therapy, prostate cancer, proton beam therapy.
Introduction Since the discovery of X-rays in 1895, X-ray and gamma-ray (photon) beams have been widely used in RT for malignant tumors. Recent technical advances of external beam RT using photons – for example, SBRT and IMRT – have permitted the delivery of a higher dose to the tumors and a lower dose to the surrounding tissues. These high-precision photon radiotherapies have improved treatment outcomes in various cancers, including prostate cancer. In the treatment of prostate cancer, IMRT has been widely used as the most advanced form of photon RT. In addition, especially in the treatment of prostate cancer, brachytherapy has been used as an alternative to external beam RT. At the same time, basic and clinical research into external RT using particles (particle RT) has been carried out for the purpose of establishing a more effective and non-invasive treatment. As a medical application of particle beams for cancer therapy, proton beam therapy was first proposed in the USA in 1946 by Wilson,1 and the clinical research was started at the LBNL in 1954.2 Since then, the efficacy of proton beam therapy for cancer treatment has been widely investigated throughout the world. In addition, clinical investigations of heavy ion RT using primarily helium and neon ions were carried out at LBNL between 1977 and 1992. Unfortunately, these studies were terminated before full-fledged clinical application as a result of financial difficulties.2 Soon thereafter, in 1994, clinical research into heavy ion RT was started again at the NIRS in Japan.2–4 The NIRS chose carbon ions as suitable heavy ions, and has continued to show their clinical efficacy for the treatment of a variety of tumors through clinical trials. Attempts have also been made to use fast neutrons for cancer therapy, but these particles have failed to show a clear clinical advantage, and thus, clinical expectations for fast neutrons are already subsiding. At present, the main particles used in external RT are protons and carbon ions, and the clinical introduction has been steadily accumulating in both cases. As the result, more than 100 000 patients have already been treated with particle beams around the world. Prostate cancer has been 33
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one of the most frequent disease targets among these cases. The aim of the present article was to review the clinical results of particle RT for prostate cancer, and to discuss the present and future roles of particle RT for this disease.
Physical and radiobiological characteristics of particles Physical aspects Particles are categorized into charged particles and noncharged particles. Protons and carbon ions are charged particles, whereas neutrons are non-charged particles. Both proton beams and carbon ion beams stop at a certain depth in a material, and produce an energy surge known as a Bragg peak at the end of their range, whereas neutrons do not exhibit an energy surge.5 The depth-dose profile of protons and carbon ion beams allows a highly localized deposition of energy that can be utilized for increasing the radiation doses to tumors while minimizing irradiation to adjacent normal tissues. Dose concentration and escalation without increase of risk is the most basic and important principle in RT. This property of protons and carbon ions thus constitutes a distinct advantage over photons and neutrons. However, there are also several important differences between protons and carbon ion beams. The peak-to-plateau ratio in the depth-dose profile is higher for carbon ion beams than proton beams. Furthermore, the lateral fall-off around the target is steeper for carbon ion beams than proton beams. In other words, the penumbra is smaller in the case of carbon ion beams. Thus, carbon ion beams have a sharper dose distribution compared with proton beams. In contrast, the dose in the region beyond the distal end of the peak is a little higher in carbon ion beams than proton beams. This is because primary carbon ions undergo nuclear interactions and fragment into particles with a lower atomic number, producing a fragmentation tail beyond the peak.2,6,7
Radiobiological aspects As aforementioned, protons and carbon ion beams possess similar depth-dose profiles, and both profiles are more effective for targeting tumors than the depth-dose profile of photons. However, the biological characteristics are markedly different between protons and carbon ion beams. One major difference is the relative biological effectiveness, which is the ratio of cancer cells killed by a particular beam at the same physical dose as that used during photon or gamma-ray irradiation. The relative biological effectiveness of the carbon ion beams has been estimated as 2.0–3.0, whereas that of the proton beams has been estimated as approximately 1.1.8 Therefore, carbon ion beams are two- to threefold more effective at killing cancer cells than proton or photon beams. Cancer cell death in RT is generally caused by DNA damage, which is categorized as single-strand DNA breaks or double-strand DNA breaks. Single-strand DNA breaks can be easily repaired, whereas double-strand DNA breaks are difficult to repair.9 Double-strand DNA breaks are induced with increasing frequency according to the increase of mean energy delivered per unit length (LET) of their trajectory. Therefore, LET is well correlated with the biological effects of radiation; relative biological effectiveness has been shown to 34
increase correlatively when LET increases up to 100 keV/μm.10 When divided by the level of LET, carbon ion beams are categorized as a form of high-LET radiation, whereas proton and photon beams are categorized as low-LET radiation. As a result, carbon ion beams commonly cause double-strand DNA breaks after a single hit, resulting in the most significant event for cancer cell death.9 In addition, high-LET radiation, such as carbon ion beams, also have several biological advantages in radiosensitivity compared with protons or photons – namely, these modalities are characterized by: (i) a low oxygen enhancement ratio; (ii) low cell-cycle dependency; (iii) potential suppression of metastases; and (iv) efficacy against cancer stem cells.11–13 These biological characteristics of high-LET radiation offer theoretical advantages for the control of tumors, such as adenocarcinoma, adenoid cystic carcinoma, malignant melanoma and sarcoma, which are considered to be resistant to low-LET radiations. Furthermore, the LET of carbon ion beams increases until reaching a maximum in the peak region according to the depth in the body.14 This property becomes a therapeutic advantage when carbon ion beams are used as cancer therapy for deep-seated tumors. In contrast, neutron beams are also categorized as high-LET radiation, but the LET of neutrons is uniform at any depth in the body. Therefore, neutron beams do not generally show superiority in a clinical setting, except for some superficial tumors.
Facilities Currently, there are 43 proton therapy centers in the world, and approximately 50% of them are located in the USA (14 facilities) and Japan (nine facilities). In addition, there are at least 26 facilities under construction and 11 facilities in the planning stage. Proton facilities have been increasing rapidly across the globe, including in private hospitals. Indeed, more than 95 000 patients have already been treated with proton therapy worldwide. In contrast, there are just seven carbon ion therapy centers under operation: four facilities in Japan (NIRS, Hyogo Ion Beam Medical Center, Gunma University Heavy Ion Medical Center [GHMC], and Ion Beam Therapy Center in Saga), one in China (Institute of Modern Physics in Lanzhou), one in Germany (Heidelberg Ion-Beam Therapy Center) and one in Italy (National Center for Oncological Treatment in Pavia). Also, at least three carbon ion therapy centers are under development, one in Austria, one in China and one in Japan. NIRS is the first carbon ion therapy facility for medical use, and has treated cancers at various sites in more than 8000 patients so far. Proton therapy has also been carried out at Hyogo Ion Beam Medical Center, Heidelberg Ion-Beam Therapy Center and National Center for Oncological Treatment in Pavia. In total, over 12 000 patients have been treated with carbon ion RT worldwide.
Clinical results in prostate cancer Neutron therapy Neutron therapy is one of the high-LET radiation therapies, which have biological advantages for the treatment of slowgrowing and radioresistant tumors. Accordingly, the efficacy of neutron therapy for prostate cancer was extensively investigated © 2014 The Japanese Urological Association
Particle RT for prostate cancer
in the decades from 1970 to 1990. Several randomized clinical trials for locally advanced prostate cancer comparing neutron therapy and conventional photon therapy have shown an advantage of neutron therapy in terms of local control and survival. In the Radiation Therapy Oncology Group 77-04 trial comparing 7-week treatment of mixed RT (photons followed by a neutron boost) with a 70-Gy equivalent versus photon RT alone with 70 Gy in 7 weeks, the 10-year rates of local control and survival in the mixed neutron arm were 70% and 46%, respectively, whereas those in the photon arm were 58% and 29%, respectively.15 In another randomized trial by the Neutron Therapy Collaborative Group comparing neutron therapy alone with 20.4-Gy equivalent using a hypofractionated regimen of 12 fractions versus photon RT with 70 Gy using standard fractionation for 178 patients with stage T2–4 prostate cancers, significantly better local control and biochemical relapse-free survival were observed in the neutron therapy arm.16 However, in both clinical trials, morbidity of grade 3 or greater adverse events, including rectal and musculoskeletal toxicities, was significantly higher in the patients treated with neutron therapy (24% vs 8% in the Radiation Therapy Oncology Group 77-04, 11% vs 3% in the Neutron Therapy Cooperative Group).15,16 In contrast, Forman et al. developed an approach using 3-D conformal mixed beam RT with neutrons and photons, and found that it yielded encouraging clinical outcomes with acceptable toxicities. In addition, they showed that the combined use of neutron and photon therapy is beneficial in improving disease-free survival for patients with risk factors of cT3, Gleason score >7 or prostate-specific antigen >10 ng/mL.17 However, most of the clinical studies using neutrons could not be continued because of the high incidence of adverse events observed in previous studies. Neutrons have a high radiobiological effect, but unfortunately have no physical advantages in terms of confining the dose to the tumor. It can be considered that the theoretical possibility of an increase in second malignancies in addition to the unimproved dose distribution and integral doses when compared with photons prevented full-fledged clinical application.
Proton beam therapy The effectiveness of proton beam therapy for prostate cancer has been investigated for several decades. In addition, there have been many reports on the treatment outcomes of a combined therapy with protons and photons. However, the published reports regarding long-term treatment outcomes of proton beam therapy alone are limited. In a prospective phase III randomized trial carried out at the Massachusetts General Hospital in which 202 patients with locally advanced (T3–4) prostate cancers were enrolled, the treatment outcomes were compared between patients who underwent combined RT with photons and a proton boost of 75.6 CGE versus those who underwent 67.2-Gy photon RT alone.18 Although there was no difference in overall survival, disease-free survival or local control between the two groups, a significant improvement of the local control rate was seen in the high-dose arm in which patients with poorly differentiated tumors received the combination treatment with a proton boost compared with those who received photon RT alone (94% vs 64% at 5 years). However, the incidence of GI and GU toxicities © 2014 The Japanese Urological Association
was significantly increased in the high-dose arm with a proton boost: the actuarial incidences of rectal bleeding and urethral stricture at 8 years were 32% and 19%, respectively (vs 12% and 8% in the arm receiving photon RT alone). In another phase III study carried out by a cooperative study group (PROG 95-09) that compared a proton boost dose of 19.8 CGE versus 28.8 CGE followed by 50.4-Gy photon beam therapy, the 5-year biochemical relapse-free rate was significantly better in the high-dose proton boost group (80.4%) compared with the modest-dose proton boost group (61.4%). However, the incidence rates of late GI and GU toxicities in the high-dose proton boost group were 18% and 21%, respectively.19 Recently, Johansson et al. reported the treatment outcomes for 278 patients with T1b–T4 disease after a hypofractionated proton boost of 20 Gy in five fractions combined with photon beam therapy of 50 Gy in 25 fractions.20 The 5-year biochemical relapse-free rates were 100%, 95% and 74% for the low-, intermediate- and high-risk patients, respectively. The 5-year late GU toxicities of grade ≥2, grade ≥3 and grade 4 toxicities were 31%, 8% and 1%, respectively, whereas the 5-year late GI toxicities of grade ≥2 and grade ≥3 were 10% and 0%, respectively. Regarding the outcomes of proton therapy alone, a group at Loma Linda University reported that the biochemical relapsefree survival rate of locally advanced prostate cancer patients treated with 74.0-CGE proton beam therapy in 37 fractions was 73% at 8 years, and the incidence rates of late grade 2 or greater GI and GU toxicity were reported to be 3.5% and 5.4%, respectively. Also, late grade 3 or greater morbidity was reported in less than 1% of patients.21,22 In a Japanese multi-institutional study of 151 T1–T3a N0M0 patients receiving 74-Gy CGE proton beam therapy in 37 fractions with or without androgen deprivation therapy, the incidence rates of late grade 2 or greater rectal and bladder toxicity at 2 years were reported to be 2.0% and 4.1%, respectively.23 Mendenhall et al. reported the 5-year outcomes from three prospective trials of proton therapy for prostate cancer. A total of 211 patients (89 with low-risk, 82 with intermediate-risk and 42 with high-risk disease) were treated with 78.0 CGE in 39 fractions (low-risk patients), 78–82 CGE (intermediate-risk) or 78 CGE with concomitant docetaxel therapy followed by androgen deprivation therapy (high-risk). The 5-year rates of biochemical and clinical freedom from disease progression were reported to be 99%, 99% and 76% in low-, intermediate- and high-risk patients, respectively. Also, the actuarial 5-year rates of late grade 3 GI and GU toxicity were reported as 1.0% and 5.4%, respectively. Unfortunately, however, the rates of grade 2 GI or GU toxicity were not described.24 Henderson et al. reported that the 5-year cumulative incidence of grade 2 or higher urinary toxicity was 22.9% in the 171 low- and intermediate-risk patients who were treated with 78.0–82.0 CGE in 39 fractions enrolled in two prospective trials.25 Recently, the effectiveness of hypofractionated RT using protons has also been investigated. Kim et al. reported the initial results of a phase II prospective study investigating the feasibility of hypofractionated proton therapy using five different schedules (60.0 CGE in 20 fractions/5 weeks; 54.0 CGE in 15 fractions/5 weeks; 47 CGE in 10 fractions/5 weeks; 35.0 CGE in 5 fractions/2.5 weeks; and 35.0 CGE in 5 35
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Table 1
Comparison of biochemical relapse-free survival rate between carbon ion RT, proton beam therapy, and photon beam radiotherapy
Authors
Method
27
D’Amico et al. Zelefsky et al.28 Vora et al.29 Martin et al.30 Zelefsky et al.31 Cahlon et al.32 Johansson et al.20 Mendenhall et al.24 Kim et al.26 Ishikawa et al.33
Total dose
3DCRT 3DCRT 3DCRT IMRT IMRT IMRT Proton boost after 3CDRT Proton Proton Carbon
66.0–70.0 Gy 64.8–81.0 Gy 66.0–71.0 Gy 79.8 Gy 81.0 Gy 86.4 Gy 70.0 CGE 78.0–82.0 CGE 35.0–60.0 CGE 57.6–66.0 GyE
Fractions
33–35 36–45 33–38 45 45 48 30 34–41 5–20 16–20
Proportion of ADT (low-/intermediate-/high-)
5-year biochemical relapse-free survival Low
Intermediate
High
None 29% 18% 14%/11%/46% 34%/52%/92% 66% 22%/45%/76% 0%/0%/100%† None 0%/100%/100%
80% 85% 89% 88% 85% 98% 100% 99% 92%‡ 90%
65–75% 65% 68% 77% 76% 85% 95% 99% 90%‡ 97%
40% 35% 49% 78% 72% 70% 74% 76% 75%‡ 88%
†Concurrent docetaxel followed by long-course ADT, ‡4 years.
Table 2
Comparison of grade 2 or greater late morbidity rates according to RT methods
Authors
Michalski et al.
Method
34
Vora et al.29 Madsen et al.35 King et al.36 Cahlon et al.32 Martin et al.30 Takeda et al.37 Kupelian et al.38 Coote et al.39 Martin et al.40 Schulte et al.22 Nihei et al.23 Kim et al.26 Ishikawa et al.33 Tsujii et al.2 Nomiya et al.41
3DCRT 3DCRT 3DCRT SBRT SBRT IMRT IMRT IMRT IMRT IMRT IMRT Proton Proton Proton Carbon Carbon Carbon Carbon
No. patients
118 275 271 40 41 478 259 141 770 60 92 901 151 82 927 216 539 46
Total dose
78.0 Gy 68.4–79.2 Gy 66.0–71.0 Gy 33.5 Gy 36.25 Gy 86.4 Gy 79.8 Gy 76.0–80.0 Gy 70.0 Gy 60.0 Gy 60.0 Gy 75.0 CGE 74.0 CGE 35.0–60.0 CGE 57.6–66.0 GyE 63.0 GyE 57.6 GyE 51.2 GyE
fractions/5 weeks) for T1-T3N0M0 prostate cancer. The 4-year biochemical relapse-free survival rate was 85% (93% for lowrisk, 85% for intermediate-risk and 75% for high-risk disease), and the incidences of grade 2 or greater late GI and GU toxicities were 16.0% and 7.0%, respectively with a median follow up of 42 months.26 To summarize the various findings for proton beam therapy, the combined use of protons as boost irradiation with photon beam therapy resulted in a relatively higher occurrence of severe GI and GU toxicities. Proton beam therapy as a single treatment modality offered favorable outcomes with respect to disease control and also toxicities. Tables 1 and 2 summarize the biochemical relapse-free survival rates and grade 2 or greater late morbidity rates, respectively, according to RT methods. The biochemical relapse-free rates of proton beam therapy are thought to be better than those of 3DCRT;27–29 however, they are almost the same as those of IMRT.30–32 The incidences of grade 2 or greater late GI and GU toxicities are considered to be lower than those by 3DCRT29,34 or SBRT,35,36 and comparable with those of the IMRT series.30,32,37–40 36
Fractions
39 38–41 33–38 5 5 48 45 38–40 28 20 20 39 37 5–20 16–20 20 16 12
Morbidity rate ≥grade 2 GI
GU
25.0–26.0% 7.0–16.0% 16.0% 7.5% 15.0% 4.0% 13.7% 6.0% 4.4% 9.5% 6.3% 3.5% 2.0% 16.0% 1.9% 2.3% 0.6% 0%
23.0–28.0% 18.0–29.0% 21.0% 22.5% 29.0% 16.0% 12.1% 6.3% 5.2% 4.0% 10.0% 5.4% 4.1% 7.0% 6.3% 6.1% 1.9% 0%
Carbon ion RT Since 1994, many clinical trials of carbon ion RT have been carried out for various cancers at NIRS. Among them, prostate cancer is one of the diseases that have been most energetically investigated in terms of efficacy and safety.2–4 At NIRS, based on the assumption that hypofractionation is radiobiologically beneficial for the treatment of prostate cancer, hypofractionated regimens have been consistently used from the time of their initial study. At first, clinical trials using 20 fractions over 5 weeks were carried out at NIRS. Two phase I/II studies in the early period showed that the recommended dose should be 66.0 GyE, and the use of a shrinking field technique is essential to reduce the rectal toxicity.42,43 Subsequently, a phase II study was carried out for T1–T3 prostate cancers using fixed-dose fractionation (66.0 GyE in 20 fractions over 5 weeks), and excellent disease control was reported with acceptable toxicity; the 4-year overall survival and biochemical relapse-free survival rates in 176 patients including 142 high-risk patients were 91% and 87%, © 2014 The Japanese Urological Association
Particle RT for prostate cancer
Fig. 1 Dose distribution and dose–volume histogram in a patient with T3bN0M0 prostate cancer treated with carbon ion RT using 51.6 GyE in 12 fractions. (a) Axial section, (b) coronal section, (c) sagittal section and (d) dose–volume histograms for the rectum, urinary bladder, clinical target volume and planning target volume. Clinical target volume consists of the whole prostate and seminal vesicle. Planning target volume is created by expanding the clinical target volume by 8 mm in the anterior and lateral directions, and by 5 mm in the superior, inferior and posterior directions. The high-dose area is focused to the targets. In contrast, the irradiated volumes of the rectum and urinary bladder are kept low. In carbon ion RT, not only the high-dose volumes, but also the medium- and low-dose volumes of the adjacent organs at risk can be kept lower compared with photon RT represented by IMRT.
(a)
(b)
(c)
(d)
respectively, and the incidence of grade 2 late toxicity was 2.0% for GI and 5.0% for GU.44 This dose fraction protocol was used until 2005 at the NIRS. However, the late grade 2 GI and GU morbidities were increased slightly up to 3.2% and 13.6%, respectively, according to longer follow up, although there was no grade 3 or greater toxicity.33 Accordingly, the total dose was reduced to 63.0 GyE in 20 fractions. Thereafter, a hypofractionated regimen using 57.6 GyE in 16 fractions over 4 weeks, which has an antitumor effect considered to be equivalent to that of 63.0 GyE in 20 fractions based on the L/Q model, was investigated at the NIRS. Okada et al. reported a retrospective analysis of 740 prostate cancer patients treated with carbon ion RT using three different dose fractionation schedules of 63 GyE in 20 fractions, 66 GyE in 20 fractions or 57.6 GyE in 16 fractions.45 The incidence rates of late grade 2 GI toxicity in 66.0 GyE in 20 fractions, 63.0 GyE in 20 fractions and 57.6 GyE in 16 fractions were reported to be 3.2%, 2.3% and 1.5%, respectively. The incidence rates of late grade 2 morbidity in 66.0 GyE in 20 fractions, 63.0 GyE in 20 fractions and 57.6 GyE in 16 fractions were reported to be 13.6%, 6.5% and 2.0%, respectively. Regarding the late grade 3 or greater morbidity, only one patient who was treated with 20 fractions suffered from GU complications, but no grade 4 or higher toxicity was observed.45 Recently, the results of a phase I/II prospective study to evaluate the feasibility of a more hypofractionated regimen using 51.6 GyE in 12 fractions for 3 weeks were reported from NIRS.41 A total of 46 patients (12 low-risk, 9 intermediate-risk and 25 high-risk cases) were enrolled in that study. Regarding acute toxicity, just two patients (4%) showed grade 2 urinary frequency, and no other acute grade 2 toxicities were observed. Regarding the late toxicities, no grade 2 or greater toxicities were observed in any patients within the median follow-up period of 32 months.41 In addition, at the Ion Beam Therapy Center in Saga, Japan, a phase II prospective study using 51.6 GyE in 12 fractions for 3 weeks began in August 2013. The two fields technique (opposing lateral fields) was routinely used for the carbon ion RT planning. The dose distributions and dose-volume histograms in the representative cases with T3b prostate cancer are shown in Figure 1. © 2014 The Japanese Urological Association
Bladder Rectum
Regarding the antitumor effect in carbon ion RT for prostate cancer, Ishikawa et al. reported the updated data of survival and biochemical relapse-free rates in 927 patients (159 with lowrisk, 278 with intermediate-risk and 490 with high-risk disease) treated with carbon ion RT using 20 or 16 fractions at the NIRS.33 In this cohort, neoadjuvant ADT within 6 months was combined with carbon ion RT for the intermediate-risk group, and adjuvant ADT was continued for a total duration of 24–36 months for the high-risk group. The 5-year overall survival and cause-specific survival rates for all patients were 95.3% and 98.8%, respectively. The 5-year relapse-free and local control rates were 90.6% and 98.3%, respectively. There were no differences in the survival or disease control rates between the fractionated schedules. The 5-year biochemical relapse-free rates of the low-, intermediate- and high-risk groups were reported to be 89.6%, 96.8% and 88.4%, respectively.33 As shown in Table 1, it is especially noteworthy that excellent outcomes for biochemical relapse-free survival were obtained even in the high-risk group compared with the photon series27–32 or proton series.20,24,26 The toxicity was even smaller when using 12 or 16 fractions than 20 fractions, although there was no difference in antitumor effect among the fractionated schedules. Also, the incidence of late toxicities in the group receiving carbon ion RT with a hypofractionated regimen could be considered to be lower than those of the groups receiving low-LET radiation therapy including 3DCRT,29,34–36 IMRT30,32,37–40 or proton beam therapy22,23,26 (Table 2). These results can be thought of as proof of the physical and biological advantages of the carbon ion RT over low-LET radiations (photons or protons) or high-LET neutrons. Furthermore, these results offer important clinical evidence that hypofractionated carbon ion RT has radiobiological benefit for prostate cancer.
New techniques and future perspectives At present, two types of beam delivery system have been used in proton beam therapy and carbon ion RT. In the treatment of tumors with various shapes and sizes, the original peak must be 37
Y SHIOYAMA ET AL.
tailored to conform to the tumors. A beam-scattering method with a passive beam delivery system has been widely used so far.2 In this method, the narrow peaks are swept over an extended region by a ridge filter to create the spread-out Bragg peak corresponding to the size of the target volume with the combination of a range modulator, collimator and compensator.6,7 This method is technically stable, and can deliver a uniform dose to the target. However, an undesirable high-dose area is produced in some parts of the proximal normal tissues of the target. Recently, a beam-scanning method with an active beam delivery system was developed.46–49 In the beam-scanning method, in contrast, the peak position is dynamically moved within the target by changing the beam energy and/or changing the beam penetration using absorbers, and thus a sufficient dose can be delivered that precisely conforms to the target volume. This pencil beam-scanning method offers better and more flexible dose distribution, and can shorten the preparation time until the start of treatment from computed tomography acquisition. Currently, this beam-scanning method is rapidly being used in the field of particle therapy.50,51 The pencil-beam scanning will allow us to treat prostate cancers with a more desirable dose distribution by using intensity-modulated particle therapy. This novel technique might further contribute to the tumor control rate, and further reduce the risk of normal tissue toxicity and radiation-induced secondary cancer. In conclusion, proton therapy and carbon ion RT are considered to be effective treatment modalities for prostate cancer. In particular, carbon ion RT has a theoretical radiobiological advantage in addition to its physical advantage for the treatment for prostate cancer. The favorable outcomes in terms of not only tumor control, but also toxicity, obtained from prospective trials carried out at the NIRS can be thought of as apparent evidence of these advantages of hypofractionated carbon ion RT. In the near future, it is expected that this evidence will be confirmed by multi-institutional studies in Japan.
Conflict of interest None declared.
References 1 Wilson RR. Radiological use of fast protons. Radiology 1946; 47: 487–91. 2 Tsujii H, Kamada T. A review of update: clinical results of carbon ion radiotherapy. Jpn J. Clin. Oncol. 2012; 42: 670–85. 3 Hirao Y, Ogawa H, Yamada S et al. Heavy ion synchrotron for medical use HIMAC project at NIRS-JAPAN. Nucl. Phys. A 1992; 538: 541–50. 4 Tsujii H, Morita S, Miyamoto T et al. Preliminary results of phase I/II carbon-ion therapy at the National Institute of Radiological Sciences. J. Brachyther. Int. 1997; 13: 1–8. 5 Greco C. Particle therapy in prostate cancer: a review. Prostate Cancer Prostatic Dis. 2007; 10: 323–30. 6 Chen GTY, Castro JR, Quivey JM. Heavy charged particle radiotherapy. Annu. Rev. Biophys. Bioeng. 1981; 10: 499–529. 7 Kanai T, Furusawa Y, Fukutsu K et al. Irradiation of mixed beam and design of spread-out Bragg peak for heavy-ion radiotherapy. Radiat. Res. 1997; 147: 78–85. 8 Kanai T, Matsufuji N, Myyamoto T et al. Examination of GyE system for HIMAC carbon therapy. Int. J. Radiat. Oncol. Biol. Phys. 2006; 64: 650–56. 9 Hamada N, Imaoka T, Masunaga S et al. Recent advances in the biology of heavy-ion cancer therapy. J. Radiat. Res. 2010; 51: 365–83. 10 Weyrather WK, Ritter S, Scholz M, Kraft G. RBE for carbon track-segment irradiation in cell lines of differing repair capacity. Int. J. Radiat. Biol. 1999; 75: 1357–64.
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11 Ando K, Kase Y. Biological characteristics of carbon-ion therapy. Int. J. Radiat. Biol. 2009; 85: 715–28. 12 Ogata T, Teshima T, Kagawa K et al. Particle irradiation suppresses metastatic potential of cancer cells. Cancer Res. 2005; 65: 113–20. 13 Cui X, Oonishi K, Tsujii H et al. Effects of carbon ion beam on putative colon cancer stem cells and its comparison with X-rays. Cancer Res. 2011; 71: 3676–87. 14 Fukumura A, Tsujii H, Kamada T et al. Carbon-ion radiotherapy: clinical aspects and related dosimetry. Radiat. Prot. Dosimetry 2009; 137: 149–55. 15 Laramore GE, Krall JM, Thomas FJ, Griffin TW, Maor MH, Hendrickson FR. Fast neutron radiotherapy for locally advanced prostate cancer: results of an RTOG randomized study. Int. J. Radiat. Oncol. Biol. Phys. 1985; 11: 1621–27. 16 Russell KJ, Caplan RJ, Laramore GE et al. Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. Int. J. Radiat. Oncol. Biol. Phys. 1994; 28: 47–54. 17 Forman JD, Yudelev M, Bolton S, Tekyi-Mensah S, Maughan R. Fast neutron irradiation for prostate cancer. Cancer Metastasis Rev. 2002; 21: 131–5. 18 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. 19 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: 1233–9. 20 Johansson S, Astrom L, Sandin F, Isacsson U, Montelius A, Turesson I. Hypofractionated proton boost combined with external beam radiotherapy for treatment of localized prostate cancer. Prostate Cancer 2012; 654861: 1–14. 21 Slater JD, Rossi CJ Jr, Yonemoto LT et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int. J. Radiat. Oncol. Biol. Phys. 2004; 59: 348–52. 22 Schulte RW, Slater JD, Rossi CJ Jr, Slater JM. Value and perspectives of proton radiation therapy for limited stage prostate cancer. Strahlenther. Onkol. 2000; 176: 3–8. 23 Nihei K, Ogino T, Onozawa M et al. Multi-institutional Phase II study of proton beam therapy for organconfined prostate cancer focusing on the incidence of late rectal toxicities. Int. J. Radiat. Oncol. Biol. Phys. 2011; 81: 390–6. 24 Mendenhall NP, Hoppe BS, Nichols RC et al. Five-year outcomes from 3 prospective trials of image-guided proton therapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2014; 88: 596e–602. 25 Henderson RH, Hoppe BS, Marcus RB Jr et al. Urinary functional outcomes and toxicity five years after proton therapy for low- and intermediate-risk prostate cancer: results of two prospective trials. Acta Oncol. 2013; 52: 463–9. 26 Kim YJ, Cho KH, Pyo HR et al. A phase II study of hypofractionated proton therapy for prostate cancer. Acta Oncol. 2013; 52: 477–85. 27 D’Amico AV, Whittington R, Malkowicz SB et al. Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer 2002; 95: 281–6. 28 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. 29 Vora SA, Wong WW, Schild S, Ezzell G, Halyard MY. Analysis of biochemical control and prognostic factors in patients treated with either low-dose three-dimensional conformal radiation therapy or high-dose intensity modulated radiotherapy FOR localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2007; 68: 1053–8. 30 Martin JM, Bayley A, Bristow R et al. Image guided dose escalated prostate radiotherapy: still room to improve. Radiat. Oncol. 2009; 4: 50. 31 Zelefsky MJ, Chan H, Hunt M, Yamada Y, Shippy AM, Amols H. Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J. Urol. 2006; 176: 1415–19. 32 Cahlon O, Zelefskym J, Shippy A et al. Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer: toxicity and biochemical outcomes. Int. J. Radiat. Oncol. Biol. Phys. 2008; 71: 330–7. 33 Ishikawa H, Tsuj H, Kamada H et al. Carbon-ion radiation therapy for prostate cancer. Int. J. Urol. 2012; 19: 296–305.
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34 Michalski JM, Bae K, Roach M et al. Long-term toxicity following 3D conformal radiation therapy for prostate cancer from the RTOG 9406 phase I/II dose escalation study. Int. J. Radiat. Oncol. Biol. Phys. 2010; 76: 14–22. 35 Madsen BL, Hsi RA, Pham HT, Fowler JF, Esagui L, Corman J. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results. Int. J. Radiat. Oncol. Biol. Phys. 2007; 67: 1099–105. 36 King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC Jr. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int. J. Radiat. Oncol. Biol. Phys. 2009; 73: 1043–8. 37 Takeda K, Takai Y, Narazaki K et al. Treatment outcome of high-dose image-guided intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer at a single institute in Japan. Radiat. Oncol. 2012; 7: 105. 38 Kupelian PA, Thakkar VV, Khuntia D, Reddy CA, Klein EA, Mahadevan A. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: long-term outcomes. Int. J. Radiat. Oncol. Biol. Phys. 2005; 63: 1463–8. 39 Coote JH, Wylie JP, Cowan RA, Logue JP, Swindell R, Livsey JE. Hypofractionated intensity-modulated radiotherapy for carcinoma of the prostate: analysis of toxicity. Int. J. Radiat. Oncol. Biol. Phys. 2009; 74: 1121–7. 40 Martin JM, Rosewall T, Bayley A et al. Phase II trial of hypofractionated image-guided intensity-modulated radiotherapy for localized prostate adenocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2007; 69: 1084–9.
41 Nomiya T, Tsuji H, Maruyama K et al. Phase I/II trial of definitive carbon ion radiotherapy for prostate cancer: evaluation of shortening of treatment period to 3 weeks. Br. J. Cancer 2014; 110: 2389–95. 42 Akakura K, Tsujii H, Morita S et al. Phase I/II clinical trials of carbon ion therapy for prostate cancer. Prostate 2004; 58: 252–8. 43 Tsuji H, Yanagi T, Ishikawa H et al. Hypofractionated radiotherapy with carbon ion beams for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2005; 63: 1153–60. 44 Ishikawa H, Tsuji H, Kamada T et al. Carbon ion radiation therapy for prostate cancer: results of a prospective phase II study. Radiother. Oncol. 2006; 81: 57–64. 45 Okada T, Tsuji H, Kamada H et al. Carbon ion radiotherapy in advanced hypofractionated regimens for prostate cancer: from 20 to 16 fractions. Int. J. Radiat. Oncol. Biol. Phys. 2012; 84: 968–72. 46 Haberer T, Becher W, Schardt D et al. Magnetic scanning system for heavy ion therapy. Nucl. Instrum. Methods 1993; A330: 295–305. 47 Kraft G. Tumor therapy with heavy charged particles. Prog. Part. Nucl. Phys. 2000; 45: S473–544. 48 Flanz J, Smith A et al. Technology for proton therapy. Cancer J. 2009; 15: 292–7. 49 Mori S, Shibayama K, Tanimoto K et al. First clinical experience in carbon ion scanning beam therapy: retrospective analysis of patient positional accuracy. J. Radiat. Res. 2012; 53: 760–8. 50 Kamada T. Clinical evidence of particle beam therapy (carbon). Int. J. Clin. Oncol. 2012; 17: 85–8. 51 Pugh TJ, Munsell MF, Choi S et al. Quality of life and toxicity from passively scattered and spot-scanning proton beam therapy for localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2013; 87: 946–53.
Editorial Comment Editorial Comment to Particle radiotherapy for prostate cancer According to the Medicare database between 2002 and 2007, radiation therapy consistently accounted for half (46.2–49.9%) of the total treatment options of prostate cancer within 1 year after diagnosis.1 Remarkably, intensity-modulated radiation therapy replaced 3-D conformal radiation therapy as the most common method of radiation therapy, accounting for 77% of external beam radiotherapy by 2007.1 Furthermore, particle radiotherapy such as protons and carbon ions have been developed, and are expected to have more effective dose concentration with hypofractionation and less toxicity. In this review article, Shioyama et al. summarized the latest treatment outcomes of particle radiotherapy on prostate cancer, as well as physical and radiobiological properties of this treatment for the urologist.2 The long-term outcomes should be necessary to evaluate its real efficacy and safety. However, 5-year treatment outcome and safety profiles are highly acceptable as treatment modalities of localized prostate cancer. Although cost reduction is one of the most important issues to be overcome, particle radiotherapy for prostate cancer has moved to bedside treatment from clinical trials.
Conflict of interest None declared.
References 1 Dinan MA, Robinson TJ, Zagar TM et al. Changes in initial treatment for prostate cancer among Medicare beneficiaries, 1999–2007. Int. J. Radiat. Oncol. Biol. Phys. 2012; 82: e781–6. 2 Shioyama Y, Tsuji H, Suefuji H et al. Particle radiotherapy for prostate cancer. Int. J. Urol. 2015; 22: 33-9.
Akira Yokomizo M.D., Ph.D. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan [email protected] DOI: 10.1111/iju.12658 © 2014 The Japanese Urological Association
39
International Journal of Urology (2015) 22, 33–39
Review Article
Particle radiotherapy for prostate cancer Yoshiyuki Shioyama,1 Hiroshi Tsuji,2 Hiroaki Suefuji,1 Makoto Sinoto,1 Akira Matsunobu,1 Shingo Toyama,1 Katsumasa Nakamura3 and Sho Kudo1 1
Ion Beam Therapy Center, SAGA-HIMAT Foundation, Tosu, Sagan, 2National Institute of Radiological Sciences, Chiba, Chiba, and Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka, Japan
3
Abbreviations & Acronyms 3DCRT = 3-dimensional conformal radiation therapy ADT = androgen deprivation therapy CGE = cobalt gray equivalent GI = gastrointestinal GU = genitourinary IMRT = intensity-modulated radiation therapy LBNL = Lawrence Berkeley National Laboratory LET = linear energy transfer NIRS = National Institute of Radiological Sciences RT = radiotherapy SBRT = stereotactic body radiotherapy Correspondence: Yoshiyuki Shioyama M.D., Ph.D., Ion Beam Therapy Center, SAGA-HIMAT Foundation, 415 Harakoga-machi, Tosu 841-0071, Japan. Email: shioyama-yoshiyuki@saga -himat.jp Received 16 July 2014; accepted 3 September 2014. Online publication 12 October 2014
© 2014 The Japanese Urological Association
Abstract: Recent advances in external beam radiotherapy have allowed us to deliver higher doses to the tumors while decreasing doses to the surrounding tissues. Dose escalation using high-precision radiotherapy has improved the treatment outcomes of prostate cancer. Intensity-modulated radiation therapy has been widely used throughout the world as the most advanced form of photon radiotherapy. In contrast, particle radiotherapy has also been under development, and has been used as an effective and non-invasive radiation modality for prostate and other cancers. Among the particles used in such treatments, protons and carbon ions have the physical advantage that the dose can be focused on the tumor with only minimal exposure of the surrounding normal tissues. Furthermore, carbon ions also have radiobiological advantages that include higher killing effects on intrinsic radioresistant tumors, hypoxic tumor cells and tumor cells in the G0 or S phase. However, the degree of clinical benefit derived from these theoretical advantages in the treatment of prostate cancer has not been adequately determined. The present article reviews the available literature on the use of particle radiotherapy for prostate cancer as well as the literature on the physical and radiobiological properties of this treatment, and discusses the role and the relative merits of particle radiotherapy compared with current photon-based radiotherapy, with a focus on proton beam therapy and carbon ion radiotherapy. Key words: carbon ion radiotherapy, intensity-modulated radiation therapy, prostate cancer, proton beam therapy.
Introduction Since the discovery of X-rays in 1895, X-ray and gamma-ray (photon) beams have been widely used in RT for malignant tumors. Recent technical advances of external beam RT using photons – for example, SBRT and IMRT – have permitted the delivery of a higher dose to the tumors and a lower dose to the surrounding tissues. These high-precision photon radiotherapies have improved treatment outcomes in various cancers, including prostate cancer. In the treatment of prostate cancer, IMRT has been widely used as the most advanced form of photon RT. In addition, especially in the treatment of prostate cancer, brachytherapy has been used as an alternative to external beam RT. At the same time, basic and clinical research into external RT using particles (particle RT) has been carried out for the purpose of establishing a more effective and non-invasive treatment. As a medical application of particle beams for cancer therapy, proton beam therapy was first proposed in the USA in 1946 by Wilson,1 and the clinical research was started at the LBNL in 1954.2 Since then, the efficacy of proton beam therapy for cancer treatment has been widely investigated throughout the world. In addition, clinical investigations of heavy ion RT using primarily helium and neon ions were carried out at LBNL between 1977 and 1992. Unfortunately, these studies were terminated before full-fledged clinical application as a result of financial difficulties.2 Soon thereafter, in 1994, clinical research into heavy ion RT was started again at the NIRS in Japan.2–4 The NIRS chose carbon ions as suitable heavy ions, and has continued to show their clinical efficacy for the treatment of a variety of tumors through clinical trials. Attempts have also been made to use fast neutrons for cancer therapy, but these particles have failed to show a clear clinical advantage, and thus, clinical expectations for fast neutrons are already subsiding. At present, the main particles used in external RT are protons and carbon ions, and the clinical introduction has been steadily accumulating in both cases. As the result, more than 100 000 patients have already been treated with particle beams around the world. Prostate cancer has been 33
Y SHIOYAMA ET AL.
one of the most frequent disease targets among these cases. The aim of the present article was to review the clinical results of particle RT for prostate cancer, and to discuss the present and future roles of particle RT for this disease.
Physical and radiobiological characteristics of particles Physical aspects Particles are categorized into charged particles and noncharged particles. Protons and carbon ions are charged particles, whereas neutrons are non-charged particles. Both proton beams and carbon ion beams stop at a certain depth in a material, and produce an energy surge known as a Bragg peak at the end of their range, whereas neutrons do not exhibit an energy surge.5 The depth-dose profile of protons and carbon ion beams allows a highly localized deposition of energy that can be utilized for increasing the radiation doses to tumors while minimizing irradiation to adjacent normal tissues. Dose concentration and escalation without increase of risk is the most basic and important principle in RT. This property of protons and carbon ions thus constitutes a distinct advantage over photons and neutrons. However, there are also several important differences between protons and carbon ion beams. The peak-to-plateau ratio in the depth-dose profile is higher for carbon ion beams than proton beams. Furthermore, the lateral fall-off around the target is steeper for carbon ion beams than proton beams. In other words, the penumbra is smaller in the case of carbon ion beams. Thus, carbon ion beams have a sharper dose distribution compared with proton beams. In contrast, the dose in the region beyond the distal end of the peak is a little higher in carbon ion beams than proton beams. This is because primary carbon ions undergo nuclear interactions and fragment into particles with a lower atomic number, producing a fragmentation tail beyond the peak.2,6,7
Radiobiological aspects As aforementioned, protons and carbon ion beams possess similar depth-dose profiles, and both profiles are more effective for targeting tumors than the depth-dose profile of photons. However, the biological characteristics are markedly different between protons and carbon ion beams. One major difference is the relative biological effectiveness, which is the ratio of cancer cells killed by a particular beam at the same physical dose as that used during photon or gamma-ray irradiation. The relative biological effectiveness of the carbon ion beams has been estimated as 2.0–3.0, whereas that of the proton beams has been estimated as approximately 1.1.8 Therefore, carbon ion beams are two- to threefold more effective at killing cancer cells than proton or photon beams. Cancer cell death in RT is generally caused by DNA damage, which is categorized as single-strand DNA breaks or double-strand DNA breaks. Single-strand DNA breaks can be easily repaired, whereas double-strand DNA breaks are difficult to repair.9 Double-strand DNA breaks are induced with increasing frequency according to the increase of mean energy delivered per unit length (LET) of their trajectory. Therefore, LET is well correlated with the biological effects of radiation; relative biological effectiveness has been shown to 34
increase correlatively when LET increases up to 100 keV/μm.10 When divided by the level of LET, carbon ion beams are categorized as a form of high-LET radiation, whereas proton and photon beams are categorized as low-LET radiation. As a result, carbon ion beams commonly cause double-strand DNA breaks after a single hit, resulting in the most significant event for cancer cell death.9 In addition, high-LET radiation, such as carbon ion beams, also have several biological advantages in radiosensitivity compared with protons or photons – namely, these modalities are characterized by: (i) a low oxygen enhancement ratio; (ii) low cell-cycle dependency; (iii) potential suppression of metastases; and (iv) efficacy against cancer stem cells.11–13 These biological characteristics of high-LET radiation offer theoretical advantages for the control of tumors, such as adenocarcinoma, adenoid cystic carcinoma, malignant melanoma and sarcoma, which are considered to be resistant to low-LET radiations. Furthermore, the LET of carbon ion beams increases until reaching a maximum in the peak region according to the depth in the body.14 This property becomes a therapeutic advantage when carbon ion beams are used as cancer therapy for deep-seated tumors. In contrast, neutron beams are also categorized as high-LET radiation, but the LET of neutrons is uniform at any depth in the body. Therefore, neutron beams do not generally show superiority in a clinical setting, except for some superficial tumors.
Facilities Currently, there are 43 proton therapy centers in the world, and approximately 50% of them are located in the USA (14 facilities) and Japan (nine facilities). In addition, there are at least 26 facilities under construction and 11 facilities in the planning stage. Proton facilities have been increasing rapidly across the globe, including in private hospitals. Indeed, more than 95 000 patients have already been treated with proton therapy worldwide. In contrast, there are just seven carbon ion therapy centers under operation: four facilities in Japan (NIRS, Hyogo Ion Beam Medical Center, Gunma University Heavy Ion Medical Center [GHMC], and Ion Beam Therapy Center in Saga), one in China (Institute of Modern Physics in Lanzhou), one in Germany (Heidelberg Ion-Beam Therapy Center) and one in Italy (National Center for Oncological Treatment in Pavia). Also, at least three carbon ion therapy centers are under development, one in Austria, one in China and one in Japan. NIRS is the first carbon ion therapy facility for medical use, and has treated cancers at various sites in more than 8000 patients so far. Proton therapy has also been carried out at Hyogo Ion Beam Medical Center, Heidelberg Ion-Beam Therapy Center and National Center for Oncological Treatment in Pavia. In total, over 12 000 patients have been treated with carbon ion RT worldwide.
Clinical results in prostate cancer Neutron therapy Neutron therapy is one of the high-LET radiation therapies, which have biological advantages for the treatment of slowgrowing and radioresistant tumors. Accordingly, the efficacy of neutron therapy for prostate cancer was extensively investigated © 2014 The Japanese Urological Association
Particle RT for prostate cancer
in the decades from 1970 to 1990. Several randomized clinical trials for locally advanced prostate cancer comparing neutron therapy and conventional photon therapy have shown an advantage of neutron therapy in terms of local control and survival. In the Radiation Therapy Oncology Group 77-04 trial comparing 7-week treatment of mixed RT (photons followed by a neutron boost) with a 70-Gy equivalent versus photon RT alone with 70 Gy in 7 weeks, the 10-year rates of local control and survival in the mixed neutron arm were 70% and 46%, respectively, whereas those in the photon arm were 58% and 29%, respectively.15 In another randomized trial by the Neutron Therapy Collaborative Group comparing neutron therapy alone with 20.4-Gy equivalent using a hypofractionated regimen of 12 fractions versus photon RT with 70 Gy using standard fractionation for 178 patients with stage T2–4 prostate cancers, significantly better local control and biochemical relapse-free survival were observed in the neutron therapy arm.16 However, in both clinical trials, morbidity of grade 3 or greater adverse events, including rectal and musculoskeletal toxicities, was significantly higher in the patients treated with neutron therapy (24% vs 8% in the Radiation Therapy Oncology Group 77-04, 11% vs 3% in the Neutron Therapy Cooperative Group).15,16 In contrast, Forman et al. developed an approach using 3-D conformal mixed beam RT with neutrons and photons, and found that it yielded encouraging clinical outcomes with acceptable toxicities. In addition, they showed that the combined use of neutron and photon therapy is beneficial in improving disease-free survival for patients with risk factors of cT3, Gleason score >7 or prostate-specific antigen >10 ng/mL.17 However, most of the clinical studies using neutrons could not be continued because of the high incidence of adverse events observed in previous studies. Neutrons have a high radiobiological effect, but unfortunately have no physical advantages in terms of confining the dose to the tumor. It can be considered that the theoretical possibility of an increase in second malignancies in addition to the unimproved dose distribution and integral doses when compared with photons prevented full-fledged clinical application.
Proton beam therapy The effectiveness of proton beam therapy for prostate cancer has been investigated for several decades. In addition, there have been many reports on the treatment outcomes of a combined therapy with protons and photons. However, the published reports regarding long-term treatment outcomes of proton beam therapy alone are limited. In a prospective phase III randomized trial carried out at the Massachusetts General Hospital in which 202 patients with locally advanced (T3–4) prostate cancers were enrolled, the treatment outcomes were compared between patients who underwent combined RT with photons and a proton boost of 75.6 CGE versus those who underwent 67.2-Gy photon RT alone.18 Although there was no difference in overall survival, disease-free survival or local control between the two groups, a significant improvement of the local control rate was seen in the high-dose arm in which patients with poorly differentiated tumors received the combination treatment with a proton boost compared with those who received photon RT alone (94% vs 64% at 5 years). However, the incidence of GI and GU toxicities © 2014 The Japanese Urological Association
was significantly increased in the high-dose arm with a proton boost: the actuarial incidences of rectal bleeding and urethral stricture at 8 years were 32% and 19%, respectively (vs 12% and 8% in the arm receiving photon RT alone). In another phase III study carried out by a cooperative study group (PROG 95-09) that compared a proton boost dose of 19.8 CGE versus 28.8 CGE followed by 50.4-Gy photon beam therapy, the 5-year biochemical relapse-free rate was significantly better in the high-dose proton boost group (80.4%) compared with the modest-dose proton boost group (61.4%). However, the incidence rates of late GI and GU toxicities in the high-dose proton boost group were 18% and 21%, respectively.19 Recently, Johansson et al. reported the treatment outcomes for 278 patients with T1b–T4 disease after a hypofractionated proton boost of 20 Gy in five fractions combined with photon beam therapy of 50 Gy in 25 fractions.20 The 5-year biochemical relapse-free rates were 100%, 95% and 74% for the low-, intermediate- and high-risk patients, respectively. The 5-year late GU toxicities of grade ≥2, grade ≥3 and grade 4 toxicities were 31%, 8% and 1%, respectively, whereas the 5-year late GI toxicities of grade ≥2 and grade ≥3 were 10% and 0%, respectively. Regarding the outcomes of proton therapy alone, a group at Loma Linda University reported that the biochemical relapsefree survival rate of locally advanced prostate cancer patients treated with 74.0-CGE proton beam therapy in 37 fractions was 73% at 8 years, and the incidence rates of late grade 2 or greater GI and GU toxicity were reported to be 3.5% and 5.4%, respectively. Also, late grade 3 or greater morbidity was reported in less than 1% of patients.21,22 In a Japanese multi-institutional study of 151 T1–T3a N0M0 patients receiving 74-Gy CGE proton beam therapy in 37 fractions with or without androgen deprivation therapy, the incidence rates of late grade 2 or greater rectal and bladder toxicity at 2 years were reported to be 2.0% and 4.1%, respectively.23 Mendenhall et al. reported the 5-year outcomes from three prospective trials of proton therapy for prostate cancer. A total of 211 patients (89 with low-risk, 82 with intermediate-risk and 42 with high-risk disease) were treated with 78.0 CGE in 39 fractions (low-risk patients), 78–82 CGE (intermediate-risk) or 78 CGE with concomitant docetaxel therapy followed by androgen deprivation therapy (high-risk). The 5-year rates of biochemical and clinical freedom from disease progression were reported to be 99%, 99% and 76% in low-, intermediate- and high-risk patients, respectively. Also, the actuarial 5-year rates of late grade 3 GI and GU toxicity were reported as 1.0% and 5.4%, respectively. Unfortunately, however, the rates of grade 2 GI or GU toxicity were not described.24 Henderson et al. reported that the 5-year cumulative incidence of grade 2 or higher urinary toxicity was 22.9% in the 171 low- and intermediate-risk patients who were treated with 78.0–82.0 CGE in 39 fractions enrolled in two prospective trials.25 Recently, the effectiveness of hypofractionated RT using protons has also been investigated. Kim et al. reported the initial results of a phase II prospective study investigating the feasibility of hypofractionated proton therapy using five different schedules (60.0 CGE in 20 fractions/5 weeks; 54.0 CGE in 15 fractions/5 weeks; 47 CGE in 10 fractions/5 weeks; 35.0 CGE in 5 fractions/2.5 weeks; and 35.0 CGE in 5 35
Y SHIOYAMA ET AL.
Table 1
Comparison of biochemical relapse-free survival rate between carbon ion RT, proton beam therapy, and photon beam radiotherapy
Authors
Method
27
D’Amico et al. Zelefsky et al.28 Vora et al.29 Martin et al.30 Zelefsky et al.31 Cahlon et al.32 Johansson et al.20 Mendenhall et al.24 Kim et al.26 Ishikawa et al.33
Total dose
3DCRT 3DCRT 3DCRT IMRT IMRT IMRT Proton boost after 3CDRT Proton Proton Carbon
66.0–70.0 Gy 64.8–81.0 Gy 66.0–71.0 Gy 79.8 Gy 81.0 Gy 86.4 Gy 70.0 CGE 78.0–82.0 CGE 35.0–60.0 CGE 57.6–66.0 GyE
Fractions
33–35 36–45 33–38 45 45 48 30 34–41 5–20 16–20
Proportion of ADT (low-/intermediate-/high-)
5-year biochemical relapse-free survival Low
Intermediate
High
None 29% 18% 14%/11%/46% 34%/52%/92% 66% 22%/45%/76% 0%/0%/100%† None 0%/100%/100%
80% 85% 89% 88% 85% 98% 100% 99% 92%‡ 90%
65–75% 65% 68% 77% 76% 85% 95% 99% 90%‡ 97%
40% 35% 49% 78% 72% 70% 74% 76% 75%‡ 88%
†Concurrent docetaxel followed by long-course ADT, ‡4 years.
Table 2
Comparison of grade 2 or greater late morbidity rates according to RT methods
Authors
Michalski et al.
Method
34
Vora et al.29 Madsen et al.35 King et al.36 Cahlon et al.32 Martin et al.30 Takeda et al.37 Kupelian et al.38 Coote et al.39 Martin et al.40 Schulte et al.22 Nihei et al.23 Kim et al.26 Ishikawa et al.33 Tsujii et al.2 Nomiya et al.41
3DCRT 3DCRT 3DCRT SBRT SBRT IMRT IMRT IMRT IMRT IMRT IMRT Proton Proton Proton Carbon Carbon Carbon Carbon
No. patients
118 275 271 40 41 478 259 141 770 60 92 901 151 82 927 216 539 46
Total dose
78.0 Gy 68.4–79.2 Gy 66.0–71.0 Gy 33.5 Gy 36.25 Gy 86.4 Gy 79.8 Gy 76.0–80.0 Gy 70.0 Gy 60.0 Gy 60.0 Gy 75.0 CGE 74.0 CGE 35.0–60.0 CGE 57.6–66.0 GyE 63.0 GyE 57.6 GyE 51.2 GyE
fractions/5 weeks) for T1-T3N0M0 prostate cancer. The 4-year biochemical relapse-free survival rate was 85% (93% for lowrisk, 85% for intermediate-risk and 75% for high-risk disease), and the incidences of grade 2 or greater late GI and GU toxicities were 16.0% and 7.0%, respectively with a median follow up of 42 months.26 To summarize the various findings for proton beam therapy, the combined use of protons as boost irradiation with photon beam therapy resulted in a relatively higher occurrence of severe GI and GU toxicities. Proton beam therapy as a single treatment modality offered favorable outcomes with respect to disease control and also toxicities. Tables 1 and 2 summarize the biochemical relapse-free survival rates and grade 2 or greater late morbidity rates, respectively, according to RT methods. The biochemical relapse-free rates of proton beam therapy are thought to be better than those of 3DCRT;27–29 however, they are almost the same as those of IMRT.30–32 The incidences of grade 2 or greater late GI and GU toxicities are considered to be lower than those by 3DCRT29,34 or SBRT,35,36 and comparable with those of the IMRT series.30,32,37–40 36
Fractions
39 38–41 33–38 5 5 48 45 38–40 28 20 20 39 37 5–20 16–20 20 16 12
Morbidity rate ≥grade 2 GI
GU
25.0–26.0% 7.0–16.0% 16.0% 7.5% 15.0% 4.0% 13.7% 6.0% 4.4% 9.5% 6.3% 3.5% 2.0% 16.0% 1.9% 2.3% 0.6% 0%
23.0–28.0% 18.0–29.0% 21.0% 22.5% 29.0% 16.0% 12.1% 6.3% 5.2% 4.0% 10.0% 5.4% 4.1% 7.0% 6.3% 6.1% 1.9% 0%
Carbon ion RT Since 1994, many clinical trials of carbon ion RT have been carried out for various cancers at NIRS. Among them, prostate cancer is one of the diseases that have been most energetically investigated in terms of efficacy and safety.2–4 At NIRS, based on the assumption that hypofractionation is radiobiologically beneficial for the treatment of prostate cancer, hypofractionated regimens have been consistently used from the time of their initial study. At first, clinical trials using 20 fractions over 5 weeks were carried out at NIRS. Two phase I/II studies in the early period showed that the recommended dose should be 66.0 GyE, and the use of a shrinking field technique is essential to reduce the rectal toxicity.42,43 Subsequently, a phase II study was carried out for T1–T3 prostate cancers using fixed-dose fractionation (66.0 GyE in 20 fractions over 5 weeks), and excellent disease control was reported with acceptable toxicity; the 4-year overall survival and biochemical relapse-free survival rates in 176 patients including 142 high-risk patients were 91% and 87%, © 2014 The Japanese Urological Association
Particle RT for prostate cancer
Fig. 1 Dose distribution and dose–volume histogram in a patient with T3bN0M0 prostate cancer treated with carbon ion RT using 51.6 GyE in 12 fractions. (a) Axial section, (b) coronal section, (c) sagittal section and (d) dose–volume histograms for the rectum, urinary bladder, clinical target volume and planning target volume. Clinical target volume consists of the whole prostate and seminal vesicle. Planning target volume is created by expanding the clinical target volume by 8 mm in the anterior and lateral directions, and by 5 mm in the superior, inferior and posterior directions. The high-dose area is focused to the targets. In contrast, the irradiated volumes of the rectum and urinary bladder are kept low. In carbon ion RT, not only the high-dose volumes, but also the medium- and low-dose volumes of the adjacent organs at risk can be kept lower compared with photon RT represented by IMRT.
(a)
(b)
(c)
(d)
respectively, and the incidence of grade 2 late toxicity was 2.0% for GI and 5.0% for GU.44 This dose fraction protocol was used until 2005 at the NIRS. However, the late grade 2 GI and GU morbidities were increased slightly up to 3.2% and 13.6%, respectively, according to longer follow up, although there was no grade 3 or greater toxicity.33 Accordingly, the total dose was reduced to 63.0 GyE in 20 fractions. Thereafter, a hypofractionated regimen using 57.6 GyE in 16 fractions over 4 weeks, which has an antitumor effect considered to be equivalent to that of 63.0 GyE in 20 fractions based on the L/Q model, was investigated at the NIRS. Okada et al. reported a retrospective analysis of 740 prostate cancer patients treated with carbon ion RT using three different dose fractionation schedules of 63 GyE in 20 fractions, 66 GyE in 20 fractions or 57.6 GyE in 16 fractions.45 The incidence rates of late grade 2 GI toxicity in 66.0 GyE in 20 fractions, 63.0 GyE in 20 fractions and 57.6 GyE in 16 fractions were reported to be 3.2%, 2.3% and 1.5%, respectively. The incidence rates of late grade 2 morbidity in 66.0 GyE in 20 fractions, 63.0 GyE in 20 fractions and 57.6 GyE in 16 fractions were reported to be 13.6%, 6.5% and 2.0%, respectively. Regarding the late grade 3 or greater morbidity, only one patient who was treated with 20 fractions suffered from GU complications, but no grade 4 or higher toxicity was observed.45 Recently, the results of a phase I/II prospective study to evaluate the feasibility of a more hypofractionated regimen using 51.6 GyE in 12 fractions for 3 weeks were reported from NIRS.41 A total of 46 patients (12 low-risk, 9 intermediate-risk and 25 high-risk cases) were enrolled in that study. Regarding acute toxicity, just two patients (4%) showed grade 2 urinary frequency, and no other acute grade 2 toxicities were observed. Regarding the late toxicities, no grade 2 or greater toxicities were observed in any patients within the median follow-up period of 32 months.41 In addition, at the Ion Beam Therapy Center in Saga, Japan, a phase II prospective study using 51.6 GyE in 12 fractions for 3 weeks began in August 2013. The two fields technique (opposing lateral fields) was routinely used for the carbon ion RT planning. The dose distributions and dose-volume histograms in the representative cases with T3b prostate cancer are shown in Figure 1. © 2014 The Japanese Urological Association
Bladder Rectum
Regarding the antitumor effect in carbon ion RT for prostate cancer, Ishikawa et al. reported the updated data of survival and biochemical relapse-free rates in 927 patients (159 with lowrisk, 278 with intermediate-risk and 490 with high-risk disease) treated with carbon ion RT using 20 or 16 fractions at the NIRS.33 In this cohort, neoadjuvant ADT within 6 months was combined with carbon ion RT for the intermediate-risk group, and adjuvant ADT was continued for a total duration of 24–36 months for the high-risk group. The 5-year overall survival and cause-specific survival rates for all patients were 95.3% and 98.8%, respectively. The 5-year relapse-free and local control rates were 90.6% and 98.3%, respectively. There were no differences in the survival or disease control rates between the fractionated schedules. The 5-year biochemical relapse-free rates of the low-, intermediate- and high-risk groups were reported to be 89.6%, 96.8% and 88.4%, respectively.33 As shown in Table 1, it is especially noteworthy that excellent outcomes for biochemical relapse-free survival were obtained even in the high-risk group compared with the photon series27–32 or proton series.20,24,26 The toxicity was even smaller when using 12 or 16 fractions than 20 fractions, although there was no difference in antitumor effect among the fractionated schedules. Also, the incidence of late toxicities in the group receiving carbon ion RT with a hypofractionated regimen could be considered to be lower than those of the groups receiving low-LET radiation therapy including 3DCRT,29,34–36 IMRT30,32,37–40 or proton beam therapy22,23,26 (Table 2). These results can be thought of as proof of the physical and biological advantages of the carbon ion RT over low-LET radiations (photons or protons) or high-LET neutrons. Furthermore, these results offer important clinical evidence that hypofractionated carbon ion RT has radiobiological benefit for prostate cancer.
New techniques and future perspectives At present, two types of beam delivery system have been used in proton beam therapy and carbon ion RT. In the treatment of tumors with various shapes and sizes, the original peak must be 37
Y SHIOYAMA ET AL.
tailored to conform to the tumors. A beam-scattering method with a passive beam delivery system has been widely used so far.2 In this method, the narrow peaks are swept over an extended region by a ridge filter to create the spread-out Bragg peak corresponding to the size of the target volume with the combination of a range modulator, collimator and compensator.6,7 This method is technically stable, and can deliver a uniform dose to the target. However, an undesirable high-dose area is produced in some parts of the proximal normal tissues of the target. Recently, a beam-scanning method with an active beam delivery system was developed.46–49 In the beam-scanning method, in contrast, the peak position is dynamically moved within the target by changing the beam energy and/or changing the beam penetration using absorbers, and thus a sufficient dose can be delivered that precisely conforms to the target volume. This pencil beam-scanning method offers better and more flexible dose distribution, and can shorten the preparation time until the start of treatment from computed tomography acquisition. Currently, this beam-scanning method is rapidly being used in the field of particle therapy.50,51 The pencil-beam scanning will allow us to treat prostate cancers with a more desirable dose distribution by using intensity-modulated particle therapy. This novel technique might further contribute to the tumor control rate, and further reduce the risk of normal tissue toxicity and radiation-induced secondary cancer. In conclusion, proton therapy and carbon ion RT are considered to be effective treatment modalities for prostate cancer. In particular, carbon ion RT has a theoretical radiobiological advantage in addition to its physical advantage for the treatment for prostate cancer. The favorable outcomes in terms of not only tumor control, but also toxicity, obtained from prospective trials carried out at the NIRS can be thought of as apparent evidence of these advantages of hypofractionated carbon ion RT. In the near future, it is expected that this evidence will be confirmed by multi-institutional studies in Japan.
Conflict of interest None declared.
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11 Ando K, Kase Y. Biological characteristics of carbon-ion therapy. Int. J. Radiat. Biol. 2009; 85: 715–28. 12 Ogata T, Teshima T, Kagawa K et al. Particle irradiation suppresses metastatic potential of cancer cells. Cancer Res. 2005; 65: 113–20. 13 Cui X, Oonishi K, Tsujii H et al. Effects of carbon ion beam on putative colon cancer stem cells and its comparison with X-rays. Cancer Res. 2011; 71: 3676–87. 14 Fukumura A, Tsujii H, Kamada T et al. Carbon-ion radiotherapy: clinical aspects and related dosimetry. Radiat. Prot. Dosimetry 2009; 137: 149–55. 15 Laramore GE, Krall JM, Thomas FJ, Griffin TW, Maor MH, Hendrickson FR. Fast neutron radiotherapy for locally advanced prostate cancer: results of an RTOG randomized study. Int. J. Radiat. Oncol. Biol. Phys. 1985; 11: 1621–27. 16 Russell KJ, Caplan RJ, Laramore GE et al. Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. Int. J. Radiat. Oncol. Biol. Phys. 1994; 28: 47–54. 17 Forman JD, Yudelev M, Bolton S, Tekyi-Mensah S, Maughan R. Fast neutron irradiation for prostate cancer. Cancer Metastasis Rev. 2002; 21: 131–5. 18 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. 19 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: 1233–9. 20 Johansson S, Astrom L, Sandin F, Isacsson U, Montelius A, Turesson I. Hypofractionated proton boost combined with external beam radiotherapy for treatment of localized prostate cancer. Prostate Cancer 2012; 654861: 1–14. 21 Slater JD, Rossi CJ Jr, Yonemoto LT et al. Proton therapy for prostate cancer: the initial Loma Linda University experience. Int. J. Radiat. Oncol. Biol. Phys. 2004; 59: 348–52. 22 Schulte RW, Slater JD, Rossi CJ Jr, Slater JM. Value and perspectives of proton radiation therapy for limited stage prostate cancer. Strahlenther. Onkol. 2000; 176: 3–8. 23 Nihei K, Ogino T, Onozawa M et al. Multi-institutional Phase II study of proton beam therapy for organconfined prostate cancer focusing on the incidence of late rectal toxicities. Int. J. Radiat. Oncol. Biol. Phys. 2011; 81: 390–6. 24 Mendenhall NP, Hoppe BS, Nichols RC et al. Five-year outcomes from 3 prospective trials of image-guided proton therapy for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2014; 88: 596e–602. 25 Henderson RH, Hoppe BS, Marcus RB Jr et al. Urinary functional outcomes and toxicity five years after proton therapy for low- and intermediate-risk prostate cancer: results of two prospective trials. Acta Oncol. 2013; 52: 463–9. 26 Kim YJ, Cho KH, Pyo HR et al. A phase II study of hypofractionated proton therapy for prostate cancer. Acta Oncol. 2013; 52: 477–85. 27 D’Amico AV, Whittington R, Malkowicz SB et al. Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer 2002; 95: 281–6. 28 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. 29 Vora SA, Wong WW, Schild S, Ezzell G, Halyard MY. Analysis of biochemical control and prognostic factors in patients treated with either low-dose three-dimensional conformal radiation therapy or high-dose intensity modulated radiotherapy FOR localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2007; 68: 1053–8. 30 Martin JM, Bayley A, Bristow R et al. Image guided dose escalated prostate radiotherapy: still room to improve. Radiat. Oncol. 2009; 4: 50. 31 Zelefsky MJ, Chan H, Hunt M, Yamada Y, Shippy AM, Amols H. Long-term outcome of high dose intensity modulated radiation therapy for patients with clinically localized prostate cancer. J. Urol. 2006; 176: 1415–19. 32 Cahlon O, Zelefskym J, Shippy A et al. Ultra-high dose (86.4 Gy) IMRT for localized prostate cancer: toxicity and biochemical outcomes. Int. J. Radiat. Oncol. Biol. Phys. 2008; 71: 330–7. 33 Ishikawa H, Tsuj H, Kamada H et al. Carbon-ion radiation therapy for prostate cancer. Int. J. Urol. 2012; 19: 296–305.
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34 Michalski JM, Bae K, Roach M et al. Long-term toxicity following 3D conformal radiation therapy for prostate cancer from the RTOG 9406 phase I/II dose escalation study. Int. J. Radiat. Oncol. Biol. Phys. 2010; 76: 14–22. 35 Madsen BL, Hsi RA, Pham HT, Fowler JF, Esagui L, Corman J. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results. Int. J. Radiat. Oncol. Biol. Phys. 2007; 67: 1099–105. 36 King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC Jr. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int. J. Radiat. Oncol. Biol. Phys. 2009; 73: 1043–8. 37 Takeda K, Takai Y, Narazaki K et al. Treatment outcome of high-dose image-guided intensity-modulated radiotherapy using intra-prostate fiducial markers for localized prostate cancer at a single institute in Japan. Radiat. Oncol. 2012; 7: 105. 38 Kupelian PA, Thakkar VV, Khuntia D, Reddy CA, Klein EA, Mahadevan A. Hypofractionated intensity-modulated radiotherapy (70 Gy at 2.5 Gy per fraction) for localized prostate cancer: long-term outcomes. Int. J. Radiat. Oncol. Biol. Phys. 2005; 63: 1463–8. 39 Coote JH, Wylie JP, Cowan RA, Logue JP, Swindell R, Livsey JE. Hypofractionated intensity-modulated radiotherapy for carcinoma of the prostate: analysis of toxicity. Int. J. Radiat. Oncol. Biol. Phys. 2009; 74: 1121–7. 40 Martin JM, Rosewall T, Bayley A et al. Phase II trial of hypofractionated image-guided intensity-modulated radiotherapy for localized prostate adenocarcinoma. Int. J. Radiat. Oncol. Biol. Phys. 2007; 69: 1084–9.
41 Nomiya T, Tsuji H, Maruyama K et al. Phase I/II trial of definitive carbon ion radiotherapy for prostate cancer: evaluation of shortening of treatment period to 3 weeks. Br. J. Cancer 2014; 110: 2389–95. 42 Akakura K, Tsujii H, Morita S et al. Phase I/II clinical trials of carbon ion therapy for prostate cancer. Prostate 2004; 58: 252–8. 43 Tsuji H, Yanagi T, Ishikawa H et al. Hypofractionated radiotherapy with carbon ion beams for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2005; 63: 1153–60. 44 Ishikawa H, Tsuji H, Kamada T et al. Carbon ion radiation therapy for prostate cancer: results of a prospective phase II study. Radiother. Oncol. 2006; 81: 57–64. 45 Okada T, Tsuji H, Kamada H et al. Carbon ion radiotherapy in advanced hypofractionated regimens for prostate cancer: from 20 to 16 fractions. Int. J. Radiat. Oncol. Biol. Phys. 2012; 84: 968–72. 46 Haberer T, Becher W, Schardt D et al. Magnetic scanning system for heavy ion therapy. Nucl. Instrum. Methods 1993; A330: 295–305. 47 Kraft G. Tumor therapy with heavy charged particles. Prog. Part. Nucl. Phys. 2000; 45: S473–544. 48 Flanz J, Smith A et al. Technology for proton therapy. Cancer J. 2009; 15: 292–7. 49 Mori S, Shibayama K, Tanimoto K et al. First clinical experience in carbon ion scanning beam therapy: retrospective analysis of patient positional accuracy. J. Radiat. Res. 2012; 53: 760–8. 50 Kamada T. Clinical evidence of particle beam therapy (carbon). Int. J. Clin. Oncol. 2012; 17: 85–8. 51 Pugh TJ, Munsell MF, Choi S et al. Quality of life and toxicity from passively scattered and spot-scanning proton beam therapy for localized prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 2013; 87: 946–53.
Editorial Comment Editorial Comment to Particle radiotherapy for prostate cancer According to the Medicare database between 2002 and 2007, radiation therapy consistently accounted for half (46.2–49.9%) of the total treatment options of prostate cancer within 1 year after diagnosis.1 Remarkably, intensity-modulated radiation therapy replaced 3-D conformal radiation therapy as the most common method of radiation therapy, accounting for 77% of external beam radiotherapy by 2007.1 Furthermore, particle radiotherapy such as protons and carbon ions have been developed, and are expected to have more effective dose concentration with hypofractionation and less toxicity. In this review article, Shioyama et al. summarized the latest treatment outcomes of particle radiotherapy on prostate cancer, as well as physical and radiobiological properties of this treatment for the urologist.2 The long-term outcomes should be necessary to evaluate its real efficacy and safety. However, 5-year treatment outcome and safety profiles are highly acceptable as treatment modalities of localized prostate cancer. Although cost reduction is one of the most important issues to be overcome, particle radiotherapy for prostate cancer has moved to bedside treatment from clinical trials.
Conflict of interest None declared.
References 1 Dinan MA, Robinson TJ, Zagar TM et al. Changes in initial treatment for prostate cancer among Medicare beneficiaries, 1999–2007. Int. J. Radiat. Oncol. Biol. Phys. 2012; 82: e781–6. 2 Shioyama Y, Tsuji H, Suefuji H et al. Particle radiotherapy for prostate cancer. Int. J. Urol. 2015; 22: 33-9.
Akira Yokomizo M.D., Ph.D. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan [email protected] DOI: 10.1111/iju.12658 © 2014 The Japanese Urological Association
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