Abstract
Carbon-ion radiotherapy (CIRT) offers superior dose distributions and greater
biological effectiveness than conventional photon-based radiotherapy (RT). Due
to its higher linear energy transfer and relative biological effectiveness, CIRT
is particularly effective against radioresistant tumors and those located near
critical organs. Since the first dedicated CIRT facility was established in
Japan in 1994, CIRT has demonstrated remarkable efficacy against various
malignancies, including head and neck tumors, skull base and upper cervical
spine tumors, non-small-cell lung cancer, hepatocellular carcinoma, pancreatic
cancer, prostate cancer, and bone and soft tissue sarcomas. This narrative
review provides a comprehensive overview of the current status of CIRT,
highlighting its clinical indications and future directions. According to
clinical studies, CIRT achieves high local control rates with manageable
toxicity across multiple cancer types. For instance, in head and neck tumors
(e.g., adenoid cystic carcinoma and mucosal melanoma), CIRT has achieved local
control rates exceeding 80%. In early-stage non-small-cell lung cancer, CIRT has
resulted in local control rates over 90% with minimal toxicity. Moreover, CIRT
has shown promise in treating challenging cases of hepatocellular carcinoma and
pancreatic cancer, where conventional therapies are limited. Nonetheless, the
global adoption of CIRT remains limited due to high costs and complexity. Future
directions include conducting randomized controlled trials to establish
high-level evidence, integrating new technologies such as ultrahigh-dose-rate
(FLASH) therapy, and expanding CIRT facilities globally with strategic planning
and cost-effectiveness analyses. If these challenges are addressed, CIRT is
poised to play a transformative role in cancer treatment, improving survival
rates and the quality of life.
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Keywords: Carbon-ion radiotherapy; Charged particle therapy; Bragg peak; Review; Radioresistant tumors
Introduction
Background
Radiotherapy (RT) has long been a cornerstone of cancer treatment. It employs
ionizing radiation to damage the DNA in tumor cells, initiating a series of
biochemical reactions that result in cell death. Among the various types of
ionizing radiation, X-rays and gamma rays are most commonly used, with X-ray
therapy being the standard in clinical settings. Despite its prevalent use,
X-ray therapy faces significant challenges, particularly in avoiding damage to
healthy tissues near the tumor, especially when these tissues are close to vital
organs. These challenges have spurred the development of alternative RT methods
that offer more favorable dose distributions and improved biological
effects.
In recent years, charged particle beam therapy, often referred to as particle
therapy, has become a significant advancement in the field of RT. This
innovative method includes proton and carbon-ion radiotherapy (CIRT), offering
substantial physical and biological advantages over traditional photon-based
therapies. Notably, carbon ions have a higher linear energy transfer and
relative biological effectiveness (RBE) than protons, enhancing their
effectiveness in controlling tumors, particularly those that are radioresistant
or situated near critical organs [
1,
2]. The establishment of the first dedicated
CIRT facility in Japan in 1994 was a pivotal moment in the history of RT. This
development was inspired by earlier research that recognized the therapeutic
potential of high-linear energy transfer radiation. Since then, CIRT has been
successfully implemented in a limited number of countries, including China,
Germany, Italy, Japan, and Korea, where it has shown remarkable efficacy in
treating various malignancies. A recent meta-analysis also confirmed that CIRT
is a safe and effective option for achieving local control (LC) in patients with
solid tumors [
3].
In Korea, the Yonsei Cancer Center has been at the forefront of adopting CIRT,
marking a significant milestone in the nation's medical advancement. The
planning for the Heavy Ion Therapy Center at Yonsei Cancer Center began in 2013,
leading to the establishment of Korea's first CIRT facility, which became
operational in April 2023. This center is globally recognized for its
state-of-the-art infrastructure, including the world's first
configuration with a fixed beam and two superconducting gantries dedicated to
CIRT. The Heavy Ion Therapy Center at the Yonsei Cancer Center represents a
decade of meticulous planning and collaboration, with over 200 prostate cancer
patients successfully treated by mid-2024. The center has expanded its treatment
offerings to include CIRT for pancreatic, liver, and lung cancers starting in
May 2024. The Yonsei Cancer Center's commitment to advancing CIRT not
only enhances treatment options for Korean patients but also positions the
center as a leading institution in the global CIRT community.
Despite the clear therapeutic benefits of CIRT, its global adoption remains
limited primarily due to the high costs and complexity associated with
establishing such facilities. However, the increasing number of CIRT centers and
ongoing clinical research are expanding its applications and accessibility.
Objectives
This review aimed to provide a comprehensive overview of the current status of
CIRT, encompassing its physical and biological characteristics, clinical
indications, and future directions. By exploring the progress and potential of
CIRT, this study sought to highlight its crucial role in advancing cancer
treatment and the need for wider implementation of this advanced technology.
Ethics statement
As this study is a literature review, it did not require institutional review board
approval or individual consent.
Head and neck tumors
Surgical resection is the primary treatment for head and neck malignancies. However,
the complexity of this region often makes it challenging to achieve complete
resection without significant morbidity. Consequently, RT is frequently used as
either primary or adjuvant therapy. CIRT is particularly effective in these cases
due to its superior dose distribution and enhanced biological efficacy. It enables
precise targeting of the tumor while sparing radiosensitive structures such as the
salivary glands, cranial nerves, and brainstem. CIRT has shown favorable outcomes,
especially in treating radioresistant tumors like adenoid cystic carcinoma (ACC) and
chordomas, achieving high LC rates with manageable toxicity. Although direct
comparative studies with conventional treatments are limited, both CIRT and proton
therapy have been successfully used as primary and postoperative treatments, either
alone or in combination with photon therapy.
ACC in the head and neck poses significant treatment challenges due to its propensity
for perineural invasion and involvement of the skull base, which complicates
achieving complete surgical resection. CIRT has emerged as a promising treatment
option for managing ACC, especially in patients with postoperative residual disease
or unresectable tumors. An initial study [
4]
from the Heavy Ion Research Center (GSI) in Heidelberg reported 1- and 3-year LC
rates of 80.8% and 64.6%, respectively, for patients treated with a combination of
photon therapy and a CIRT boost, totaling 72 Gy(RBE). At the National Institute of
Radiological Sciences (NIRS) in Japan, a dose-escalation trial identified the
maximum tolerated dose as 70.2 Gy(RBE) in 18 fractions, resulting in a 5-year LC
rate of 73% [
5]. The COSMIC trial, a phase II
study in Heidelberg, reported a 3-year LC rate of 81.9% for ACC, with higher control
rates observed in patients with residual disease post-resection [
6]. Large-scale studies at the GSI [
7] and NIRS [
8] confirmed these findings, with 3- and 5-year LC rates of
approximately 81% and 73%, respectively, and low incidence of severe toxicity.
Additionally, a sub-analysis of a Japanese multicenter study (1402 HN) by the Japan
Carbon-Ion Radiation Oncology Study Group (J-CROS) [
9] reported 2- and 5-year LC rates of 88% and 68%, respectively.
Meanwhile, the 2- and 5-year overall survival (OS) rates were 94% and 74%,
respectively, with 15% of the patients experiencing grade 3 or higher toxicities,
such as osteoradionecrosis and vision loss. These studies highlight the
effectiveness of CIRT in managing ACC, particularly in challenging cases involving
residual disease.
CIRT has also shown significant effectiveness in treating head and neck mucosal
melanoma, a notably aggressive and radioresistant cancer. Various studies, including
both prospective and retrospective analyses from institutions such as the NIRS
[
5,
8], Hyogo Ion Beam Medical Center [
10], National Centre for Oncological Hadrontherapy in Italy [
11], Gunma University Heavy Ion Medical Center
[
12], and Heidelberg Ion Beam Therapy
Center (HIT) in Germany [
13], have documented
the benefits of CIRT in this context. A multicenter retrospective study [
14] in Japan, which included 260 patients with
mucosal melanoma, reported a 2-year LC rate of 83.9% and an OS rate of 69.4%, with
grade 3 or higher toxicities occurring in 19% of the patients. At the NIRS, dose
adjustments over time, from 70.2 Gy(RBE) in 18 fractions to 57.6 Gy(RBE) in 16
fractions, resulted in a 5-year LC rate of 75% and an OS rate of 35% [
5,
8]. The
HIT in Germany reported a 3-year LC rate of 58.3% and an OS rate of 16.2% for
paranasal sinus melanoma [
13], highlighting
the challenges in treating this type of tumor. In cases of choroidal melanoma, NIRS
reported a 5-year LC rate of 92.8% and an OS rate of 80.4%, although 31.6% of
patients experienced neovascular glaucoma as a late toxicity [
15,
16]. These findings
demonstrate the potential of CIRT to achieve high LC rates in challenging melanoma
cases, particularly in anatomically complex regions such as the head, neck, and
choroid.
Skull base and upper cervical spine tumors
Several studies have demonstrated the effectiveness of CIRT in treating tumors
located at the skull base and upper spine, particularly in patients with sarcoma
where surgical resection is challenging or incomplete. A prospective study [
17] involving 27 patients with unresected
sarcomas of mixed histology reported a 3-year LC rate of 91.8% following CIRT
administration at a dose of 70.4 Gy(RBE) in 16 fractions. However, 23.1% of these
patients experienced late radiation-related complications of grade 3 or higher.
Similarly, another prospective study [
18]
conducted at Gunma University included 10 patients with unresectable bone or soft
tissue sarcomas at the skull base. These patients received CIRT at the same dosage
and reported a 3-year LC rate of 72.9%. These studies underscore the potential of
CIRT to achieve substantial LC in regions that are difficult to treat, although
concerns about late toxicity remain unresolved.
Chordomas and chondrosarcomas of the skull base have been significant targets for
charged-particle therapy due to their complex anatomical locations and the high
radiation doses needed for effective treatment [
19,
20]. At HIT, a retrospective
study [
21] conducted in 155 patients with
skull base chordomas treated with 60 Gy(RBE) in 20 fractions reported 5-year and
10-year LC rates of 72% and 54%, respectively. Another follow-up study [
22] at HIT involving 111 patients treated with
66 Gy(RBE) in 22 fractions reported a 5-year LC rate of 65%. In Italy, a study
carried out at the National Centre for Oncological Hadrontherapy reported a 5-year
LC rate of 71% in 135 patients treated with 70.4 Gy(RBE) in 16 fractions for skull
base chordoma [
23]. For chondrosarcoma,
German studies [
24–
26] demonstrated a 3-year LC rate of 96.2% and
a 10-year LC rate of 88% in patients treated with 60 Gy(RBE) in 20 fractions, with a
low incidence of severe toxicity. These findings underscore the efficacy of CIRT in
managing these rare but challenging tumors, providing long-term control with an
acceptable safety profile.
Non-small-cell lung cancer
RT is a crucial treatment modality for lung cancer and the second most common
treatment in Korea [
27]. CIRT has become a
viable and effective treatment option for localized non-small-cell lung cancer
(NSCLC), especially in patients who are not suitable candidates for surgery due to
comorbidities or advanced age. Since its introduction for NSCLC in November 1994,
CIRT has shown effectiveness in treating early-stage NSCLC, particularly in tumors
located peripherally and in selected cases of central tumors. CIRT offers potential
advantages over traditional treatments for patients who need to minimize radiation
exposure to the lungs, such as those suffering from interstitial lung disease (ILD).
Multiple studies have confirmed the efficacy of CIRT in improving LC with an
acceptable toxicity profile (
Table 1).
Table 1. Clinical studies and outcomes of patients with NSCLC treated with
CIRT
|
Author |
Study design |
No. of patients |
CIRT dose |
LC |
OS |
Acute toxicity |
Late toxicity |
|
Early-stage NSCLC |
|
Miyamoto et al. [28] |
Phase I/II |
81 |
59.4–95.4 Gy(RBE)/9–18
fr |
First trial: 64%
Second trial:
84% |
5-yr 42% |
Gr3 RP=3 |
|
|
Miyamoto et al. [29] |
Phase II |
50 |
72 Gy(RBE)/9 fr |
5-yr 94.7% |
5-yr 50% (IA 55.2%, IB 42.9%) |
No Gr3≤toxicity
Gr 2
skin=1,
Gr 2 RP=1 |
Gr 3 skin=1
Gr 2 skin=1
Gr
2 lung=2 |
|
Miyamoto et al. [30] |
Phase II |
79 |
52.8 Gy(RBE)/4 fr for stage IA, 60
Gy(RBE)/4 fr for stage IB |
5-yr 90% |
Overall: 5-yr 45%,
stage IA: 5-yr
62%,
stage IB: 25% |
No Gr3≤toxicity
Gr 2
skin=5
Gr 2 lung=1 |
No Gr3≤toxicity
Gr 2
skin=1
Gr 2 lung=1 |
|
Yamamoto et al. [31] |
Phase I/II |
218 |
28–50 Gy(RBE)/1 fr |
36–50 Gy(RBE):
3-yr 84.2%,
5-yr 80.5%
28-34 Gy(RBE):
3-yr 63.7%, 5-yr 54.4% |
36–50 Gy(RBE):
3-yr 76.2%,
5-yr 56.8%
28–34 Gy(RBE):
3-yr 50.7%, 5-yr
32.8% |
No
Gr3≤toxicity
Gr 2 toxicity=2%
Gr 3 chest wall
pain=1 (50 Gy(RBE)) |
|
Saitoh et al. [32] |
Phase II |
37 |
52.8–60 Gy(RBE)/4 fr |
Overall:
2-yr 91.2%, 5-yr
88.1%
T1:
2-yr 91.3%, 5-yr
86.7%
T2:
2-yr 90%, 5-yr 90% |
Overall:
2-yr 91.9%, 5-yr
74/9%
T1:
5-yr 80%
T2:
66.7% |
No Gr 4≤toxicity,
Gr 3 RP=1,
Gr 2 RP=1 |
|
Ono et al. [33] |
Retrospective |
57 |
50 Gy(RBE)/1 fr |
3-yr 96.4%, 5-yr 91.8% |
3-yr 91.2%, 5-yr 81.7% |
No Gr
3≤toxicity
Gr 2 rib fracture=4 (7.0%)
Gr 2
peripheral motor neuropathy=2 (3.5%) |
|
Kubo et al. (J-CROS-LUNG) [34] |
Multicenter prospective observational
registry study |
95 |
72 Gy(RBE)/16 fr–50 Gy(RBE)/1
fr |
3-yr 87.3% |
3-yr 59.3% |
No Gr 4≤toxicity,
3-yr Gr2≤ RP rate=3.2%,
Risk factor for
RP=FEV1<0.9L, dose≥67 Gy(RBE) |
|
Locally advanced NSCLC |
|
Takahashi et al. [37] |
Phase I/II |
62 |
68–76 Gy(RBE)/16 fr |
2-yr 93.1%
(cT3–4N0 only:
2-yr 100%) |
2-yr 51.9%
(cT3–4N0 only:
2-yr 69.3%) |
Gr 2 RP=6.5%
Gr 3 RP=1.6% |
Gr 3 tracheoesophageal
fistula=1
No grade 4/5 toxicity |
|
Hayashi et al. [38] |
Retrospective |
141 |
54–76 Gy(RBE)/12–16
fr |
2-yr 80.3%, 3-yr 75.4% |
2-yr 58.7%, 3-yr 47.5% |
Gr 2 skin=13.5% |
Gr 4 mediastinal
hemorrhage=0.7%
Gr 3 RP=3.5%
Gr 3 bronchial
fistula=7% |
|
Karube et al. [39] |
Retrospective |
64 |
52.8–60 Gy(RBE)/4 fr,
64–70.4 Gy(RBE)/16 fr |
2-yr 81.8% |
Overall: 2-yr 62.2%
N0: 2-yr
67.8%
N1-N2: 2-yr 62.2% |
Gr 2 lung infection=3
Gr 2 lung
reaction=4
Gr 2 skin reaction=3
Gr 2 chest wall
pain=1 |
NR |
|
Anzai et al. [40] |
Retrospective |
24 |
64–76 Gy(RBE)/16 fr |
2-yr 73.9%, 3-yr 70.2% |
2-yr 54.9%, 3-yr 42% |
No Gr 3≤toxicity |
Gr 4 mediastinal hemorrhage=1
Gr
3 RP=4
Gr 3 bronchial fistula=1 |
At the NIRS in Japan, several hypofractionation and dose-escalation studies explored
the optimal dosing regimens for CIRT in stage I NSCLC. An initial dose of 59.4
Gy(RBE) in 18 fractions was progressively refined to 72 Gy(RBE) in nine fractions,
52.8 Gy(RBE) in four fractions, and even a single-fraction dose of 50 Gy(RBE). These
studies [
28–
32] reported a 3-year OS rate of approximately 70%–80%
and a 3-year LC rate exceeding 90% in patients with stage IA tumors, although the LC
rate was lower in patients with stage IB tumors. The incidence of grade 2 or higher
toxicity was less than 2%. Recent phase I/II Japanese studies [
31] and other recent studies [
33] have identified 50 Gy(RBE) as the optimal dose for dose-escalated,
single-fraction CIRT, demonstrating its feasibility as a treatment option with high
LC and low toxicity rates. In a Japanese multicenter study (J-CROS-LUNG) [
34], 95 patients with inoperable stage I NSCLC
received CIRT using regimens such as 64–72 Gy(RBE) in 12–16 fractions,
54–64 Gy(RBE) in four fractions, and 50 Gy(RBE) in one fraction. This study
reported a 3-year LC rate of 87.3%, an OS rate of 59.3%, and a 3-year cumulative
incidence of grade 2 or higher radiation pneumonitis of 3.2%. A retrospective,
single-institutional study [
35] directly
comparing CIRT and stereotactic body RT for early-stage NSCLC found that CIRT
achieved significantly higher 3-year OS rates (80.1% vs. 71.6%) and LC rates (87.7%
vs. 79.1%) than stereotactic body RT. Furthermore, a cost-effectiveness analysis at
Gunma University [
36] suggested that while
CIRT is cost-effective for stage I NSCLC, careful resource management could enhance
its economic viability. These outcomes highlight CIRT's potential to achieve
high LC with low toxicity, particularly in patients with limited surgical
options.
CIRT has shown promising results in treating locally advanced NSCLC (LA-NSCLC),
despite the inherent challenges associated with this stage of the disease. In a
phase I/II study [
37] at NIRS involving 62
patients with stage IIA–IIIA NSCLC treated with CIRT at a dose of 76 Gy(RBE),
the 2-year LC and OS rates were 93% and 52%, respectively. Notably, patients with N0
disease exhibited a 2-year LC rate of 100% and an OS rate of 69%, with cases pf no
grade 3 or higher toxicity observed following treatment with 72 Gy(RBE). A
retrospective study [
38] of 141 patients with
LA-NSCLC treated with a median dose of 72 Gy(RBE) in 16 fractions reported 2-year LC
and OS rates of 80.3% and 58.7%, respectively. In a Japanese multicenter study
[
39] of patients with LA-NSCLC, the
2-year LC and OS rates were 81.8% and 62.2%, respectively, with no reported adverse
effects higher than grade 2. Similarly, Anzai et al. [
40] analyzed 65 patients with stage III NSCLC treated at NIRS
with a median dose of 72 Gy(RBE), resulting in 2-year LC and OS rates of 74% and
55%, respectively. These studies suggest that CIRT, even without concurrent
chemotherapy, may be a viable treatment option for patients with LA-NSCLC, achieving
substantial LC and survival rates. However, further research is needed to clarify
the role of CIRT in combination with systemic treatments, such as chemotherapy or
immunotherapy.
Treating NSCLC in patients with ILD presents significant challenges due to the risk
of acute exacerbation. However, recent research indicates that proton therapy [
41] or CIRT may be safe and effective options.
A retrospective study [
42] of 124 patients
with stage I NSCLC, including 26 with ILD, found that although patients with ILD had
a lower OS (59.7% vs. 83.2%), CIRT did not significantly increase the incidence of
severe side effects. Additionally, a multi-institutional study [
43] of 30 patients with ILD reported a 3-year
LC rate of 88.1%, with only 3.3% experiencing grade 2 or higher radiation
pneumonitis. These findings suggest that CIRT could be a viable treatment for
early-stage NSCLC in patients with ILD.
Hepatocellular carcinoma
CIRT has demonstrated significant potential in treating hepatocellular carcinoma
(HCC), proving effective not only in early-stage cases but also in more complex
situations where alternative treatments are limited. It is particularly beneficial
for patients with large tumors, tumors in difficult anatomical locations such as
near the porta hepatis or major blood vessels, and for those with compromised liver
function. In cases where surgical resection or photon therapy may present
significant risks, CIRT offers a safer alternative. Moreover, CIRT is a viable
treatment option for patients experiencing recurrent HCC following previous
interventions like transarterial chemoembolization or radiofrequency ablation (RFA),
where it is critical to minimize additional liver damage.
In 2004, the NIRS conducted a prospective phase I trial [
44] to explore the impact of increasing the dose from 49.5
Gy(RBE) to 79.5 Gy(RBE) in 15 fractions. The trial found no severe adverse effects
and reported an 81% LC rate at both 3 and 5 years. Subsequent phase I and II trials
[
45] established 52.8 Gy(RBE) in four
fractions as the recommended dose, with no cases of dose-limiting toxicity. Gunma
University reported a 92.3% LC rate at 2 years and 76.5% at 4 years using doses of
52.8 Gy(RBE) and 60 Gy(RBE) in four fractions, with only grade 3 hepatobiliary
toxicity reported in two patients [
46,
47]. A multi-institutional retrospective study
[
48] conducted by the J-CROS Group in 174
patients with HCC treated with CIRT (48–60 Gy(RBE) in two to four fractions)
reported a 3-year LC rate of 81.0% and a 3-year OS rate of 73.3%, with only a few
patients experiencing grade 3 or higher acute or late toxicity. Recent studies have
refined the dosing strategy, using two or four fractions for tumors distant from the
gastrointestinal tract and 12 or more fractions for those closer to the
gastrointestinal tract to minimize adverse effects [
49–
52].
The majority of existing literature on CIRT has focused primarily on its usage, with
only a limited number of small retrospective studies comparing it to other treatment
modalities. Shiba et al. [
50] compared CIRT
with transarterial chemoembolization after propensity score matching. They found
that CIRT led to significantly better 3-year OS (88% vs. 58%, P<0.05) and LC
(80% vs. 26%, P<0.01) rates. Fujita et al. [
53] compared the efficacy of CIRT and RFA in early-stage HCC in a study
of 560 patients. CIRT was associated with significantly lower cumulative
intrasubsegmental recurrence rates than RFA (2 years: 12.6% vs. 31.7%; 5 years:
15.5% vs. 49.6%), although the local recurrence, progression-free survival, and OS
rates were similar between the groups. Notably, no grade 3 or higher adverse events
were reported in the CIRT group, while 1.2% of the patients in the RFA group
experienced grade 3 adverse events. Additionally, a comparative study by Komatsu et
al. [
54] reported similar outcomes between
CIRT and proton beam therapy, with 5-year LC and OS rates of 93% and 36.3%,
respectively, for CIRT.
CIRT has demonstrated significant potential in managing complex HCC cases, where
conventional RT may pose considerable risks. Studies have demonstrated that CIRT can
effectively minimize radiation-induced liver disease while still achieving high LC
rates, even in patients with compromised liver function or large tumors. Hiroshima
et al. [
55] reported a low incidence of grade
3 toxicity in patients with Child-Pugh B liver function treated with CIRT.
Meanwhile, Tomizawa et al. [
52] reported no
grade 4 toxicity in patients who underwent re-irradiation with CIRT for intrahepatic
HCC recurrence. Furthermore, CIRT has proven effective in treating HCC located near
critical structures such as the caudate lobe and porta hepatis, maintaining high LC
rates and reducing the incidence of adverse effects in these challenging scenarios
[
56,
57].
Pancreatic cancer
Pancreatic cancer is known for its resistance to conventional RT and its generally
poor prognosis, underscoring the urgency for more effective treatment approaches.
The pancreas's close proximity to radiosensitive organs like the stomach and
bowel restricts the amount of radiation that can be safely administered using photon
therapy. CIRT has not only shown a strong biological rationale in vitro [
58,
59],
but has also yielded promising clinical results, especially in cases of locally
advanced pancreatic cancer. Recent studies have further investigated the potential
of CIRT in treating resectable and borderline resectable pancreatic cancers, aiming
to improve surgical outcomes and decrease recurrence rates.
CIRT has emerged as a promising alternative for treating locally advanced pancreatic
cancer, where conventional treatments often show limited efficacy. A phase 1/2
prospective clinical trial conducted at the NIRS [
60] assessed the maximum tolerated dose of CIRT combined with
gemcitabine. The study reported a 2-year local progression-free rate of 83% and a
2-year OS rate of 48% for patients receiving more than 45.6 Gy(RBE). A multicenter
study (J-CROS 1403) [
61] reported a median
survival of 21.5 months, with a 2-year OS rate of 46% and a 2-year local recurrence
rate of 24%. Notably, only 1% of patients experienced late grade 3 gastrointestinal
toxicity, and no cases of severe toxicity were observed. Additionally, a study from
Gunma University [
62], which analyzed
patients treated with concurrent chemotherapy (±neoadjuvant or adjuvant
multiagent chemotherapy), reported a 2-year LC rate of 76.1%, a 2-year OS rate of
56.6%, and a median survival of 29.6 months. These findings suggest that CIRT may
improve outcomes in patients with locally advanced pancreatic cancer. However,
further research is needed to comprehensively define its role and determine the
optimal combination strategies with chemotherapy.
For resectable or borderline resectable pancreatic cancers, CIRT has been
investigated as a preoperative treatment to enhance surgical outcomes and decrease
recurrence rates. Promising results have emerged from studies conducted by
Japan's NIRS. A phase I trial [
63]
demonstrated that 90% of patients could undergo R0 resection after receiving CIRT at
30–36.8 Gy(RBE) in eight fractions, with no local recurrences reported. The
5-year OS rate of patients who underwent surgery was 52%. Based on these findings, a
subsequent phase II study [
64] reported that
89% of patients underwent surgery after receiving CIRT, with a 5-year LC rate of
92.3% and an OS rate of 49%. Ongoing trials, such as the PIOPPO study in Italy
[
65], will further explore the efficacy
of CIRT combined with chemotherapy in improving surgical outcomes for this group of
patients.
Prostate cancer
For prostate cancer, RT is crucial for achieving optimal tumor control while
minimizing gastrointestinal and genitourinary toxicities. While photon therapy is
widely used, charged-particle therapies such as proton therapy and CIRT offer
improved dose distribution and a lower incidence of side effects. This advantage is
similar to what is observed in breast cancer [
66,
67]. The low alpha/beta ratio
in prostate cancer makes it particularly amenable to hypofractionated treatment
schedules [
68]. Hypofractionated CIRT has
shown high rates of biochemical recurrence-free survival (bRFS) with reduced
toxicity compared to photon therapy. Although direct comparisons are limited,
current studies suggest that CIRT may offer significant benefits in the treatment of
prostate cancer.
Since 1995, CIRT has been administered to over 4,100 prostate cancer patients in
Japan, with its use refined through numerous clinical trials. Initial phase I/II
trials at NIRS escalated the doses from 54 Gy(RBE) to 72 Gy(RBE) across 20 fractions
[
69,
70]. The second trial (protocol 9703) established 66 Gy(RBE) as the
recommended dose [
70,
71]. A subsequent phase II trial (protocol 9904) [
72] validated this regimen and reported 4-year
bRFS rates of 87% in low-risk patients and 88% in high-risk patients. In this group,
5% experienced grade 2 genitourinary toxicity, 2% had gastrointestinal toxicity, and
there were no grade 3 or higher events. Further research led to a reduction in dose
to 63 Gy(RBE) in 20 fractions and subsequently to 57.6 Gy(RBE) in 16 fractions,
achieving a 5-year bRFS rate of 88.5% with fewer cases of grade 2 genitourinary
toxicity [
73]. In 2010, protocol 1002 [
74] adopted 51.6 Gy(RBE) in 12 fractions as the
standard, with 5-year bRFS rates of 95.1%, 90.9%, and 91.1% in low-, intermediate-,
and high-risk groups, respectively, and late grade 2 genitourinary and
gastrointestinal toxicity in only 6.3% and 0.4% of patients, respectively. A
Japanese multicenter study (J-CROS1501PR) [
75] involving 2,157 patients further validated these outcomes, with 5-year
RFS rates of 92%, 89%, and 92% in the respective risk groups and a lower incidence
of grade 2 genitourinary and gastrointestinal toxicity.
In Germany and Italy, CIRT for prostate cancer has demonstrated favorable safety and
efficacy outcomes. A clinical trial [
76] at
the HIT in Germany reported that CIRT was associated with a lower incidence of
genitourinary and gastrointestinal toxicities compared to proton therapy. Among
those treated with CIRT, 28.9% experienced grade 1 cystitis, 13.3% experienced grade
2 cystitis, 11.1% experienced grade 1 proctitis, and 2.2% experienced grade 2
proctitis. In Italy, a trial that combined CIRT with photon therapy for patients at
high risk of prostate cancer indicated that this combined approach might offer
better outcomes than photon therapy alone [
77,
78]. Additionally, quality of
life assessments from studies conducted in Germany, Japan, and China [
76,
79,
80] showed that CIRT had a
minimal long-term impact on the quality of life. These studies reported transient
acute genitourinary toxicity and no cases of significant gastrointestinal toxicity,
reinforcing its safety and efficacy in prostate cancer.
Bone and soft tissue sarcoma
Sarcomas are known for their radioresistance and often develop in anatomically
challenging locations, which complicates surgical resection. As a result, RT plays a
pivotal role, especially for patients with unresectable tumors or residual disease.
While traditional photon therapy is commonly employed, there is a growing preference
for charged-particle therapies, such as CIRT, due to their enhanced efficacy. CIRT
has demonstrated effectiveness in treating sarcomas, particularly those that are
radioresistant or situated in complex anatomical areas. There is substantial
evidence supporting the effectiveness of CIRT in improving LC and OS rates in
patients with various types of sarcomas (
Table
2).
Table 2. Clinical studies and outcomes of patients with bone and soft tissue
sarcomas treated with CIRT
|
Author |
Study design |
Tumor type and location |
No. of patients |
CIRT dose (Gy(RBE)) |
LC |
OS |
Acute toxicity |
Late toxicity |
|
Bone sarcoma |
|
Imai et al. [81] |
Retrospective |
Sacral chordoma |
188 |
64–73.6 |
5-yr 77.2% |
5-yr 81.1% |
NR |
Gr 3 peripheral nerve toxicity=6, Gr 4
skin=2 |
|
Imai et al. [82] |
Retrospective |
Chondrosarcoma |
73 |
64–73.6 |
5-yr 53% |
5-yr 53% |
NR |
Gr 3≤toxicity=8, Gr 3 skin=3,
bone fracture=4, bone necrosis=1 |
|
Wu et al. [83] |
Retrospective |
Chordoma or chondrosarcoma |
21 |
57–80 |
1-yr 93.8%, 2-yr 85.2% |
1-yr 100%, 2-yr 100% |
Gr 1 skin=14.2%, Gr 1
myelosuppression=33.3%
No Gr 2≤toxicity. |
No severe late toxicity |
|
Bostel et al. [84] |
Retrospective |
Primary or recurrent sacrococcygeal
chordoma |
68 |
60–70.4 |
Overall: 1-yr 90%, 2-yr 80%, 3-yr 65%,
5-yr 53%
Primary: 1-yr 96%, 2-yr 88%, 3-yr 77%, 5-yr
62%
Recurrent: 1-yr 68%, 2-yr 54%, 3-yr 27%, 5-yr 27% |
Overall:
1-yr 97%, 2-yr 97%, 3-yr
86%, 5-yr 74% |
NR |
Radiogenic toxicity=40 (59%; 14 received
at least 80 GyE)
Gr 3≤=21%, Sacral insufficiency
fractures=49% |
|
Shiba et al. [85] |
Retrospective |
Bone sarcoma |
53 |
64–70.4 |
Overall: 3-yr 88.6%, 5-yr
73.8%
Chordoma: 3-yr 92.5%, 5-yr 84.8%
Non-chordoma:
3-yr 82.2%, 5-yr 54.8%
Osteosarcoma: 3-yr
87.5%
Chondrosarcoma: 3-yr 60% |
Overall: 3-yr 79.7%, 5-yr
79.7%
Chordoma: 3-yr 91.3%, 5-yr 91.3%
Non-chordoma:
3-yr 60.7%, 5-yr 60.7%
Osteosarcoma: 3-yr
36.5%
Chondrosarcoma: 3-yr 59.3% |
No Gr 3≤toxicity.
Gr 1
dermatitis=21
Gr 2 dermatitis=6
Gr 1
neuropathy=6
Gr 2 neuropathy 2 |
Gr 3 dermatitis=5
Gr 3 GI tract=1
Gr 3 infection=5
Gr 3 dermatitis=3
Gr 3 GI
tract=1
Gr 2 neuropathy=12
Gr 2 urinary=3
Gr 2
bone fracture=4 |
|
Matsunobu et al. [86] |
Retrospective |
Trunk osteosarcoma |
78 |
52.8–73.6 |
5-yr 62% |
5-yr 33%,
<70
Gy(RBE)=56%
≥70Gy(RBE)=27% |
Gr 3 skin=3 |
Gr 3 skin/soft tissue=4
Gr 4
skin/soft tissue=3
Bone fracture requiring surgery=2 |
|
Matsumoto et al. [87] |
Retrospective |
Primary spinal sarcoma |
47 |
52.8–70.4 |
5-yr 79% |
5-yr 52% |
Gr 3 skin=1 |
Gr 3 skin 1, Gr 4 skin ulcer
1,
Vertebral body compression=7 (more common in ≥70.4
GyE)
Gr 3 myelopathy=1 |
|
Sugahara et al. [88] |
Phase I/II |
Extremity sarcoma |
17 |
52.8–70.4 |
3-yr 76%, 5-yr 76% |
3-yr 68%, 5-yr 56% |
Gr 1 skin=16 (94%) |
Gr 2 skin=1 (6%)
Gr 2
neuropathy=4 (24%) |
|
Pediatric/young adult
sarcoma |
|
Mohamad et al. [89] |
Retrospective |
Unresectable truncal osteosarcoma |
26 |
52.8–73.6 |
3-yr 70%, 5-yr 63% |
3-yr 50%, 5-yr 42% |
None |
Gr 3–4=4
(1 Gr 3 skin, 1
Gr 4 skin, 2 neuropathy) |
|
Combs et al. [90] |
Retrospective |
Skull base chordoma or
chondrosarcoma |
17 |
60–66.6 |
Only 1 tumor progression (60 months
after CIRT) |
NR |
Only mild (Gr 1 or 2)
Focal
alopecia=1 (6%), skin=1 (6%) |
No severe late toxicity,
2
hormone deficiency requiring hormone substitution,
No
secondary malignancy |
|
Soft tissue sarcoma |
|
Serizawa et al. [91] |
Retrospective |
Unresectable retroperitoneal
sarcoma |
24 |
52.8–73.6 |
2-yr 77%, 5-yr 69% |
2-yr 75%, 5-yr 50% |
Gr 1 skin=83%,
Gr 2
skin=17% |
Gr2 neurotoxicity=21%
No
Gr3≤toxicity |
|
Imai et al. [92] |
Phase I/II |
Unresectable axial soft tissue sarcoma
(deep 96%, subdeep 4%) |
128 |
64–73.6 |
3-yr 68%, 5-yr 65% |
3-yr 60%, 5-yr 46% |
NR |
Gr3≤=4
Gr 3 spinal cord
injury=1
Gr 3 peripheral nerve injury=1
Gr 4 colon
injury=1
Gr 3 skin=1 |
CIRT has demonstrated significant efficacy in treating various types of bone
sarcomas, particularly those that are inoperable or resistant to conventional
therapies. In a study involving 188 patients treated with CIRT, Imai et al. [
81,
82]
reported a 5-year LC rate of 77.2% and a 5-year OS rate of 81% in patients treated
with CIRT at a dose of 64–73.6 Gy(RBE). More recent studies have also
reported a 2-year LC rate exceeding 80% in patients with sacral chordomas or
chondrosarcomas [
83,
84]. Furthermore, Shiba et al. [
85] found that patients with inoperable bone sarcomas treated with CIRT
exhibited a 3-year LC rate of 62% and an OS rate of 51%. For the treatment of
primary spinal sarcomas, Matsunobu et al. [
86] demonstrated that CIRT delivered at a dose of 64 Gy(RBE) in 16 fractions
achieved a 5-year LC rate of 79% and an OS rate of 52%. The effectiveness of CIRT
has also been prospectively evaluated in primary spinal sarcomas [
87] or localized primary sarcomas of the
extremities [
88]. Moreover, it has shown
potential in pediatric and young adult patients with bone tumors [
89,
90],
providing effective treatment without significant growth disturbances or secondary
malignancies, as observed in studies from the NIRS in Japan and HIT in Germany.
These results collectively illustrate CIRT’s ability to provide effective
tumor control with a manageable toxicity profile across various challenging bone
sarcomas.
CIRT has shown promising results in treating retroperitoneal sarcoma, a particularly
challenging subtype of soft tissue sarcomas due to their proximity to critical
structures like the gastrointestinal tract. Since 1997, CIRT has been used at the
NIRS to manage unresectable retroperitoneal sarcomas that are not extensively
attached to the intestines and measure less than 20 cm, employing a dose of 70.4
Gy(RBE) delivered in 16 fractions over 4 weeks. Serizawa et al. [
91] reported a 5-year LC rate of 69% and an OS
rate of 50% in patients with unresectable retroperitoneal sarcomas with no
gastrointestinal complications or grade 2 or higher toxicity. This finding suggests
that CIRT is an effective treatment option for these cases. Additionally, Imai et
al. [
92] evaluated 128 patients with
unresectable axial soft tissue sarcomas treated with CIRT at doses of 64–73.6
Gy(RBE). They reported a 5-year LC rate of 54% and a 5-year OS rate of 46%, with
grade 3 or higher late adverse events occurring in four patients.
Although the administration of high-dose CIRT is associated with the risk of late
toxicity, particularly osteoradionecrosis and soft tissue necrosis, its ability to
achieve high LC rates in both bone and soft tissue sarcomas makes it an invaluable
treatment option. The use of surgical spacers for tumors located near the
gastrointestinal tract has proven to be an effective strategy for reducing the risk
of severe complications [
93,
94], thereby enabling safer delivery of CIRT
and improving patient outcomes.
Future directions
CIRT has demonstrated significant clinical efficacy across various types of
malignancies and offers distinct advantages over conventional therapies due to its
unique physical and biological properties. However, the lack of high-level evidence,
especially from randomized controlled trials, challenges the establishment of
CIRT's superiority over conventional therapies. To further solidify
CIRT's role in modern oncology, it is crucial to address these gaps by
conducting well-designed randomized controlled trials that directly compare CIRT
with conventional therapies. In addition to these trials, adopting a multifaceted
approach that includes long-term clinical cohort studies and the establishment of
robust multicenter registries is essential. These initiatives will provide a deeper
understanding of CIRT’s clinical benefits across diverse patient populations,
refine patient selection criteria, and optimize treatment protocols. Moreover,
future advancements in CIRT will be influenced by translational research. Key areas
of exploration include the integration of ultrahigh-dose-rate (FLASH) therapy, which
could further enhance the therapeutic window of CIRT by reducing the risk of normal
tissue toxicity. Additionally, investigating the immunogenic effects of particle
therapy could reveal potential synergies with emerging immunotherapies. As CIRT
facilities continue to expand globally, particularly in leading countries such as
Japan, the United States, Europe, and Korea, this growth must be managed through
strategic planning and comprehensive cost-effectiveness analyses. These efforts
should be complemented by initiatives to standardize treatment protocols and
facilitate international collaboration to ensure that the benefits of CIRT are
accessible to a broad range of patients worldwide. By addressing these challenges
and capitalizing on new research opportunities, CIRT is expected to play a
transformative role in cancer treatment.
Conclusion
The establishment of Korea's first CIRT center at the Yonsei Cancer Center,
along with the development of additional CIRT centers in Korea and abroad, offers a
significant opportunity to gather compelling evidence that could substantiate the
clinical advantages of CIRT and broaden its uses. By coordinating clinical and
translational research with carefully devised expansion strategies, CIRT is
well-positioned to improve survival rates, enhance the quality of life for cancer
patients, and potentially decrease the risk of secondary malignancies. These
advancements highlight the pivotal role of CIRT as a critical modality in modern
cancer treatment, setting the stage for its incorporation into worldwide oncological
practices.
Authors' contributions
-
Project administration: Lee IJ
Conceptualization: Choi SH, Lee IJ
Methodology & data curation: Choi SH, Koom WS, Yoon HI, Kim KH, Wee CW,
Cho J, Kim YB, Keum KC, Lee IJ
Funding acquisition: Choi SH, Lee IJ
Writing – original draft: Choi SH
Writing – review & editing : Choi SH, Koom WS, Yoon HI, Kim KH, Wee
CW, Cho J, Kim YB, Keum KC, Lee IJ
Conflict of interest
-
No potential conflict of interest relevant to this article was reported.
Funding
-
This research was supported by Quantum Computing Based on Quantum Advantage
Challenge Research (RS-2023-00257561) through the National Research Foundation
of Korea funded by the Korean government (Ministry of Science and Information
and Communication Technology). This research was supported by grants from the
Korean Cancer Survivors Healthcare R&D Project through the National
Cancer Center, funded by the Ministry of Health & Welfare, Republic of
Korea (grant numbers: RS-2023-CC139405 and RS-2023-CC139716).
Data availability
-
Not applicable.
Acknowledgments
Not applicable.
Supplementary materials
-
Not applicable.
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, Woong Sub Koom1
