Skip Navigation
Skip to contents

Cancer Res Treat : Cancer Research and Treatment

OPEN ACCESS

Articles

Page Path
HOME > Cancer Res Treat > Volume 53(3); 2021 > Article
Special Article Who Will Benefit from Charged-Particle Therapy?
Kyung Su Kim1, Hong-Gyun Wu2,3,4,5
Cancer Research and Treatment : Official Journal of Korean Cancer Association 2021;53(3):621-634.
DOI: https://doi.org/10.4143/crt.2021.299
Published online: June 21, 2021

1Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Korea

2Department of Radiation Oncology, Seoul National University Hospital, Seoul, Korea

3Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea

4Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

5Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Korea

Correspondence: Hong-Gyun Wu, Department of Radiation Oncology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea,
Tel: 82-2-2072-3177, Fax: 82-2-742-2073, E-mail: wuhg@snu.ac.kr
• Received: March 8, 2021   • Accepted: June 14, 2021

Copyright © 2021 by the Korean Cancer Association

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

  • 7,026 Views
  • 237 Download
  • 6 Web of Science
  • 7 Crossref
prev next
  • Charged-particle therapy (CPT) such as proton beam therapy (PBT) and carbon-ion radiotherapy (CIRT) exhibit substantial physical and biological advantages compared to conventional photon radiotherapy. As it can reduce the amount of radiation irradiated in the normal organ, CPT has been mainly applied to pediatric cancer and radioresistent tumors in the eloquent area. Although there is a possibility of greater benefits, high set-up cost and dearth of high level of clinical evidence hinder wide applications of CPT. This review aims to present recent clinical results of PBT and CIRT in selected diseases focusing on possible indications of CPT. We also discussed how clinical studies are conducted to increase the number of patients who can benefit from CPT despite its high cost.
Radiation therapy is an essential element in cancer treatment, with some estimates that approximately 25% to 30% of cancer patients undergo radiotherapy during their treatment course in Korea [1]. Charged-particle therapy (CPT) using proton or carbon ion, has physical and biological advantages over conventional X-ray therapy. Bragg peak and sharp penumbra allows high tumor dose while saving normal tissue and reduced spread dose. Moreover, carbon ion has greater relative biological effectiveness (RBE) than photon or proton.
Unique physical properties of particle therapy enable dose escalation to the tumor while limiting toxicity in normal tissues, which increases the therapeutic window for cancer patients. Indication for CPT includes unresectable tumors located in eloquent areas or patients with poor organ function, which are of serious concern when treated with X-ray radiotherapy. Proton beam therapy (PBT) can also benefit pediatric cancer patients because it can reduce late side effects and secondary malignancy. In addition, because of the high linear energy transfer (LET) of carbon ion radiotherapy (CIRT), the general indications for CIRT are radioresistant tumor types [26].
However, high set-up cost of particle therapy facilities makes it difficult to be widely applied to all cancer patients. Countries with CPT facilities have their own recommendation or public health insurance indication (Table 1) [710]. Pediatric cancer is the most common indication for PBT, as concerns regarding late effects. CPT is also indicated for certain rare cancers in adults such as tumors located in the eye, skull base and re-irradiation cases because of concern about radiation damage to adjacent normal tissues. Although there is a lack of consensus regarding the comparative effectiveness of CPT for common adult cancer types, the benefits of CPT may be demonstrated in a subset of patients with prostate, lung, liver, pancreas, and breast cancers [11].
In the following sections, we present recent clinical outcomes of PBT and CIRT in selected diseases. In addition, we propose clinical research methods to increase the number of patients who can benefit from CPT, given the limitation of its high cost.
1. Pediatric cancer
Childhood cancer survivors who undergo radiotherapy are at high risk of deleterious effects on growth and development and of tissue late effects, including secondary malignancies.
In addition to the long life expectancy of children, germline predisposition to second malignancy of the childhood cancer is also the reason we should reduce normal tissue irradiation as much as possible in pediatric cancer patients. Hence, PBT has recently attracted worldwide attention as a radiotherapy modality for pediatric cancer.
Long-term outcome data showing favorable toxic profile of PBT for the treatment of pediatric central nervous system cancer such as medulloblastoma has been published [1214]. Furthermore, the relationship between PBT and secondary cancer has been clarified. Sethi et al. [15] reported that the incidence of secondary cancer in 86 patients with retinoblastoma who were treated with PBT (n=55) or photon radiotherapy (n=31). Ten-year cumulative incidence of in-field secondary malignancies with PBT was lower than with conventional photon radiotherapy (0% vs. 14%, p= 0.015).
There is only limited research on the role of CIRT for pediatric cancer. Even though it could be efficient for radioresistant tumors of the children, long-term safety data is needed because of dosimetric uncertainty different from PBT.
2. Uveal melanoma
Uveal melanoma is a rare disease that has traditionally treated with surgery, brachytherapy, and particle therapy. Treatment with PBT was started in 1975 and has been beneficial in preserving vision and controlling disease [16,17]. A meta-analysis reported a superior local control (LC) rate and fewer adverse events in PBT compared to brachytherapy [18]. Treatment using carbon ions also showed promising results, with an LC rate of 97.4% at 3 years [19].
3. Head and neck cancer
CPT has been applied to radioresistant tumors other than squamous cell carcinoma of the head and neck. Adenoid cystic carcinoma arising from the salivary gland is a typical example with promising results using particle therapy. Although surgery and postoperative radiotherapy are the standard of care, it is still difficult to treat cancerous lesions in locations unfit for surgery, and locally advanced cancer with perineural invasion makes treatment difficult. PBT [20,21] or CIRT [22,23] used as a boost or primary treatment showed a high LC rate with acceptable toxicity.
Another suitable indication for particle therapy for head and neck cancer is malignant melanoma [24,25]. A multicenter retrospective study in Japan reported promising results in 260 patients with mucosal melanoma of the head and neck when treated with CIRT [25]. Seventy-eight patients had lesions in the nasal cavity, and concurrent chemotherapy was administered to 129 patients. The LC rate and overall survival (OS) rates at 2 years were 83.9% and 69.4%, respectively. Grade-3 or higher late toxicities were reported in 19% of the patients.
In addition, the treatment outcomes of particle therapy have been reported for tumors arising from the paranasal sinus and nasal cavity, including squamous cell carcinoma and rare histologic tumors in the head and neck [2629]. A systematic review and meta-analysis concluded that particle therapy could be associated with better outcomes in tumors in the paranasal sinus and nasal cavity [26]. In the case of re-irradiation, particle therapy could have advantages owing to its dose gradient and decreased integral dose [30].
4. Bone and soft-tissue sarcoma
Chordoma is a rare bone tumor with slow growth. However, these tumors tend to be locally aggressive and have a high local recurrence rate. Moreover, they are located along the neural axis, clivus, and sacrum, where total resection is almost impossible to achieve. For skull-base chordoma, the proximity to vital structures also makes it difficult for definitive radiotherapy to be applied without complications. Therefore, particle therapy is preferred over conventional radiotherapy therapy to deliver a sufficient dose to the designated site. The LC rate has been reported to be 69.7%–87.9% [3134] with an OS rate range of 80%–88.3% at 5 years [3133]. For sacral chordoma, a similar outcome has been reported for PBT [3436]. Although direct comparison of photon and particle therapy has not been reported, a recent analysis of 863 patients with chordoma and chondrosarcoma from the National Cancer Center Database showed that PBT was associated with an improved OS compared to photon radiotherapy [37]. CIRT results from the treatment of skull-base chordoma and chondrosarcoma were summarized in a recent meta-analysis [38]. An estimated LC rate of 80% and 89% at 5 years was reported in chordoma-only and chondrosarcoma-only studies, respectively. Estimates of OS probability at 5 years in chordoma-only studies and chondrosarcoma-only studies were 94% and 95%, respectively. An active investigation of randomized trials comparing PBT and CIRT of skull-base chordoma and chondrosarcoma is ongoing [39,40]. CIRT of the sacral chordoma also showed promising results, with OS rates ranging from 78% to 84% at 5 years [4144].
Possible indication for CIRT include soft-tissue sarcomas arising from the axial skeleton or retroperitoneal space because they are difficult to approach using surgical methods [4547].
5. Lung cancer

1) Early-stage non-small-cell lung cancer

For inoperable stage I–II non–small cell lung cancer (NSCLC), stereotactic body radiotherapy (SBRT) of photons is widely used in the clinic. By delivering an ablative radiation dose to the gross tumor within a few fractions, we can achieve an LC rate of over 90%. However, a high tumor-control rate through SBRT using photons cannot always be achieved in clinical practice. Such conditions include patients who have large or centrally located diseases and are prone to severe side effects due to poor general conditions, decreased pulmonary function, or recurrent diseases [48]. Particle therapy could be advantageous over SBRT under such conditions. For large T2 tumors, Iwata et al. [49] reported a 4-year LC rate and OS of 75% and 58% with CPT, respectively. Moreover, particle therapy can safely obtain high LCs in cases of centrally located tumors [50]; in patients with poor pulmonary function, such as those with idiopathic pulmonary fibrosis [5153]; or the elderly [54]. There are no randomized controlled trials (RCTs) that directly compare SBRT with particle therapy. However, Chi et al. [55] conducted a systematic review and meta-analysis, and reported that even with more advanced tumors in terms of size and T category, patients treated with particle therapy were found to have significantly better OS and progression-free survival (PFS) than those treated with photon SBRT in the weighted multivariate analysis [55]. A retrospective comparison of CIRT with SBRT demonstrated a positive efficacy profile of CIRT for early-stage NSCLC over SBRT [56].
When CIRT was used, 18 fractions over 6 weeks were reduced to nine fractions over 3 weeks and finally to four fractions over one week with acceptable efficacy and safety [5759]. A recent study on CIRT reported that even one fraction could achieve favorable outcomes with acceptable toxicity [60,61]. In addition to the advantages of providing convenience to the patient by providing single-day treatment, CIRT can provide an advantage in terms of cost-effectiveness because the number of particle therapy facilities is limited.

2) Locally advanced NSCLC

It is well known that improved LC in locally advanced NSCLC is associated with improved OS. The Radiation Therapy Oncology Group 0617 trial failed to show that increased doses guarantee improved outcomes. However, excessive doses to the lungs and heart are considered to be associated with poor outcomes [62,63]. Particle therapy can deliver an adequate radiation dose to the target while avoiding normal tissue in patients with locally advanced NSCLC. A retrospective and phase-I/II study reported the feasibility of PBT [64,65] and CIRT [6670] for locally advanced NSCLC.
Even with the known advantages of particle therapy, one randomized phase-II trial performed to date reported that PBT did not have benefits over photons in advanced NSCLC [71]. In this study, PBT did not show benefits in LC or incidence rates of grade-3 pneumonitis in patients with stage IIB - oligometastatic diseases. However, the results of this study should be interpreted carefully. The sample of the study was very heterogeneous, with variability in disease states and target coverage, and randomization was performed after the initial screening with treatment plans of the two modalities. Finally, the learning curve of PBT delivery was developed through the study period instead of being established before the study began [72]. The patient population that will benefit from particle therapy should be well defined, and studies that integrate chemotherapy and immunotherapy should be conducted in the future to reflect current clinical practices.
There are many limitations in delivering particle therapy to organs that move due to respiratory motion, such as the lungs. The uncertainty arising from the interplay between the scanning beam and moving target needs to be controlled. Recently, technical advances have been made to control respiratory motion, such as four-dimensional computed tomography, respiratory-gated systems, and fast scanning systems, as previously discussed [73,74].
6. Liver cancer
The role of radiotherapy in the management of hepatocellular carcinoma (HCC) is increasing in clinical practice. Recent progress in radiation oncology has enabled the concentration of higher-radiation-dose photon beams to the tumor surrounded by relatively radiosensitive normal liver tissue, and SBRT has become one of the ablative treatment options for HCC [75]. The results of particle therapy for HCC using protons have been reported at Tsukuba University in Japan [76]. The second most common cancer treated with PBT is HCC in Japan [77]. The CIRT facility in Japan has also started treatment of HCC, and currently 5%–6% of the treated patients are HCC patients [78]. Pooled analyses of the results of HCC patients treated with particle therapy have been reported [79]. By analyzing 16 studies containing reports from 17 cohorts with a total of 1,516 patients treated with protons or carbon, the authors concluded that the LC rate was 87% and OS was 59% at 3 years. This study showed favorable outcomes similar to those of SBRT [80], but it should be noted that the population of this study included patients with large tumors, portal vein tumor thrombosis (PVTT), and liver cirrhosis. The indications for particle therapy of HCC have not yet been determined, but by exploiting superior dose profiles, we can apply particle therapy in difficult cases of clinical situations that are ineligible for photon therapy [81,82]. These conditions include large tumor sizes [8385], central lesions near the porta hepatis [8688], tumors with PVTT [8991] or inferior vena cava tumor thrombosis [92], tumors with close proximity to gastrointestinal (GI) organs [93], patients with poor liver function or cirrhosis [94], and elderly patients [95].
Selected studies in particle therapy reported excellent tumor control and OS [96,97]. Sanford et al. [82] reported a superior OS with PBT over photons-based therapy in their retrospective studies. Moreover, studies comparing the efficacy of particle therapy with other local treatment modalities, such as radio-frequency ablation [98] and transarterial chemoembolization [99,100] have been reported recently. Regarding the fractionation schedule of CIRT, an attempt to reduce the fraction schedule from four to two would increase the convenience to patients receiving the therapy [97,101]. Based on these results, studies should be conducted to clarify the benefits of particle therapy in the management of HCC.
The effectiveness of particle therapy in treating unresectable cholangiocarcinoma has also been investigated [102104]. In these studies, particle therapy showed a high LC rate, but distant metastasis still limited the OS gain. Further studies are needed to establish optimal treatment strategies for unresectable cholangiocarcinoma by combining chemotherapy and particle.
7. Pancreatic cancer

1) Unresectable locally advanced disease

Multi-agent chemotherapy is the standard treatment for unresectable, locally advanced pancreatic cancer. The role of local therapy remains controversial. The LAP07 trial showed significantly longer period without treatment (6.1 months vs. 3.7 months) and reduced local tumor progression (32% vs. 46%, p < 0.05) in the chemo-radiotherapy group after induction chemotherapy, even though it did not show an OS benefit compared to the chemotherapy-alone group. Several studies that performed autopsies reported that approximately 30% of patients with pancreatic cancer did not show evidence of distant metastasis at death. In addition, the possibility of OS improvement by improving the LC through SBRT or dose escalation has been shown in recent studies [105,106]. Therapeutic gains can be obtained in pancreatic cancer from particle therapy because of the limitations in sufficient dose escalation of X-rays due to close proximity to the duodenum, stomach, etc. With these theoretical advantages, favorable outcomes of unresectable pancreatic cancer treated with PBT have been reported [107113]. These studies used diverse fraction sizes of 1.8–4.5 Gy, and reported favorable toxicity profiles [114]. Moreover, pancreatic cancers are known to be hypoxic; thus, the radiobiological advantages of carbon ions with high-LET property can be maximized [115]. A few clinical trials and retrospective studies have evaluated CIRT for unresectable pancreatic cancer in Japan [116121]. Shinoto et al. [117] reported the treatment results of 64 unresectable pancreatic cancer patients treated with CIRT. Chemotherapy was administered before CIRT to 78% of patients, and 88% of the patients were treated with concurrent gemcitabine and/or S-1. In 75% of patients, the distance between the tumor and the GI tract was within 5 mm. The prescribed dose was 55.2 Gy (relative biological effectiveness, RBE) with 12 fractions. They reported an excellent 2-year OS rate of 53%, and grade-3 ulcer/bleeding was reported in two patients. Two multi-institutional prospective phase-III trials comparing photon intensity modulated radiotherapy (IMRT) and CIRT are ongoing (NCT03403049 and NCT03535182).

2) Potentially resectable disease

In resectable or borderline-resectable pancreatic cancer, the role of neoadjuvant treatment is actively being investigated [122124]. The potential increase in R0 resection rate, decrease in locoregional recurrence rate, and better patient compliance could be the advantages of incorporating radiotherapy in the neoadjuvant setting. Retrospective and phase-I/II trials of PBT [107,122,124127] and CIRT [119,128] have been reported, but more prospective trials are needed for radiotherapy, including particle therapy, to be established as a standard treatment.
8. Prostate cancer
Radiotherapy is used as a definitive treatment for patients with prostate cancer. Due to the dose-dependent tumor-control rate and frequent late GI and genitourinary toxicity, IMRT is commonly used in the clinic. PBT and CIRT have advantageous physical properties over photon-based radiotherapy because they can provide adequate dose distribution with fewer beam portals. Theoretically, PBT and CIRT may seem ideal for subsequent dose escalation with minimal toxicity. However, due to the lack of clinical trials that directly compare the effects of particle therapy with photon beam radiotherapy, it is difficult to evaluate the superiority of particle therapy. The limited number of institutions that can conduct clinical studies involving particle therapy is also a major limitation.
Despite these limitations, many studies have reported that PBT [129133] and CIRT [134138] show lower toxicity compared to IMRT [139]. Prostate cancer is characterized by a very low α/β ratio, thus leading to the theoretical superiority of particle therapy with a hypofractionated schedule over conventional photon radiotherapy. With 12 fractions at 3 weeks, CIRT showed superior 5-year biochemical-free survival (88%–92%) in high-risk prostate cancer patients compared to the previously reported result of the IMRT group [134,135].
As particle therapy is a limited medical resource, there are constraints on its widespread use for prostate cancer. With a gradual decrease in the cost of the facility, efficiency of the hypofractionation schedule, low toxicity profile, high biochemical control rate of intermediate or high-risk disease, and reduced secondary cancer risk [140], it is expected that particle therapy of prostate cancer will become a cost-effective treatment in the near future. Since April 2018, particle therapy for prostate cancer has been covered by the Japanese National Health Insurance System [139]. The majority of patients treated with CPT in Japan were prostate cancer patients [77,78].
9. GI malignancy

1) Esophageal cancer

There is still little evidence on the role of particle therapy in the treatment of esophageal cancer. However, many studies have shown that toxicity can be reduced by reducing the dose to the heart and lungs during particle therapy, and recent studies have reported that acute hematologic toxicity of grade 4 or higher can be reduced using PBT compared to IMRT in the treatment of esophageal cancer [141]. Moreover, PBT reduced the risk and severity of adverse events compared to IMRT while maintaining a similar PFS in a randomized phase-IIB trial [142]. Regarding oncological outcomes, there are no RCTs that directly compare PBT and photon therapy, and a retrospective study has reported the improved OS of PBT over IMRT [143]. Xi et al. [143] reported that patients who received PBT had significantly higher 5-year OS rates than IMRT (41.6% vs. 31.6%), and PBT was a significant factor for OS in multivariate analysis. Akutsu et al. [144] reported a clinical trial of a preoperative short-course CIRT for esophageal cancer. In their report, a complete response was achieved in 39% of the patients, and 42% of patients achieved a partial response after treatment with a total dose of 28.8 Gy (RBE) and up to 36.8 Gy (RBE) in 8 fractions. Further studies are needed to select the optimal patient to benefit from particle therapy in the treatment of esophageal cancer.

2) Recurrent rectal cancer

Local recurrence occurs in 5%–10% of patients after surgical resection of rectal cancer [145]. Therapeutic options for salvage treatment of locally recurrent rectal cancer are limited, especially in patients who have undergone preoperative radiotherapy [146]. CIRT has shown promising results in these diseases. Shinoto et al. [147] reported multi-institutional retrospective data of 224 patients treated with CIRT in Japan. They reported an LC rate of 93% and an OS rate of 73% at 3 years with limited toxicity. In the case of re-irradiation, CIRT shows promising results [148150].
10. Breast cancer
The largest proportion of patients receiving radiotherapy are breast cancer patients. It is well known that radiation dose to the heart is associated with late cardiovascular disease after breast radiotherapy [151]. The use of protons would spare the heart from radiation and could result in fewer morbidities later in life. Thus, PBT can be cost-effective for patients with one or more cardiac risk factors. The risk factors include left breast cancer, post-mastectomy chest wall irradiation, and node-positive disease receiving for regional nodal irradiation [152].
We have to admit that there are lack of high level of evidence to support superiority of particle therapy over conventional photon therapy. RCTs are crucial in defining the role of CPT but cannot and should not be used exclusively to investigate this. RCTs between CPT and conventional photon treatment in a population that are not particularly abundant as individuals who are likely to experience a difference are not a suitable tool to the identification and quantification of the clinical benefit of CPT. Several different methodological approaches are needed. Establishing the relative role of CPT will include estimating the magnitude of benefit, which is likely to be different in different patient groups. In addition, understanding the scientific principles, and uncertainties or ensuring safety, underlying CPT is crucial to achieving greatest clinical benefit for patients [8]. These clinical studies involve clinical cohort study with long-term outcome tracking of every patient treated. Since the number of CPT center is limited, introduction of an appropriate referral system and multicenter registry are essential to successfully carry out these studies. Beside clinical studies, translational studies to maximize the possible benefit of particle therapy should be conducted in parallel. These studies include the application of ultra-high dose-rate (FLASH) therapy of proton beam, clinical application potent immunogenic effect of CPT and studies to understand basic biologic interaction of heavy ions such as carbon or oxygen ions.
There are several factors that influence the optimal number of particle therapy facilities needed in one society. The expansion of the particle therapy facility should be accompanied by studies necessary to select patients who can benefit from the CPT as described above, and at the same time, cost-effective analysis considering nationwide medical cost and changes in healthcare insurance policy should be carefully considered [153]. The proportion of the patients treated with PBT or CIRT in California, Japan, and United Kingdom were summarized in Table 2 [8,11,77,78]. Recently in United States, the number of proton centers has expanded rapidly from two centers in 2004 to 27 centers in 2020. However, decline of insurance coverage and shortage of patient brought financial problem to one-third of the institutions [154,155]. On the other hand, in United Kingdom, two proton centers opened in 2018 and 2020 and started to treat patients focusing on pediatric patients after decade-long careful planning [8]. In Nethelands, the three new proton beam therapy centers will use a normal tissue complication probability model to select patients who are expected to benefit significantly from PBT on the basis of comparative planning for individual patients [156]. In Japan, there are 18 proton centers and six carbon centers, and coverage of national health insurance for particle therapy are expanding including prostate cancer.
In Korea, two proton centers have been established from 2007 (National Cancer Center, Goyang) and 2015 (Samsung Medical Center, Seoul). National Cancer Center is planning the installation of the second cyclotron for PBT. Moreover, Seoul National University Hospital and Yonsei University Hospital decided to set up CIRT centers in Busan and Seoul, respectively, and these centers will open within 3 to 4 years. At the beginning of the expanding CPT facilities in Korea, efforts should be made to build high-level evidence that can confirm clinical benefits of particle therapy. Along with these efforts, it is necessary to carefully increase the number of patients who can benefit from CPT in consideration with the nationwide medical cost. In addition, the initial set-up cost of these facilities is gradually decreasing. Eventually, with these efforts, CPT will improve the survival rate and quality of life of cancer patients and contribute to the decline of secondary malignancy among cancer survivors.

Author Contributions

Conceived and designed the analysis: Wu HG.

Collected the data: Kim KS, Wu HG.

Contributed data or analysis tools: Wu HG.

Performed the analysis: Kim KS.

Wrote the paper: Kim KS.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Acknowledgements
This work was supported by the National Research Foundation of Korea (NRF) with a grant funded by the Korean government (MSIT) (No. 2019R1F1A1040583) and the Radiation Technology R&D program through the National Research Foundation of Korea, funded by the Ministry of Science and ICT (2019M2A2B4095126).
Table 1
Recommended or public health insurance covered indications for charged-particle therapy from several countries
Country Recommendation or Indication
United States [7] Astro Model Policy, group 1: disease sites that frequently the use of proton ocular tumors, including intraocular melanomas
 Tumors that approach or are located at the base of skull, including but not limited to chordoma or chondrosarcomas
 Primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated
 Hepatocellular cancer
 Primary or benign solid tumors in children treated with curative intent and occasional palliative treatment of childhood tumors when at least one of the four criteria noted above apply
 Patients with genetic syndromes making total volume of radiation minimization crucial such as but not limited to NF-1 patients and retinoblastoma patients
 Malignant and benign primary CNS tumors
 Advanced (e.g., T4) and/or unresectable head and neck cancers
 Cancers of the paranasal sinuses and other accessory sinuses
 Non-metastatic retroperitoneal sarcomas
 Re-irradiation cases (where cumulative critical structure dose would exceed tolerance dose)
United NHS Kingdom [8] England Indications of PBT
 Pediatric tumor
  Most pediatric tumors, malignant and benign
 Adult
  Base of skull tumors (radioresistant)
  Spinal and paraspinal tumors (radioresistant)
  Paranasal sinus tumors with base of skull involvement
Netherlands [9] Health Council of the Netherlands. Proton Radiotherapy
 Standard indication
  Skull base or spinal chordoma and chondrosarcoma
  Other intracranial, spinal, and paraspinal tumors, including meningioma
  Pediatric tumors, including bone tumors, soft-tissue sarcoma, low-grade glioma, meningioma, medulloblastoma, ependymoma, and neuroblastoma
 Potential indications (cases for which protons may be specifically utilized to improve local control)
  Re-irradiation (malignant brain tumors, head and neck cancer)
  Paranasal sinus tumors, nasopharyngeal carcinoma, prostate, NSCLC, retroperitoneal sarcoma
 Model based indication (cases where proton will be utilized to reduce side effect)
  Re-irradiation (meningioma, head and neck cancer)
  Head and neck cancers, prostate
 Reduction of secondary cancer
  Breast cancer
  Lymphoma
  Testis
Japan [10] Public Health Insurance of Particle Therapy
 PBT
  Pediatric cancer
  Bone and soft tissue sarcoma
  Head and neck
  Prostate
 CIRT
  Bone and soft tissue sarcoma
  Head and neck
  Prostate
Korea [10] Public Health Insurance of PBT
 Pediatric cancer
 Re-RT
 Brain, skull base, and spinal tumors
 Head and neck cancer including orbit
 Thorax tumor (lung, esophagus, and mediastinum except breast cancer)
 Abdominal tumors (hepatobiliary, pancreas, and retroperitoneum

Astro, American Society for Radiation Oncology; CIRT; carbon ion radiotherapy, CNS, central nervous system; NHS, National Health Service; NSCLC, non–small cell lung cancer; PBT, proton beam therapy; RT, radiotherapy.

Table 2
The number of patients treated by charged particle therapy based on tumor site in several countries
California, PBT (2003–2016) [11] Japan, PBT (1979–2013) [77] Japan, CIRT (1994–2017) [78] UK (Christie), PBT (2018–2019) [8]




Site Percentage Site Percentage Site Percentage Population Site Percentage
Prostate 41.3 Prostate 30.0 Prostate 24.7 Pediatric and CNS 38.9

Breast 14.0 Liver 19.0 Bone and soft tissue 11.5 young adult H&N 15.7

Eye/orbit 11.8 H&N 13.0 H&N 9.6 (~24 yr) Body 10.2

Lung 6.1 Lung 12.0 Lung 9.2 Spine 6.5

CNS 6.0 GI 6.0 Pancreas 5.4 CSI 1.9

Lymphoma/leukemia 2.9 Pancreas 4.0 Liver 5.3 Adult CNS 8.3

Liver 2.4 Sarcoma 3.0 Rectum (recur) 4.9 H&N 3.7

H&N 2.3 CNS 3.0 Uterus 2.5 Body 0.9

Female genital 2.1 Others 10.0 Uveal melanoma 1.8 Spine 13.9

Colon and rectum 3.0 Abdominal LN 1.2

Others 9.1 CNS 0.9

GI tract 0.8

Re-irradiation 9.2

Others 13.0

Total 100 (n=8,609) Total 100 (n=15,000 approximately) Total 100 (n=11,580) Total 100 (n=108)

CIRT; carbon ion radiotherapy, CNS, central nervous system; CSI, cranio-spinal irradiation; GI, gastrointestinal; H&N, head and neck; LN, lymph node; PBT, proton beam therapy.

  • 1. Seo YS, Kim MS, Kang JK, Jang WI, Kim HJ, Cho CK, et al. The clinical utilization of radiation therapy in Korea between 2011 and 2015. Cancer Res Treat. 2018;50:345–55. ArticlePubMed
  • 2. Mohamad O, Sishc BJ, Saha J, Pompos A, Rahimi A, Story MD, et al. Carbon ion radiotherapy: a review of clinical experiences and preclinical research, with an emphasis on DNA damage/repair. Cancers (Basel). 2017;9:66.ArticlePubMedPMC
  • 3. Dreher C, Combs SE. Clinical rationale and indications for particle therapy. . In: Guckenberger M, Combs SE, Zips D, editors. Advances in radiotherapy. 44. Basel: Karger Publishers; 2018. p. 89–104. Article
  • 4. Durante M, Orecchia R, Loeffler JS. Charged-particle therapy in cancer: clinical uses and future perspectives. Nat Rev Clin Oncol. 2017;14:483–95. ArticlePubMed
  • 5. Rackwitz T, Debus J. Clinical applications of proton and carbon ion therapy. Semin Oncol. 2019;46:226–32. ArticlePubMed
  • 6. Schaub L, Harrabi SB, Debus J. Particle therapy in the future of precision therapy. Br J Radiol. 2020;93:20200183.ArticlePubMedPMC
  • 7. ASTRO Targeting Cancer CareModel policies [Internet]. Arlington, VA: American Society for Radiation Oncology; 2021. [cited 2021 May 30]. Available from: https://www.astro.org/Daily-Practice/Reimbursement/Model-Policies
  • 8. Burnet NG, Mackay RI, Smith E, Chadwick AL, Whitfield GA, Thomson DJ, et al. Proton beam therapy: perspectives on the National Health Service England clinical service and research programme. Br J Radiol. 2020;93:20190873.ArticlePubMedPMC
  • 9. Health Council of the NetherlandsProton radiotherapy. Hague: Health Council of the Netherlands; 2009.
  • 10. Huh SJ, Nishimura T, Park W, Onishi H, Ahn YC, Nakamura K. Current status and comparison of national health insurance systems for advanced radiation technologies in Korea and Japan. Radiat Oncol J. 2020;38:170–5. ArticlePubMedPMC
  • 11. Parikh-Patel A, Morris CR, Maguire FB, Daly ME, Kizer KW. A population-based assessment of proton beam therapy utilization in California. Am J Manag Care. 2020;26:e28–35. ArticlePubMed
  • 12. Yock TI, Bhat S, Szymonifka J, Yeap BY, Delahaye J, Donaldson SS, et al. Quality of life outcomes in proton and photon treated pediatric brain tumor survivors. Radiother Oncol. 2014;113:89–94. ArticlePubMedPMC
  • 13. Yock TI, Yeap BY, Ebb DH, Weyman E, Eaton BR, Sherry NA, et al. Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study. Lancet Oncol. 2016;17:287–98. ArticlePubMed
  • 14. Tabrizi S, Yeap BY, Sherman JC, Nachtigall LB, Colvin MK, Dworkin M, et al. Long-term outcomes and late adverse effects of a prospective study on proton radiotherapy for patients with low-grade glioma. Radiother Oncol. 2019;137:95–101. ArticlePubMedPMC
  • 15. Sethi RV, Shih HA, Yeap BY, Mouw KW, Petersen R, Kim DY, et al. Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy. Cancer. 2014;120:126–33. ArticlePubMed
  • 16. Gragoudas ES. Proton beam irradiation of uveal melanomas: the first 30 years. The Weisenfeld Lecture. Invest Ophthalmol Vis Sci. 2006;47:4666–73. ArticlePubMed
  • 17. Kim TW, Choi E, Park J, Shin DH, Jung SK, Seok S, et al. Clinical outcomes of proton beam therapy for choroidal melanoma at a single institute in Korea. Cancer Res Treat. 2018;50:335–44. ArticlePubMed
  • 18. Wang Z, Nabhan M, Schild SE, Stafford SL, Petersen IA, Foote RL, et al. Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2013;86:18–26. ArticlePubMed
  • 19. Tsuji H, Ishikawa H, Yanagi T, Hirasawa N, Kamada T, Mizoe JE, et al. Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a phase I/II dose-escalation study. Int J Radiat Oncol Biol Phys. 2007;67:857–62. ArticlePubMed
  • 20. Pommier P, Liebsch NJ, Deschler DG, Lin DT, McIntyre JF, Barker FG 2nd, et al. Proton beam radiation therapy for skull base adenoid cystic carcinoma. Arch Otolaryngol Head Neck Surg. 2006;132:1242–9. ArticlePubMed
  • 21. Mendenhall WM, Dagan R, Bryant CM, Amdur RJ. Definitive radiotherapy for skin and adenoid cystic carcinoma with perineural invasion. J Neurol Surg B Skull Base. 2016;77:169–72. ArticlePubMedPMC
  • 22. Jensen AD, Poulakis M, Nikoghosyan AV, Welzel T, Uhl M, Federspil PA, et al. High-LET radiotherapy for adenoid cystic carcinoma of the head and neck: 15 years’ experience with raster-scanned carbon ion therapy. Radiother Oncol. 2016;118:272–80. ArticlePubMed
  • 23. Sulaiman NS, Demizu Y, Koto M, Saitoh JI, Suefuji H, Tsuji H, et al. Multicenter study of carbon-ion radiation therapy for adenoid cystic carcinoma of the head and neck: subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN). Int J Radiat Oncol Biol Phys. 2018;100:639–46. ArticlePubMed
  • 24. Naganawa K, Koto M, Takagi R, Hasegawa A, Ikawa H, Shimozato K, et al. Long-term outcomes after carbon-ion radiotherapy for oral mucosal malignant melanoma. J Radiat Res. 2017;58:517–22. ArticlePubMed
  • 25. Koto M, Demizu Y, Saitoh JI, Suefuji H, Tsuji H, Okimoto T, et al. Multicenter study of carbon-ion radiation therapy for mucosal melanoma of the head and neck: subanalysis of the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS) Study (1402 HN). Int J Radiat Oncol Biol Phys. 2017;97:1054–60. ArticlePubMed
  • 26. Patel SH, Wang Z, Wong WW, Murad MH, Buckey CR, Mohammed K, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. 2014;15:1027–38. ArticlePubMed
  • 27. Suefuji H, Koto M, Demizu Y, Saitoh JI, Shioyama Y, Tsuji H, et al. A retrospective multicenter study of carbon ion radiotherapy for locally advanced olfactory neuroblastomas. Anticancer Res. 2018;38:1665–70. ArticlePubMed
  • 28. Hayashi K, Koto M, Demizu Y, Saitoh JI, Suefuji H, Okimoto T, et al. A retrospective multicenter study of carbon-ion radiotherapy for external auditory canal and middle ear carcinomas. Cancer Med. 2019;8:51–7. ArticlePubMed
  • 29. Koto M, Demizu Y, Saitoh JI, Suefuji H, Tsuji H, Okimoto T, et al. Definitive carbon-ion radiation therapy for locally advanced sinonasal malignant tumors: subgroup analysis of a multicenter study by the Japan Carbon-Ion Radiation Oncology Study Group (J-CROS). Int J Radiat Oncol Biol Phys. 2018;102:353–61. ArticlePubMed
  • 30. Seidensaal K, Harrabi SB, Uhl M, Debus J. Re-irradiation with protons or heavy ions with focus on head and neck, skull base and brain malignancies. Br J Radiol. 2020;93:20190516.ArticlePubMedPMC
  • 31. Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull base. Strahlenther Onkol. 1999;175(Suppl 2):57–63. Article
  • 32. Fung V, Calugaru V, Bolle S, Mammar H, Alapetite C, Maingon P, et al. Proton beam therapy for skull base chordomas in 106 patients: a dose adaptive radiation protocol. Radiother Oncol. 2018;128:198–202. ArticlePubMed
  • 33. Noel G, Feuvret L, Calugaru V, Dhermain F, Mammar H, Haie-Meder C, et al. Chordomas of the base of the skull and upper cervical spine: one hundred patients irradiated by a 3D conformal technique combining photon and proton beams. Acta Oncol. 2005;44:700–8. ArticlePubMed
  • 34. Youn SH, Cho KH, Kim JY, Ha B, Lim YK, Jeong JH, et al. Clinical outcome of proton therapy for patients with chordomas. Radiat Oncol J. 2018;36:182–91. ArticlePubMedPMC
  • 35. Indelicato DJ, Rotondo RL, Begosh-Mayne D, Scarborough MT, Gibbs CP, Morris CG, et al. A prospective outcomes study of proton therapy for chordomas and chondrosarcomas of the spine. Int J Radiat Oncol Biol Phys. 2016;95:297–303. ArticlePubMed
  • 36. Chen YL, Liebsch N, Kobayashi W, Goldberg S, Kirsch D, Calkins G, et al. Definitive high-dose photon/proton radiotherapy for unresected mobile spine and sacral chordomas. Spine (Phila Pa 1976). 2013;38:E930–6. ArticlePubMed
  • 37. Palm RF, Oliver DE, Yang GQ, Abuodeh Y, Naghavi AO, Johnstone PA. The role of dose escalation and proton therapy in perioperative or definitive treatment of chondrosarcoma and chordoma: an analysis of the National Cancer Data Base. Cancer. 2019;125:642–51. ArticlePubMed
  • 38. Lu VM, O’Connor KP, Mahajan A, Carlson ML, Van Gompel JJ. Carbon ion radiotherapy for skull base chordomas and chondrosarcomas: a systematic review and meta-analysis of local control, survival, and toxicity outcomes. J Neurooncol. 2020;147:503–13. ArticlePubMed
  • 39. Nikoghosyan AV, Karapanagiotou-Schenkel I, Munter MW, Jensen AD, Combs SE, Debus J. Randomised trial of proton vs. carbon ion radiation therapy in patients with chordoma of the skull base, clinical phase III study HIT-1-Study. BMC Cancer. 2010;10:607.ArticlePubMedPMC
  • 40. Nikoghosyan AV, Rauch G, Munter MW, Jensen AD, Combs SE, Kieser M, et al. Randomised trial of proton vs. carbon ion radiation therapy in patients with low and intermediate grade chondrosarcoma of the skull base, clinical phase III study. BMC Cancer. 2010;10:606.ArticlePubMedPMC
  • 41. Uhl M, Welzel T, Jensen A, Ellerbrock M, Haberer T, Jakel O, et al. Carbon ion beam treatment in patients with primary and recurrent sacrococcygeal chordoma. Strahlenther Onkol. 2015;191:597–603. ArticlePubMed
  • 42. Demizu Y, Imai R, Kiyohara H, Matsunobu A, Okamoto M, Okimoto T, et al. Carbon ion radiotherapy for sacral chordoma: a retrospective nationwide multicentre study in Japan. Radiother Oncol. 2021;154:1–5. ArticlePubMed
  • 43. Mima M, Demizu Y, Jin D, Hashimoto N, Takagi M, Terashima K, et al. Particle therapy using carbon ions or protons as a definitive therapy for patients with primary sacral chordoma. Br J Radiol. 2014;87:20130512.ArticlePubMed
  • 44. Imai R, Kamada T, Araki N. Working Group for Bone and Soft Tissue SarcomasCarbon ion radiation therapy for unresectable sacral chordoma: an analysis of 188 cases. Int J Radiat Oncol Biol Phys. 2016;95:322–7. ArticlePubMed
  • 45. Imai R, Kamada T, Araki N. Working Group for Carbon Ion Radiotherapy for Bone and Soft Tissue SarcomasCarbon ion radiotherapy for unresectable localized axial soft tissue sarcoma. Cancer Med. 2018;7:4308–14. ArticlePubMedPMC
  • 46. Serizawa I, Kagei K, Kamada T, Imai R, Sugahara S, Okada T, et al. Carbon ion radiotherapy for unresectable retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys. 2009;75:1105–10. ArticlePubMed
  • 47. Kamada T, Tsujii H, Tsuji H, Yanagi T, Mizoe JE, Miyamoto T, et al. Efficacy and safety of carbon ion radiotherapy in bone and soft tissue sarcomas. J Clin Oncol. 2002;20:4466–71. ArticlePubMed
  • 48. Chang JY, Jabbour SK, De Ruysscher D, Schild SE, Simone CB 2nd, Rengan R, et al. Consensus Statement on Proton Therapy in Early-Stage and Locally Advanced Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2016;95:505–16. ArticlePubMedPMC
  • 49. Iwata H, Demizu Y, Fujii O, Terashima K, Mima M, Niwa Y, et al. Long-term outcome of proton therapy and carbon-ion therapy for large (T2a-T2bN0M0) non-small-cell lung cancer. J Thorac Oncol. 2013;8:726–35. ArticlePubMed
  • 50. Bush DA, Cheek G, Zaheer S, Wallen J, Mirshahidi H, Katerelos A, et al. High-dose hypofractionated proton beam radiation therapy is safe and effective for central and peripheral early-stage non-small cell lung cancer: results of a 12-year experience at Loma Linda University Medical Center. Int J Radiat Oncol Biol Phys. 2013;86:964–8. ArticlePubMed
  • 51. Ono T, Hareyama M, Nakamura T, Kimura K, Hayashi Y, Azami Y, et al. The clinical results of proton beam therapy in patients with idiopathic pulmonary fibrosis: a single center experience. Radiat Oncol. 2016;11:56.ArticlePubMedPMC
  • 52. Kim H, Pyo H, Noh JM, Lee W, Park B, Park HY, et al. Preliminary result of definitive radiotherapy in patients with non-small cell lung cancer who have underlying idiopathic pulmonary fibrosis: comparison between X-ray and proton therapy. Radiat Oncol. 2019;14:19.ArticlePubMedPMC
  • 53. Nakajima M, Yamamoto N, Hayashi K, Karube M, Ebner DK, Takahashi W, et al. Carbon-ion radiotherapy for non-small cell lung cancer with interstitial lung disease: a retrospective analysis. Radiat Oncol. 2017;12:144.ArticlePubMedPMCPDF
  • 54. Karube M, Yamamoto N, Nakajima M, Yamashita H, Nakagawa K, Miyamoto T, et al. Single-fraction carbon-ion radiation therapy for patients 80 years of age and older with stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys. 2016;95:542–8. ArticlePubMed
  • 55. Chi A, Chen H, Wen S, Yan H, Liao Z. Comparison of particle beam therapy and stereotactic body radiotherapy for early stage non-small cell lung cancer: a systematic review and hypothesis-generating meta-analysis. Radiother Oncol. 2017;123:346–54. ArticlePubMedPMC
  • 56. Miyasaka Y, Komatsu S, Abe T, Kubo N, Okano N, Shibuya K, et al. Comparison of oncologic outcomes between carbon ion radiotherapy and stereotactic body radiotherapy for early-stage non-small cell lung cancer. Cancers (Basel). 2021;13:176.ArticlePubMedPMC
  • 57. Miyamoto T, Yamamoto N, Nishimura H, Koto M, Tsujii H, Mizoe JE, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer. Radiother Oncol. 2003;66:127–40. ArticlePubMed
  • 58. Miyamoto T, Baba M, Sugane T, Nakajima M, Yashiro T, Kagei K, et al. Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week. J Thorac Oncol. 2007;2:916–26. ArticlePubMed
  • 59. Miyamoto T, Baba M, Yamamoto N, Koto M, Sugawara T, Yashiro T, et al. Curative treatment of Stage I non-small-cell lung cancer with carbon ion beams using a hypofractionated regimen. Int J Radiat Oncol Biol Phys. 2007;67:750–8. ArticlePubMed
  • 60. Yamamoto N, Miyamoto T, Nakajima M, Karube M, Hayashi K, Tsuji H, et al. A dose escalation clinical trial of single-fraction carbon ion radiotherapy for peripheral stage I non-small cell lung cancer. J Thorac Oncol. 2017;12:673–80. ArticlePubMed
  • 61. Ono T, Yamamoto N, Nomoto A, Nakajima M, Isozaki Y, Kasuya G, et al. Long term results of single-fraction carbon-ion radiotherapy for non-small cell lung cancer. Cancers (Basel). 2020;13:112.ArticlePubMedPMC
  • 62. Bradley JD, Paulus R, Komaki R, Masters G, Blumenschein G, Schild S, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16:187–99. ArticlePubMedPMC
  • 63. Tucker SL, Liu A, Gomez D, Tang LL, Allen P, Yang J, et al. Impact of heart and lung dose on early survival in patients with non-small cell lung cancer treated with chemoradiation. Radiother Oncol. 2016;119:495–500. ArticlePubMed
  • 64. Hoppe BS, Henderson R, Pham D, Cury JD, Bajwa A, Morris CG, et al. A phase 2 trial of concurrent chemotherapy and proton therapy for stage III non-small cell lung cancer: results and reflections following early closure of a single-institution study. Int J Radiat Oncol Biol Phys. 2016;95:517–22. ArticlePubMed
  • 65. Oshiro Y, Okumura T, Kurishima K, Homma S, Mizumoto M, Ishikawa H, et al. High-dose concurrent chemo-proton therapy for Stage III NSCLC: preliminary results of a Phase II study. J Radiat Res. 2014;55:959–65. ArticlePubMedPMC
  • 66. Anzai M, Yamamoto N, Hayashi K, Nakajima M, Nomoto A, Ogawa K, et al. Safety and efficacy of carbon-ion radiotherapy alone for stage III non-small cell lung cancer. Anticancer Res. 2020;40:379–86. ArticlePubMed
  • 67. Hayashi K, Yamamoto N, Nakajima M, Nomoto A, Tsuji H, Ogawa K, et al. Clinical outcomes of carbon-ion radiotherapy for locally advanced non-small-cell lung cancer. Cancer Sci. 2019;110:734–41. ArticlePubMedPMC
  • 68. Karube M, Yamamoto N, Shioyama Y, Saito J, Matsunobu A, Okimoto T, et al. Carbon-ion radiotherapy for patients with advanced stage non-small-cell lung cancer at multicenters. J Radiat Res. 2017;58:761–4. ArticlePubMedPMC
  • 69. Saitoh JI, Shirai K, Abe T, Kubo N, Ebara T, Ohno T, et al. A phase I study of hypofractionated carbon-ion radiotherapy for stage III non-small cell lung cancer. Anticancer Res. 2018;38:885–91. PubMed
  • 70. Takahashi W, Nakajima M, Yamamoto N, Yamashita H, Nakagawa K, Miyamoto T, et al. A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell lung cancer (NSCLC). Cancer. 2015;121:1321–7. ArticlePubMed
  • 71. Liao Z, Lee JJ, Komaki R, Gomez DR, O’Reilly MS, Fossella FV, et al. Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer. J Clin Oncol. 2018;36:1813–22. ArticlePubMedPMC
  • 72. Brooks ED, Ning MS, Verma V, Zhu XR, Chang JY. Proton therapy for non-small cell lung cancer: the road ahead. Transl Lung Cancer Res. 2019;8(Suppl 2):S202–S12. ArticlePubMedPMC
  • 73. Han Y. Current status of proton therapy techniques for lung cancer. Radiat Oncol J. 2019;37:232–48. ArticlePubMedPMC
  • 74. Kim JI, Park JM, Wu HG. Carbon ion therapy: a review of an advanced technology. Prog Med Phys. 2020;31:71–80. Article
  • 75. Park S, Yoon WS, Rim CH. Indications of external radiotherapy for hepatocellular carcinoma from updated clinical guidelines: diverse global viewpoints. World J Gastroenterol. 2020;26:393–403. ArticlePubMedPMC
  • 76. Chiba T, Tokuuye K, Matsuzaki Y, Sugahara S, Chuganji Y, Kagei K, et al. Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients. Clin Cancer Res. 2005;11:3799–805. ArticlePubMed
  • 77. Sakurai H, Ishikawa H, Okumura T. Proton beam therapy in Japan: current and future status. Jpn J Clin Oncol. 2016;46:885–92. ArticlePubMed
  • 78. Mohamad O, Makishima H, Kamada T. Evolution of carbon ion radiotherapy at the National Institute of Radiological Sciences in Japan. Cancers (Basel). 2018;10:66.ArticlePubMedPMC
  • 79. Spychalski P, Kobiela J, Antoszewska M, Blazynska-Spychalska A, Jereczek-Fossa BA, Hoyer M. Patient specific outcomes of charged particle therapy for hepatocellular carcinoma: a systematic review and quantitative analysis. Radiother Oncol. 2019;132:127–34. ArticlePubMed
  • 80. Jang WI, Bae SH, Kim MS, Han CJ, Park SC, Kim SB, et al. A phase 2 multicenter study of stereotactic body radiotherapy for hepatocellular carcinoma: safety and efficacy. Cancer. 2020;126:363–72. ArticlePubMed
  • 81. Yoo GS, Yu JI, Park HC. Proton therapy for hepatocellular carcinoma: current knowledges and future perspectives. World J Gastroenterol. 2018;24:3090–100. ArticlePubMedPMC
  • 82. Sanford NN, Pursley J, Noe B, Yeap BY, Goyal L, Clark JW, et al. Protons versus photons for unresectable hepatocellular carcinoma: liver decompensation and overall survival. Int J Radiat Oncol Biol Phys. 2019;105:64–72. ArticlePubMed
  • 83. Sugahara S, Oshiro Y, Nakayama H, Fukuda K, Mizumoto M, Abei M, et al. Proton beam therapy for large hepatocellular carcinoma. Int J Radiat Oncol Biol Phys. 2010;76:460–6. ArticlePubMed
  • 84. Kimura K, Nakamura T, Ono T, Azami Y, Suzuki M, Wada H, et al. Clinical results of proton beam therapy for hepatocellular carcinoma over 5 cm. Hepatol Res. 2017;47:1368–74. ArticlePubMed
  • 85. Shibuya K, Ohno T, Katoh H, Okamoto M, Shiba S, Koyama Y, et al. A feasibility study of high-dose hypofractionated carbon ion radiation therapy using four fractions for localized hepatocellular carcinoma measuring 3cm or larger. Radiother Oncol. 2019;132:230–5. ArticlePubMed
  • 86. Mizumoto M, Tokuuye K, Sugahara S, Nakayama H, Fukumitsu N, Ohara K, et al. Proton beam therapy for hepatocellular carcinoma adjacent to the porta hepatis. Int J Radiat Oncol Biol Phys. 2008;71:462–7. ArticlePubMed
  • 87. Imada H, Kato H, Yasuda S, Yamada S, Yanagi T, Kishimoto R, et al. Comparison of efficacy and toxicity of short-course carbon ion radiotherapy for hepatocellular carcinoma depending on their proximity to the porta hepatis. Radiother Oncol. 2010;96:231–5. ArticlePubMed
  • 88. Yoo GS, Yu JI, Park HC, Hyun D, Jeong WK, Lim HY, et al. Do biliary complications after proton beam therapy for perihilar hepatocellular carcinoma matter? Cancers (Basel). 2020;12:2395.ArticlePubMedPMC
  • 89. Sugahara S, Nakayama H, Fukuda K, Mizumoto M, Tokita M, Abei M, et al. Proton-beam therapy for hepatocellular carcinoma associated with portal vein tumor thrombosis. Strahlenther Onkol. 2009;185:782–8. ArticlePubMed
  • 90. Kim DY, Park JW, Kim TH, Kim BH, Moon SH, Kim SS, et al. Risk-adapted simultaneous integrated boost-proton beam therapy (SIB-PBT) for advanced hepatocellular carcinoma with tumour vascular thrombosis. Radiother Oncol. 2017;122:122–9. ArticlePubMed
  • 91. Lee SU, Park JW, Kim TH, Kim YJ, Woo SM, Koh YH, et al. Effectiveness and safety of proton beam therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis. Strahlenther Onkol. 2014;190:806–14. ArticlePubMed
  • 92. Komatsu S, Fukumoto T, Demizu Y, Miyawaki D, Terashima K, Niwa Y, et al. The effectiveness of particle radiotherapy for hepatocellular carcinoma associated with inferior vena cava tumor thrombus. J Gastroenterol. 2011;46:913–20. ArticlePubMed
  • 93. Nakayama H, Sugahara S, Fukuda K, Abei M, Shoda J, Sakurai H, et al. Proton beam therapy for hepatocellular carcinoma located adjacent to the alimentary tract. Int J Radiat Oncol Biol Phys. 2011;80:992–5. ArticlePubMed
  • 94. Kato H, Tsujii H, Miyamoto T, Mizoe JE, Kamada T, Tsuji H, et al. Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis. Int J Radiat Oncol Biol Phys. 2004;59:1468–76. ArticlePubMed
  • 95. Shiba S, Abe T, Shibuya K, Katoh H, Koyama Y, Shimada H, et al. Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma. BMC Cancer. 2017;17:721.ArticlePubMedPMCPDF
  • 96. Kim TH, Park JW, Kim BH, Oh ES, Youn SH, Moon SH, et al. Phase II study of hypofractionated proton beam therapy for hepatocellular carcinoma. Front Oncol. 2020;10:542.ArticlePubMedPMC
  • 97. Kasuya G, Kato H, Yasuda S, Tsuji H, Yamada S, Haruyama Y, et al. Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: combined analyses of 2 prospective trials. Cancer. 2017;123:3955–65. ArticlePubMed
  • 98. Kim TH, Koh YH, Kim BH, Kim MJ, Lee JH, Park B, et al. Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: a randomized phase III trial. J Hepatol. 2021;74:603–12. ArticlePubMed
  • 99. Bush DA, Smith JC, Slater JD, Volk ML, Reeves ME, Cheng J, et al. Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for hepatocellular carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys. 2016;95:477–82. ArticlePubMed
  • 100. Shiba S, Shibuya K, Katoh H, Kaminuma T, Miyazaki M, Kakizaki S, et al. A comparison of carbon ion radiotherapy and transarterial chemoembolization treatment outcomes for single hepatocellular carcinoma: a propensity score matching study. Radiat Oncol. 2019;14:137.ArticlePubMedPMC
  • 101. Yasuda S, Kato H, Imada H, Isozaki Y, Kasuya G, Makishima H, et al. Long-term results of high-dose 2-fraction carbon ion radiation therapy for hepatocellular carcinoma. Adv Radiat Oncol. 2020;5:196–203. ArticlePubMed
  • 102. Makita C, Nakamura T, Takada A, Takayama K, Suzuki M, Ishikawa Y, et al. Clinical outcomes and toxicity of proton beam therapy for advanced cholangiocarcinoma. Radiat Oncol. 2014;9:26.ArticlePubMedPMC
  • 103. Hong TS, Wo JY, Yeap BY, Ben-Josef E, McDonnell EI, Blaszkowsky LS, et al. Multi-Institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol. 2016;34:460–8. ArticlePubMed
  • 104. Kasuya G, Terashima K, Shibuya K, Toyama S, Ebner DK, Tsuji H, et al. Carbon-ion radiotherapy for cholangiocarcinoma: a multi-institutional study by and the Japan Carbon-ion Radiation Oncology Study Group (J-CROS). Oncotarget. 2019;10:4369–79. ArticlePubMedPMC
  • 105. Petrelli F, Comito T, Ghidini A, Torri V, Scorsetti M, Barni S. Stereotactic body radiation therapy for locally advanced pancreatic cancer: a systematic review and pooled analysis of 19 trials. Int J Radiat Oncol Biol Phys. 2017;97:313–22. ArticlePubMed
  • 106. Krishnan S, Chadha AS, Suh Y, Chen HC, Rao A, Das P, et al. Focal radiation therapy dose escalation improves overall survival in locally advanced pancreatic cancer patients receiving induction chemotherapy and consolidative chemoradiation. Int J Radiat Oncol Biol Phys. 2016;94:755–65. ArticlePubMed
  • 107. Nichols RC Jr, George TJ, Zaiden RA Jr, Awad ZT, Asbun HJ, Huh S, et al. Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity. Acta Oncol. 2013;52:498–505. ArticlePubMed
  • 108. Terashima K, Demizu Y, Hashimoto N, Jin D, Mima M, Fujii O, et al. A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis. Radiother Oncol. 2012;103:25–31. ArticlePubMed
  • 109. Hiroshima Y, Fukumitsu N, Saito T, Numajiri H, Murofushi KN, Ohnishi K, et al. Concurrent chemoradiotherapy using proton beams for unresectable locally advanced pancreatic cancer. Radiother Oncol. 2019;136:37–43. ArticlePubMed
  • 110. Takatori K, Terashima K, Yoshida R, Horai A, Satake S, Ose T, et al. Upper gastrointestinal complications associated with gemcitabine-concurrent proton radiotherapy for inoperable pancreatic cancer. J Gastroenterol. 2014;49:1074–80. ArticlePubMed
  • 111. Kim TH, Lee WJ, Woo SM, Kim H, Oh ES, Lee JH, et al. Effectiveness and safety of simultaneous integrated boost-proton beam therapy for localized pancreatic cancer. Technol Cancer Res Treat. 2018;17:1533033818783879Article
  • 112. Sachsman S, Nichols RC Jr, Morris CG, Zaiden R, Johnson EA, Awad Z, et al. Proton therapy and concomitant capecitabine for non-metastatic unresectable pancreatic adenocarcinoma. Int J Part Ther. 2014;1:692–701. Article
  • 113. Jethwa KR, Tryggestad EJ, Whitaker TJ, Giffey BT, Kazemba BD, Neben-Wittich MA, et al. Initial experience with intensity modulated proton therapy for intact, clinically localized pancreas cancer: clinical implementation, dosimetric analysis, acute treatment-related adverse events, and patient-reported outcomes. Adv Radiat Oncol. 2018;3:314–21. ArticlePubMedPMC
  • 114. Rutenberg MS, Nichols RC. Proton beam radiotherapy for pancreas cancer. J Gastrointest Oncol. 2020;11:166–75. ArticlePubMedPMC
  • 115. Dell’Oro M, Short M, Wilson P, Bezak E. Clinical limitations of photon, proton and carbon ion therapy for pancreatic cancer. Cancers (Basel). 2020;12:163.ArticlePubMedPMC
  • 116. Kawashiro S, Yamada S, Okamoto M, Ohno T, Nakano T, Shinoto M, et al. Multi-institutional study of carbon-ion radiotherapy for locally advanced pancreatic cancer: Japan Carbon-ion Radiation Oncology Study Group (J-CROS) Study 1403 Pancreas. Int J Radiat Oncol Biol Phys. 2018;101:1212–21. ArticlePubMed
  • 117. Shinoto M, Terashima K, Suefuji H, Matsunobu A, Toyama S, Fukunishi K, et al. A single institutional experience of combined carbon-ion radiotherapy and chemotherapy for unresectable locally advanced pancreatic cancer. Radiother Oncol. 2018;129:333–9. ArticlePubMed
  • 118. Shinoto M, Yamada S, Terashima K, Yasuda S, Shioyama Y, Honda H, et al. Carbon ion radiation therapy with concurrent gemcitabine for patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2016;95:498–504. ArticlePubMed
  • 119. Shinoto M, Yamada S, Yasuda S, Imada H, Shioyama Y, Honda H, et al. Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer. Cancer. 2013;119:45–51. ArticlePubMed
  • 120. Kawashiro S, Yamada S, Isozaki Y, Nemoto K, Tsuji H, Kamada T. Carbon-ion radiotherapy for locoregional recurrence after primary surgery for pancreatic cancer. Radiother Oncol. 2018;129:101–4. ArticlePubMed
  • 121. Kawashiro S, Mori S, Yamada S, Miki K, Nemoto K, Tsuji H, et al. Dose escalation study with respiratory-gated carbon-ion scanning radiotherapy using a simultaneous integrated boost for pancreatic cancer: simulation with four-dimensional computed tomography. Br J Radiol. 2017;90:20160790.ArticlePubMedPMC
  • 122. Murphy JE, Wo JY, Ryan DP, Jiang W, Yeap BY, Drapek LC, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2018;4:963–9. ArticlePubMedPMC
  • 123. Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the Dutch randomized phase III PREOPANC trial. J Clin Oncol. 2020;38:1763–73. ArticlePubMedPMC
  • 124. Murphy JE, Wo JY, Ryan DP, Clark JW, Jiang W, Yeap BY, et al. Total neoadjuvant therapy with FOLFIRINOX in combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol. 2019;5:1020–7. ArticlePubMedPMC
  • 125. Hong TS, Lennerz JK, Wo JY, Ulysse C, Yeap BY, Clark JW, et al. Long term follow-up of a phase II study of autophagy inhibition with hydroxychloroquine (HCQ) and preoperative (Preop) short course chemoradiation (SCRT) followed by early surgery for resectable ductal adenocarcinoma of the head of pancreas (PDAC). Int J Radiat Oncol Biol Phys. 2020;108(3 Suppl):S151.Article
  • 126. Hong TS, Wo JY, Jiang W, Yeap BY, Clark JW, Ryan DP, et al. Phase II study of autophagy inhibition with hydroxychloroquine (HCQ) and preoperative (preop) short course chemoradiation (SCRT) followed by early surgery for resectable ductal adenocarcinoma of the head of pancreas (PDAC). J Clin Oncol. 2017;35(15 Suppl):4118.Article
  • 127. Hong TS, Ryan DP, Borger DR, Blaszkowsky LS, Yeap BY, Ancukiewicz M, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89:830–8. ArticlePubMedPMC
  • 128. Vitolo V, Cobianchi L, Brugnatelli S, Barcellini A, Peloso A, Facoetti A, et al. Preoperative chemotherapy and carbon ions therapy for treatment of resectable and borderline resectable pancreatic adenocarcinoma: a prospective, phase II, multicentre, single-arm study. BMC Cancer. 2019;19:922.ArticlePubMedPMC
  • 129. Iwata H, Ishikawa H, Takagi M, Okimoto T, Murayama S, Akimoto T, et al. Long-term outcomes of proton therapy for prostate cancer in Japan: a multi-institutional survey of the Japanese Radiation Oncology Study Group. Cancer Med. 2018;7:677–89. ArticlePubMedPMC
  • 130. Mendenhall NP, Hoppe BS, Nichols RC, Mendenhall WM, Morris CG, Li Z, et al. Five-year outcomes from 3 prospective trials of image-guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2014;88:596–602. ArticlePubMed
  • 131. Takagi M, Demizu Y, Terashima K, Fujii O, Jin D, Niwa Y, et al. Long-term outcomes in patients treated with proton therapy for localized prostate cancer. Cancer Med. 2017;6:2234–43. ArticlePubMedPMC
  • 132. Bryant C, Smith TL, Henderson RH, Hoppe BS, Mendenhall WM, Nichols RC, et al. Five-year biochemical results, toxicity, and patient-reported quality of life after delivery of dose-escalated image guided proton therapy for prostate cancer. Int J Radiat Oncol Biol Phys. 2016;95:422–34. ArticlePubMed
  • 133. Ha B, Cho KH, Lee KH, Joung JY, Kim YJ, Lee SU, et al. Long-term results of a phase II study of hypofractionated proton therapy for prostate cancer: moderate versus extreme hypofractionation. Radiat Oncol. 2019;14:4.ArticlePubMedPMC
  • 134. Ishikawa H, Tsuji H, Kamada T, Akakura K, Suzuki H, Shimazaki J, et al. Carbon-ion radiation therapy for prostate cancer. Int J Urol. 2012;19:296–305. ArticlePubMed
  • 135. Nomiya T, Tsuji H, Kawamura H, Ohno T, Toyama S, Shioyama Y, et al. A multi-institutional analysis of prospective studies of carbon ion radiotherapy for prostate cancer: a report from the Japan Carbon ion Radiation Oncology Study Group (J-CROS). Radiother Oncol. 2016;121:288–93. ArticlePubMed
  • 136. Ishikawa H, Tsuji H, Kamada T, Yanagi T, Mizoe JE, Kanai T, et al. Carbon ion radiation therapy for prostate cancer: results of a prospective phase II study. Radiother Oncol. 2006;81:57–64. ArticlePubMed
  • 137. Nomiya T, Tsuji H, Maruyama K, Toyama S, Suzuki H, Akakura 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. ArticlePubMedPMC
  • 138. Okada T, Tsuji H, Kamada T, Akakura K, Suzuki H, Shimazaki J, 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. ArticlePubMed
  • 139. Ishikawa H, Tsuji H, Murayama S, Sugimoto M, Shinohara N, Maruyama S, et al. Particle therapy for prostate cancer: The past, present and future. Int J Urol. 2019;26:971–9. ArticlePubMedPMC
  • 140. Mohamad O, Tabuchi T, Nitta Y, Nomoto A, Sato A, Kasuya G, et al. Risk of subsequent primary cancers after carbon ion radiotherapy, photon radiotherapy, or surgery for localised prostate cancer: a propensity score-weighted, retrospective, cohort study. Lancet Oncol. 2019;20:674–85. ArticlePubMed
  • 141. Shiraishi Y, Fang P, Xu C, Song J, Krishnan S, Koay EJ, et al. Severe lymphopenia during neoadjuvant chemoradiation for esophageal cancer: a propensity matched analysis of the relative risk of proton versus photon-based radiation therapy. Radiother Oncol. 2018;128:154–60. ArticlePubMed
  • 142. Lin SH, Hobbs BP, Verma V, Tidwell RS, Smith GL, Lei X, et al. Randomized phase IIB trial of proton beam therapy versus intensity-modulated radiation therapy for locally advanced esophageal cancer. J Clin Oncol. 2020;38:1569–79. ArticlePubMedPMC
  • 143. Xi M, Xu C, Liao Z, Chang JY, Gomez DR, Jeter M, et al. Comparative outcomes after definitive chemoradiotherapy using proton beam therapy versus intensity modulated radiation therapy for esophageal cancer: a retrospective, single-institutional analysis. Int J Radiat Oncol Biol Phys. 2017;99:667–76. ArticlePubMed
  • 144. Akutsu Y, Yasuda S, Nagata M, Izumi Y, Okazumi S, Shimada H, et al. A phase I/II clinical trial of preoperative short-course carbon-ion radiotherapy for patients with squamous cell carcinoma of the esophagus. J Surg Oncol. 2012;105:750–5. ArticlePubMed
  • 145. Kapiteijn E, Marijnen CA, Nagtegaal ID, Putter H, Steup WH, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med. 2001;345:638–46. ArticlePubMed
  • 146. Venkatesulu BP, Giridhar P, Malouf TD, Trifletti DM, Krishnan S. A systematic review of the role of carbon ion radiation therapy in recurrent rectal cancer. Acta Oncol. 2020;59:1218–23. ArticlePubMed
  • 147. Shinoto M, Yamada S, Okamoto M, Shioyama Y, Ohno T, Nakano T, et al. Carbon-ion radiotherapy for locally recurrent rectal cancer: Japan Carbon-ion Radiation Oncology Study Group (J-CROS) Study 1404 Rectum. Radiother Oncol. 2019;132:236–40. ArticlePubMed
  • 148. Habermehl D, Wagner M, Ellerbrock M, Buchler MW, Jakel O, Debus J, et al. Reirradiation using carbon ions in patients with locally recurrent rectal cancer at HIT: first results. Ann Surg Oncol. 2015;22:2068–74. ArticlePubMed
  • 149. Barcellini A, Vitolo V, Cobianchi L, Peloso A, Vanoli A, Mirandola A, et al. Re-irradiation With carbon ion radiotherapy for pelvic rectal cancer recurrences in patients previously irradiated to the pelvis. In Vivo. 2020;34:1547–53. ArticlePubMedPMC
  • 150. Cai X, Du Y, Wang Z, Li P, Yu Z, Zhang Q, et al. The role of carbon ion radiotherapy for unresectable locally recurrent rectal cancer: a single institutional experience. Radiat Oncol. 2020;15:209.ArticlePubMedPMC
  • 151. Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987–98. ArticlePubMed
  • 152. Mailhot Vega RB, Ishaq O, Raldow A, Perez CA, Jimenez R, Scherrer-Crosbie M, et al. Establishing cost-effective allocation of proton therapy for breast irradiation. Int J Radiat Oncol Biol Phys. 2016;95:11–8. ArticlePubMed
  • 153. Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer. 2016;122:1483–501. ArticlePubMed
  • 154. Zietman AL. Too big to fail? The current status of proton therapy in the USA. Clin Oncol (R Coll Radiol). 2018;30:271–3. ArticlePubMed
  • 155. Zietman AL. Can proton therapy be considered a standard of care in oncology? Lessons from the United States. Br J Cancer. 2019;120:775–6. ArticlePubMedPMC
  • 156. Widder J, van der Schaaf A, Lambin P, Marijnen CA, Pignol JP, Rasch CR, et al. The quest for evidence for proton therapy: model-based approach and precision medicine. Int J Radiat Oncol Biol Phys. 2016;95:30–6. ArticlePubMed

Figure & Data

REFERENCES

    Citations

    Citations to this article as recorded by  
    • Radiation-targeted immunotherapy: A new perspective in cancer radiotherapy
      Lihui Xuan, Chenjun Bai, Zhao Ju, Jinhua Luo, Hua Guan, Ping-Kun Zhou, Ruixue Huang
      Cytokine & Growth Factor Reviews.2024; 75: 1.     CrossRef
    • Cost-effectiveness analysis for multi adverse events of proton beam therapy for pediatric medulloblastoma in Japan
      Takaaki Yoshimura, Yasuhiro Morii, Honoka Tamori, Ryuki Kita, Takayuki Hashimoto, Hidefumi Aoyama, Katsuhiko Ogasawara
      Journal of Radiation Research.2024;[Epub]     CrossRef
    • Radioresistance-related gene signatures identified by transcriptomics characterize the prognosis and immune landscape of pancreatic cancer patients
      Dandan Wang, Jun Cao, Yanhui Chen, Lisha Zhang, Chan Zhou, Litao Huang, Yanliang Chen
      BMC Cancer.2024;[Epub]     CrossRef
    • Cellular irradiations with laser-driven carbon ions at ultra-high dose rates
      Pankaj Chaudhary, Giuliana Milluzzo, Aodhan McIlvenny, Hamad Ahmed, Aaron McMurray, Carla Maiorino, Kathryn Polin, Lorenzo Romagnani, Domenico Doria, Stephen J McMahon, Stanley W Botchway, Pattathil P Rajeev, Kevin M Prise, Marco Borghesi
      Physics in Medicine & Biology.2023; 68(2): 025015.     CrossRef
    • Efficacy and safety of particle therapy for inoperable stage II-III non-small cell lung cancer: a systematic review and meta-analysis
      Yanliang Chen, Hongtao Luo, Ruifeng Liu, Mingyu Tan, Qian Wang, Xun Wu, Tianqi Du, Zhiqiang Liu, Shilong Sun, Qiuning Zhang, Xiaohu Wang
      Radiation Oncology.2023;[Epub]     CrossRef
    • Particle radiotherapy in the era of radioimmunotherapy
      Zihan Zhou, Bingjie Guan, Huang Xia, Rong Zheng, Benhua Xu
      Cancer Letters.2023; 567: 216268.     CrossRef
    • The Rise of Particle Beam Therapy: Are We Ready for The Potential Game-Changer?
      Eui Kyu Chie, Yong Chan Ahn
      Cancer Research and Treatment.2021; 53(3): 609.     CrossRef

    • PubReader PubReader
    • ePub LinkePub Link
    • Cite
      CITE
      export Copy Download
      Close
      Download Citation
      Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

      Format:
      • RIS — For EndNote, ProCite, RefWorks, and most other reference management software
      • BibTeX — For JabRef, BibDesk, and other BibTeX-specific software
      Include:
      • Citation for the content below
      Who Will Benefit from Charged-Particle Therapy?
      Cancer Res Treat. 2021;53(3):621-634.   Published online June 21, 2021
      Close
    • XML DownloadXML Download
    Who Will Benefit from Charged-Particle Therapy?
    Who Will Benefit from Charged-Particle Therapy?

    Recommended or public health insurance covered indications for charged-particle therapy from several countries

    Country Recommendation or Indication
    United States [7] Astro Model Policy, group 1: disease sites that frequently the use of proton ocular tumors, including intraocular melanomas
     Tumors that approach or are located at the base of skull, including but not limited to chordoma or chondrosarcomas
     Primary or metastatic tumors of the spine where the spinal cord tolerance may be exceeded with conventional treatment or where the spinal cord has previously been irradiated
     Hepatocellular cancer
     Primary or benign solid tumors in children treated with curative intent and occasional palliative treatment of childhood tumors when at least one of the four criteria noted above apply
     Patients with genetic syndromes making total volume of radiation minimization crucial such as but not limited to NF-1 patients and retinoblastoma patients
     Malignant and benign primary CNS tumors
     Advanced (e.g., T4) and/or unresectable head and neck cancers
     Cancers of the paranasal sinuses and other accessory sinuses
     Non-metastatic retroperitoneal sarcomas
     Re-irradiation cases (where cumulative critical structure dose would exceed tolerance dose)
    United NHS Kingdom [8] England Indications of PBT
     Pediatric tumor
      Most pediatric tumors, malignant and benign
     Adult
      Base of skull tumors (radioresistant)
      Spinal and paraspinal tumors (radioresistant)
      Paranasal sinus tumors with base of skull involvement
    Netherlands [9] Health Council of the Netherlands. Proton Radiotherapy
     Standard indication
      Skull base or spinal chordoma and chondrosarcoma
      Other intracranial, spinal, and paraspinal tumors, including meningioma
      Pediatric tumors, including bone tumors, soft-tissue sarcoma, low-grade glioma, meningioma, medulloblastoma, ependymoma, and neuroblastoma
     Potential indications (cases for which protons may be specifically utilized to improve local control)
      Re-irradiation (malignant brain tumors, head and neck cancer)
      Paranasal sinus tumors, nasopharyngeal carcinoma, prostate, NSCLC, retroperitoneal sarcoma
     Model based indication (cases where proton will be utilized to reduce side effect)
      Re-irradiation (meningioma, head and neck cancer)
      Head and neck cancers, prostate
     Reduction of secondary cancer
      Breast cancer
      Lymphoma
      Testis
    Japan [10] Public Health Insurance of Particle Therapy
     PBT
      Pediatric cancer
      Bone and soft tissue sarcoma
      Head and neck
      Prostate
     CIRT
      Bone and soft tissue sarcoma
      Head and neck
      Prostate
    Korea [10] Public Health Insurance of PBT
     Pediatric cancer
     Re-RT
     Brain, skull base, and spinal tumors
     Head and neck cancer including orbit
     Thorax tumor (lung, esophagus, and mediastinum except breast cancer)
     Abdominal tumors (hepatobiliary, pancreas, and retroperitoneum

    Astro, American Society for Radiation Oncology; CIRT; carbon ion radiotherapy, CNS, central nervous system; NHS, National Health Service; NSCLC, non–small cell lung cancer; PBT, proton beam therapy; RT, radiotherapy.

    The number of patients treated by charged particle therapy based on tumor site in several countries

    California, PBT (2003–2016) [11] Japan, PBT (1979–2013) [77] Japan, CIRT (1994–2017) [78] UK (Christie), PBT (2018–2019) [8]




    Site Percentage Site Percentage Site Percentage Population Site Percentage
    Prostate 41.3 Prostate 30.0 Prostate 24.7 Pediatric and CNS 38.9

    Breast 14.0 Liver 19.0 Bone and soft tissue 11.5 young adult H&N 15.7

    Eye/orbit 11.8 H&N 13.0 H&N 9.6 (~24 yr) Body 10.2

    Lung 6.1 Lung 12.0 Lung 9.2 Spine 6.5

    CNS 6.0 GI 6.0 Pancreas 5.4 CSI 1.9

    Lymphoma/leukemia 2.9 Pancreas 4.0 Liver 5.3 Adult CNS 8.3

    Liver 2.4 Sarcoma 3.0 Rectum (recur) 4.9 H&N 3.7

    H&N 2.3 CNS 3.0 Uterus 2.5 Body 0.9

    Female genital 2.1 Others 10.0 Uveal melanoma 1.8 Spine 13.9

    Colon and rectum 3.0 Abdominal LN 1.2

    Others 9.1 CNS 0.9

    GI tract 0.8

    Re-irradiation 9.2

    Others 13.0

    Total 100 (n=8,609) Total 100 (n=15,000 approximately) Total 100 (n=11,580) Total 100 (n=108)

    CIRT; carbon ion radiotherapy, CNS, central nervous system; CSI, cranio-spinal irradiation; GI, gastrointestinal; H&N, head and neck; LN, lymph node; PBT, proton beam therapy.

    Table 1 Recommended or public health insurance covered indications for charged-particle therapy from several countries

    Astro, American Society for Radiation Oncology; CIRT; carbon ion radiotherapy, CNS, central nervous system; NHS, National Health Service; NSCLC, non–small cell lung cancer; PBT, proton beam therapy; RT, radiotherapy.

    Table 2 The number of patients treated by charged particle therapy based on tumor site in several countries

    CIRT; carbon ion radiotherapy, CNS, central nervous system; CSI, cranio-spinal irradiation; GI, gastrointestinal; H&N, head and neck; LN, lymph node; PBT, proton beam therapy.


    Cancer Res Treat : Cancer Research and Treatment
    Close layer
    TOP