Abstract

Purpose:

Studies are currently underway to help provide basic and clinical evidence for combination particle beam radiation therapy, on which there are few published reports. The purpose of this article is to summarize the current status in the use of particle beams combined with other modalities.

Results:

Following from experiences in x-ray radiation therapy, combination therapy with proton beams (PBT) has been attempted, and several clinical studies have reported improved survival rates for patients with non–small cell lung cancer, pancreatic cancers, esophageal cancers, and glioblastomas. Recently, basic studies combining PBT with PARP inhibitors and histone deacetylase inhibitors have also reported promising results. In the area of carbon ion therapy (CIT), there are few clinical reports on combination therapy; however, the number of basic research reports exceeds that for PBT. So far, the combined use of cytotoxic drugs with CIT yields independent additive effects. In addition, it is notable that combination therapy with CIT is effective against radioresistant cancer stem-like cells. Recent evidence also suggests that local radiation therapy can induce an effective antitumor immune response. There has been an increased use of combination immune-modulating agents and cytokines with particle beams, especially CIT. The field of radiation therapy is evolving from a strong reliance on local-regional treatment to a growing reliance on systemic immunotherapy.

Conclusions:

The combined use of anticancer agents with particle radiation therapy has a considerable potential effect. Future research in molecular targeting therapy and immunotherapy may help identify the most efficacious approach for combination therapy with protons and carbon ions.

Introduction

Particle radiation therapy for solid cancers should offer biological advantages that are yet to be understood as physical advantages. One of the reasons is that uncertainty in biological issues is much greater than that in physical issues. From a clinical point of view, it is strongly desirable to clarify not only the biological effects of particles themselves but also advantages or limitations of conjunctive use of particle beams with other biological modalities. The expected advantages of the combining radiation therapy are (1) tumor tissue radiosensitization, ideally tumor specific; (2) normal tissue protection; and (3) induction of bystander or abscopal effect in distant regions.

For proton beam radiation therapy (PBT), combination therapy has been attempted from experiences in x-ray treatments, wherein the combination of radiation with cytotoxic chemotherapy has become a standard treatment option for most locally advanced cancers. In contrast, the same does not hold true for carbon ions (C-ions), because their physical and biological characteristics are very different from photons. Robust scientific background is required to translate combination therapies with C-ions into clinical practice.

In this mini review, I summarize the status of the combined use of particle beams with other modalities from a biological point of view, focusing on the advantages and limitations of these methods.

Combination Therapy with Protons

Clinical Research on Combination Therapy with Protons

The number of PBT facilities has been increasing worldwide. Currently, there are 69 facilities in operation, 42 under construction, and 22 at the planning stage [1]. With the increased use of PBT, many clinical trials involving the conjunctive use of anticancer drugs with PBT have been attempted, based on experiences in photon therapy, as the generic relative biological effectiveness (RBE) of the proton to the photon is 1.1.

Review of the literature, that is, main publications on non–small cell lung cancers (NSCLCs), pancreatic cancers, esophageal cancers, and glioblastoma are listed in Table 1. Among these, improvements in survival rates, compared to previous data on conventional x-ray therapy, were demonstrated in stage II to III NSCLC [26]. Hoppe et al [4] mention that the improved survival rate, as compared to other reports of patients with stage III NSCLC, could be attributed to the safe delivery of a relatively high radiation dose of 74 GyE with protons, even to large bulky inoperable tumors, and other reports agree with this point. However, recently Liao et al [7] reported that although passive beam proton therapy (PSPT) significantly reduced heart exposure in terms of both radiation dose and heart volume, there was no benefit in either grade ≥ 3 radiation pneumonitis or local failure as compared to intensity-modulated (photon) radiation therapy (IMRT). The median overall survival times were 29.5 months for patients in the IMRT group and 26.1 months for patients in the PSPT group [7]. A phase III randomized trial comparing overall survival after photon versus proton chemoradiotherapy for inoperable stage II-IIIB NSCLC (RTOG1308) has been undergoing since 2013. The efficacy of proton chemoradiotherapy compared to photon chemoradiotherapy should be clarified with a high level of evidence.

Table 1

Conjunctive use of Protons and Chemothetapies

Conjunctive use of Protons and Chemothetapies
Conjunctive use of Protons and Chemothetapies

Similar levels of positive results with combination therapies have been reported in pancreatic cancers [810]. Although 1 patient showed grade-5 gastrointestinal toxicities with a high-dose PBT of 70.2 GyE concurrent with gemcitabine, progression-free and overall survival rates were more favorable than those in conventional chemoradiotherapy [8]. In combination with capecitabine, neoadjuvant short-course proton-based chemoradiation (25 GyE) has been reported to be associated with favorable local control and low incidence of toxicity in resectable pancreatic cancers [9]. Also, a definitive therapy combining proton therapy (59.4 GyE) with concomitant capecitabine was well tolerated, without serious gastrointestinal toxicity, and showed encouraging results in unresectable nonmetastatic pancreatic cancers [10].

The major benefit of PBT for esophageal cancers is that the dose to the spinal cord, heart, and lungs can be significantly reduced. Lin et al [11] reported results of definitive therapy or neoadjuvant plus surgery using PBT and “various types” of chemotherapy, and they concluded that acute treatment-related toxicities and perioperative morbidities are relatively low, whereas tumor response and disease-related outcomes are encouraging. Also, Ishikawa et al [12] summarized the results of 40 cases of stage I-III esophageal cancers treated by PBT with concurrent chemotherapy consisting of cisplatin and 5-fluorouracil. They concluded that this can be a promising concurrent chemoradiotherapy for patients with esophageal cancer, especially with regard to late cardiopulmonary toxicity.

In malignant gliomas, we previously reported the safety and efficacy of postoperative hyperfractionated concomitant boost proton radiation therapy with nimustine hydrochloride (ACNU) for supratentorial glioblastoma multiforme (GBM) [13]. We also reported that although localized radiation necrosis was inevitable, this high-dose proton beam therapy with the concurrent use of ACNU was able to control GBM pathogenesis, based on the analysis of long-term survivors [14]. In addition, the concurrent use of temozolomide (TMZ) has a tendency for better survival as well as a lower incidence of hematologic toxicity than ACNU [15].

The potential advantages of PBT combined with chemotherapy for these solid tumors is that one can minimize toxicity to the surrounding vital organs while delivering high doses to the sensitized tumors. These potential advantages of PBT are applicable to other locally advanced solid tumors. As PBT becomes more accessible and indications become wider, other protocols will be designed to sensitize tumor tissues and protect normal tissues, for establishing the next-generation standard chemo-PBT.

Prospective randomized comparisons with modern technology of x-ray IMRT and protons of broad or scanning beams is strongly desired to obtain scientific results with high-evidence levels.

Preclinical Analysis in Combination Therapy with Protons

Combination with new drugs has been researched, particularly on molecular targeting agents in vitro and in vivo. Most of these approaches target DNA damage-repair–associated molecules. Hirai et al [16] reported that the PARP inhibitor enhances radiosensitivity to the proton beam irradiation by inhibiting DNA repair, possibly by increasing the conversion of non–double-strand break lesions to lethal DNA damage. They reported that the combination effect was more significant in the Bragg peak region than in the entrance region. With high conformity and dose concentration property of proton beams, PARP inhibitor may be useful as a radiosensitizer when combined with proton beam irradiation.

Further, Yu et al [17] reported that the histone deacetylase inhibitor (HDACi) valproic acid sensitizes hepatocellular carcinoma cells to proton beams. They found that valproic acid sensitized more hepatocellular carcinoma cells to proton than to photon irradiation, inducing prolonged proton-induced DNA damage and augmented proton-induced apoptosis. In addition, we recently reported that another HDACi, suberoylanilide hydroxamic acid (SAHA), successfully sensitized cancer cells to radiation, even with high LET radiation [18]. Importantly, we proved that SAHA selectively sensitized cancer cells to photon and particle radiation (Figure 1). SAHA is an epigenetic agent with a variety of actions. Although the total picture of SAHA's unique radiosensitization mechanism has not been elucidated yet, it has been reported that SAHA suppresses homologous recombination repair only in cancer cells [19, 20]. Based on the radiation dose control, enhancement ratio, and potential lower side effects for normal cells, it is assumed that the SAHA treatment may be the most effective when combined with protons.

Figure 1

Concept of combination of suberoylanilide hydroxamic acid (SAHA) with different qualities of radiation. SAHA is an epigenetic agent that loosens the chromatin structure, enhancing DNA transcription. Abbreviations: HAT, histone acetyltransferase; HDAC, histone deacetylase.

Figure 1

Concept of combination of suberoylanilide hydroxamic acid (SAHA) with different qualities of radiation. SAHA is an epigenetic agent that loosens the chromatin structure, enhancing DNA transcription. Abbreviations: HAT, histone acetyltransferase; HDAC, histone deacetylase.

The conjunctive use of novel molecular targeting drugs with PBT has a considerable potential to improve the outcome for patients; however, the scientific biological basis of the combination therapy needs to be clarified both in vitro and in vivo. Further development of this research area is expected.

Combination Therapy with C-Ions

Clinical Research on Combination Therapy with C-Ions

Currently, there are 11 facilities in operation, 4 under construction, and 1 in the planning stage [1]. Compared to that for protons, the number of clinical reports for combination therapy involving cytotoxic drugs and C-ions therapy is very limited, and the summaries of clinical studies are listed in Table 2.

Table 2

Conjunctive use of C-ions ans Chemotherapies

Conjunctive use of C-ions ans Chemotherapies
Conjunctive use of C-ions ans Chemotherapies

For GBM, Mizoe et al [21] reported a phase I/II clinical trial for patients with malignant gliomas (16 anaplastic astrocytomas and 32 GBMs), treated with combined x-ray radiation therapy, ACNU chemotherapy, and C-ion radiation therapy [21]. The results showed the potential efficacy of chemoradiotherapy for malignant gliomas in terms of the improved survival rate for those patients who received higher C-ion doses.

Jingu et al [22] reported a prospective definitive treatment study for patients with malignant mucosal melanoma, treated with C-ions (57.6 GyE in 16 fractions) and combined use of dacarbazine, ACNU, and vincristine. Their results are favorable as compared to previously reported x-ray chemoradiotherapy, and they found that minimum apparent diffusion coefficient value in magnetic resonance images can be a predictive factor of survival rates [22].

In pancreatic cancers, Shinoto et al reported a phase I preoperative, short-course, dose-escalation study on resectable pancreatic cancers [23], and a prospective study of definitive treatment with C-ions combined with full-dose gemcitabine on unresectable locally advanced pancreatic cancers [24]. They demonstrated that C-ion radiation therapy concurrent with chemotherapy was well tolerated and was effective in both preoperative and definitive therapy in those patients.

As multiple clinical studies on the combination therapy of anticancer drugs with C-ion radiation therapy are undergoing [25], the efficacy of combination therapy should be shown in the near future. Prospective randomized comparisons of C-ions, at least with modern technology of x-ray IMRT in common cancers, is desired to obtain scientific results with high-evidence levels.

Preclinical Analysis in the Combination Therapy with C-ions

There have been many basic radiobiological studies on the adjunctive use of anticancer drugs and C-ions. It has been known that C-ion beams induce cluster DNA damage resulting in a higher proton RBE of 2.5, compared to that for photons. From their high linear energy transfer (LET), one can expect that the combination of cytotoxic drugs with C-ions may induce a “synergistic” cytotoxic effect in cancer cells. However, Combs et al [26] demonstrated that the combination of TMZ and C-ions leads to an additive effect comparable to that of photons. In addition, they showed that combinations of camptothecin, gemcitabine, paclitaxel, and cisplatinum with C-ions also yielded additive results. This is in good agreement with the findings of the other group that reported TMZ causes additive cytotoxicity when combined with radiation, regardless of the radiation quality [27]. Dehne et al [28] investigated the putative cytotoxic effects in 4 different hepatocellular carcinoma cell lines after irradiation with photons or carbon ions in combination with new targeted molecular agents. Their result demonstrated that the combination of C-ions with either of those agents exhibited independent toxicities in all cell lines. They assumed that combining C-ions with systemic substances only has independent effects because heavy ions cause direct damage owing to their high-LET character resulting in clustered DNA double strand breaks (DSBs). Although one can reduce the C-ion dose when combined with other anticancer drugs, these results indicate that effects of the combinations of anticancer drugs with C-ions are expected to be additive.

However, it is worth noting that C-ions are effective against radioresistant cancer stem-like cells (CSCs). Sai et al [29] reported that combining C-ions with cisplatin is an effective method to target triple-negative breast CSCs. Further, they reported that a C-ion beam combined with gemcitabine has superior potential to kill pancreatic CSCs [30]. They mention that these combinations induce irreparable clustered DNA DSBs, apoptosis, autophagy, and subsequent cell death at relatively low doses, compared to a C-ion beam alone or x-rays combined with GEM [28]. As CSCs are considered to play central roles for therapy resistance and tumor recurrence, targeting CSCs by using the combination of C-ions and cytotoxic drugs is an ideal strategy for the treatment of refractory solid cancers.

As for recent reports on the conjunctive use of molecular targeting agents and C-ions, the combined use of Hsp90 inhibitor–sensitized cancer cells with C-ions, as well as x-rays, provides effective tumor growth delay without affecting noncancerous cells. It has been assumed that the underlying mechanism for this radiosensitizing effect is the inhibition of 2 major DNA DSB repair pathways by the Hsp90 inhibitors [31, 32]. In addition, similar to protons, PARP-1 depletion radiosensitized cancer cells to C-ions [33]. They showed that PARP-1 depletion along with C-ion exposure synergistically increases apoptosis and decreases metastatic properties in HeLa cells. Thus, PARP inhibitors inhibit not only DNA repair but also the metastatic property of cancer cells [31, 33].

Compared to cytotoxic drugs in which the conjunctive effect was additive or independent, molecular targeting agents may be worth further research to identify an approach for an effective combination therapy with C-ions.

Immuno-particle Beam Oncology

The concept of the conjunctive use of immunotherapy with particle therapy is totally different from combination with cytotoxic drugs. Recent reports show that localized irradiation of tumors can act as an immune adjuvant, which can induce a systemic tumor immune response by killing tumor cells in situ [3436]. As shown in Figure 2, the underlying mechanism is the induction of immunogenic cell death in the tumor microenvironment and the sequential activation of systemic cellular immunity [37, 38] (Figure 2). Danger signals and the release of tumor-specific antigens after exposure to ionizing radiation can convert an irradiated tumor into an in situ vaccine. We previously reported that the preventive abscopal effect mediated by CD8+ T-cells was observed in the brain when tumors inoculated in the thigh were cured by x-ray irradiation [39]. However, to induce the abscopal effect correctly, localized radiation alone is not usually sufficient because spontaneous tumors are usually poorly immunogenic [36, 37]. Several studies on mice models have reported positive results for using a combination of radiation therapy and immunotherapy [4042]; however, most of the studies focused on immune response with x-ray radiation. Recently, Girdhani et al [43] reported that critical proangiogenic and immune-inhibitory factors, including vascular endothelial growth factor, interleukin-6 and-8, and hypoxia-inducible factor-1 alpha, were significantly downregulated after high-energy proton irradiation [43]. Also, Gameiro et al [44] demonstrated that proton irradiation mediated calreticulin cell-surface expression on tumor cells, increasing the sensitivity to cytotoxic T-lymphocyte killing. These findings suggest that proton radiation could gain expanded therapeutic use owing to its ability to suppress neovascularization and immune inhibitory mechanism [45]. In addition to the physical benefits, these unique biological effects of particle irradiation may prove superior in the systemic effect as compared to x-rays [46, 47].

Figure 2

The mechanism of antitumor immune activation by radiation. Local irradiation to tumors induces immunogenic cell death with release of various danger signals and tumor antigens. This is followed by activation of dendritic cells (DC) and cytotoxic T-lymphocytes (CD8+CTL). The balance of immune response is determined by the inhibition by checkpoint molecules (PD-1,2 and CTLA-4) and cytotoxic T-lymphocyte activation.

Figure 2

The mechanism of antitumor immune activation by radiation. Local irradiation to tumors induces immunogenic cell death with release of various danger signals and tumor antigens. This is followed by activation of dendritic cells (DC) and cytotoxic T-lymphocytes (CD8+CTL). The balance of immune response is determined by the inhibition by checkpoint molecules (PD-1,2 and CTLA-4) and cytotoxic T-lymphocyte activation.

In clinical trials with PBT, we performed a Phase I study of a combination of an intratumoral injection of hydroxyapatite as an immune adjuvant following PBT to prevent local or distant recurrence by activation of immune systems in patients with locally advanced or recurrent hepatocellular carcinoma. We reported that this combination therapy was feasible and safe, and four of the nine patients were progression free for more than one year [48]. As for C-ions, in combination with dendritic cells injection, the C-ion beam correlated with a greater amount of immune activation and prevention of metastases in mouse models [49, 50, 51]. Further, in clinical case reports, abscopal responses have been reported in patients treated with local C-ion therapy [52, 53].

Further investigation is warranted to exploit this strategy to eliminate cancer cells spreading to non-irradiated field. At this point, the combination of particle therapy with immune system modulators such as immune checkpoint inhibitors and cytokines may be promising approaches. In addition, tumor-specific immune response may be obtained by converting tumors into effective in situ vaccines by using particle radiation therapy. At the same time, investigation on the underlying immune mechanisms leading to an efficient immune response is essential to translate into more effective novel therapeutic approaches.

Conclusive Remarks

The conjunctive use of other anticancer agents with particle radiation therapy has a considerable potential to improve the outcome for patients. The scientific biological basis of the combination therapy needs to be clarified both in vitro and in vivo for clinical translation. Molecular targeting agents may be worth further research to identify an approach for an effective combination therapy with protons and C-ions. In addition, recent reports show that localized irradiation of tumors can act as an immune adjuvant. As compared to x-rays, particle irradiation may be proved to be superior in the systemic immune effect.

ADDITIONAL INFORMATION AND DECLARATIONS

Conflicts of Interest: The authors have no conflicts to disclose.

Acknowledgments: The author thanks Ms Kazuho Tsuboi for her help in manuscript preparation. This research was partially supported by JSPS KAKENHI Grant No. JP16K10384.

References

References
1
Particle Therapy Cooperative Group
.
https://www.ptcog.ch. Updated May 2017. Accessed March 18, 2018.
2
Sejpal
S,
Komaki
R,
Tsao
A,
Chang
JY,
Liao
Z,
Wei
X,
Allen
PK,
Lu
C,
Gillin
M,
Cox
JD.
Early findings on toxicity of proton beam therapy with concurrent chemotherapy for non-small cell lung cancer
.
Cancer
.
2011
;
117
:
3004
13
.
3
Oshiro
Y,
Okumura
T,
Kurishima
K,
Homma
S,
Mizumoto
M,
Ishikawa
H,
Onizuka
M,
Sakai
M,
Goto
Y,
Hizawa
N,
Sato
Y,
Sakurai
H.
High-dose concurrent chemo-proton therapy for Stage III NSCLC: preliminary results of a Phase II study
.
J Radiat Res
.
2014
;
55
:
959
65
.
4
Hoppe
BS,
Henderson
R,
Pham
D,
Cury
JD,
Bajwa
A,
Morris
CG,
D'Agostino
H
Jr,
Flampouri
S,
Huh
S,
Li
Z,
McCook
B,
Nichols
RC
Jr.
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
.
5
Nguyen
QN,
Ly
NB,
Komaki
R,
Levy
LB,
Gomez
DR,
Chang
JY,
Allen
PK,
Mehran
RJ,
Lu
C,
Gillin
M,
Liao
Z,
Cox
JD.
Long-term outcomes after proton therapy, with concurrent chemotherapy, for stage II-III inoperable non-small cell lung cancer
.
Radiother Oncol
.
2015
;
115
:
367
72
.
6
Chang
JY,
Verma
V,
Li
M,
Zhang
W,
Komaki
R,
Lu
C,
Allen
PK,
Liao
Z,
Welsh
J,
Lin
SH,
Gomez
D,
Jeter
M,
O'Reilly
M,
Zhu
RX,
Zhang
X,
Li
H,
Mohan
R,
Heymach
JV,
Vaporciyan
AA,
Hahn
S,
Cox
JD.
Proton beam radiotherapy and concurrent chemotherapy for unresectable stage III non-small cell lung cancer: final results of a phase 2 study
.
JAMA Oncol
.
2017
;
3
:
e172032
.
7
Liao
Z,
Lee
J,
Komaki
R,
Gomez
DR,
O'Reilly
MS,
Fossella
FV,
Blumenschein
GR
Jr,
Heymach
JV,
Vaporciyan
AA,
Swisher
SG,
Allen
PK,
Choi
NC,
DeLaney
TF,
Hahn
SM,
Cox
JD,
Lu
CS,
Mohan
R.
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
;
2:JCO2017740720.
8
Terashima
K,
Demizu
Y,
Hashimoto
N,
Jin
D,
Mima
M,
Fujii
O,
Niwa
Y,
TakatoriK, Kitajima N, Sirakawa S, Yonson K, Hishikawa Y, Abe M, Sasaki R, Sugimura K, Murakami M. A phase I/II study of gemcitabine-concurrent proton radiotherapy for locally advanced pancreatic cancer without distant metastasis
.
Radiother Oncol
.
2012
;
103
:
25
31
.
9
Hong
TS,
Ryan
DP,
Borger
DR,
Blaszkowsky
LS,
Yeap
BY,
Ancukiewicz
M,
Deshpande
V,
Shinagare
S,
Wo
JY,
Boucher
Y,
Wadlow
RC,
Kwak
EL,
Allen
JN,
Clark
JW,
Zhu
AX,
Ferrone
CR,
Mamon
HJ,
Adams
J,
Winrich
B,
Grillo
T,
Jain
RK,
DeLaney
TF,
Fernandez-del Castillo C, Duda DG. 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
.
10
Sachsman
S,
Nichols
RC
Jr,
Morris
CG,
Zaiden
R,
Johnson
EA,
Awad
Z,
Bose
D,
Ho
MW,
Huh
SN,
Li
Z,
Kelly
P,
Hoppe
BS.
Proton therapy and concomitant capecitabine for non-metastatic unresectable pancreatic adenocarcinoma
.
Int J Particle Ther
.
2014
;
1
:
692
701
.
11
Lin
SH,
Komaki
R,
Liao
Z,
Wei
C,
Myles
B,
Guo
X,
Palmer
M,
Mohan
R,
Swisher
SG,
Hofstetter
WL,
Ajani
JA,
Cox
JD.
Proton beam therapy and concurrent chemotherapy for esophageal cancer
.
Int J Radiat Oncol Biol Phys
.
2012
;
83
:
e345
51
.
12
Ishikawa
H,
Hashimoto
T,
Moriwaki
T,
Hyodo
I,
Hisakura
K,
Terashima
H,
Ohkohchi
N,
Ohno
T,
Makishima
H,
Mizumoto
M,
Ohnishi
K,
Okumura
T,
Sakurai
H.
Proton beam therapy combined with concurrent chemotherapy for esophageal cancer
.
Anticancer Res
.
2015
;
35
:
1757
62
.
13
Mizumoto
M,
Tsuboi
K,
Igaki
H,
Yamamoto
T,
Takano
S,
Oshiro
Y,
Hayashi
Y,
Hashii
H,
Kanemoto
A,
Nakayama
H,
Sugahara
S,
Sakurai
H,
Matsumura
A,
Tokuuye
K.
Phase I/II trial of hyperfractionated concomitant boost proton radiotherapy for supratentorial glioblastoma multiforme
.
Int J Radiat Oncol Biol Phys
.
2010
;
77
:
98
105
.
14
Mizumoto
M,
Yamamoto
T,
Takano
S,
Ishikawa
E,
Matsumura
A,
Ishikawa
H,
Okumura
T,
Sakurai
H,
Miyatake
S,
Tsuboi
K.
Long-term survival after treatment of glioblastoma multiforme with hyperfractionated concomitant boost proton beam therapy
.
Pract Radiat Oncol
.
2015
;
5
:
e9
16
.
15
Mizumoto
M,
Yamamoto
T,
Ishikawa
E,
Matsuda
M,
Takano
S,
Ishikawa
H,
Okumura
T,
Sakurai
H,
Matsumura
A,
Tsuboi
K.
Proton beam therapy with concurrent chemotherapy for glioblastoma multiforme: comparison of nimustine hydrochloride and temozolomide
.
J Neurooncol
.
2016
;
130
:
165
170
.
16
Hirai
T,
Saito
S,
Fujimori
H,
Matsushita
K,
Nishio
T,
Okayasu
R,
Masutani
M.
Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells
.
Biochem Biophys Res Commun
.
2016
;
478
:
234
240
.
17
Yu
JI,
Choi
C,
Shin
SW,
Son
A,
Lee
GH,
Kim
SY,
Park
HC.
Valproic acid sensitizes hepatocellular carcinoma cells to proton therapy by suppressing NRF2 activation
.
Sci Rep
.
2017
;
7
:
14986
.
18
Gerelchuluun
A,
Maeda
J,
Manabe
E,
Brents
CA,
Sakae
T,
Fujimori
A,
Chen
DJ,
Tsuboi
K,
Kato
TA.
Histone deacetylase inhibitor induced radiation sensitization effects on human cancer cells after photon and hadron radiation exposure
.
Int J Mol Sci
.
2018
;
19:pii: E496.
19
Lee
JH,
Choy
ML,
Ngo
L,
Foster
SS,
Marks
PA.
Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair
.
Proc Natl Acad Sci U S A
.
2010
;
107
:
14639
44
.
20
Chen
X,
Wong
P,
Radany
EH,
Stark
JM,
Laulier
C,
Wong
JY.
Suberoylanilide hydroxamic acid as a radiosensitizer through modulation of RAD51 protein and inhibition of homology-directed repair in multiple myeloma
.
Mol Cancer Res
.
2012
;
10
:
1052
64
.
21
Mizoe
JE,
Tsujii
H,
Hasegawa
A,
Yanagi
T,
Takagi
R,
Kamada
T,
Tsuji
H,
Takakura
K;
Organizing Committee of the Central Nervous System Tumor Working Group. Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy
.
Int J Radiat Oncol Biol Phys
.
2007
;
69
:
390
6
.
22
Jingu
K,
Kishimoto
R,
Mizoe
JE,
Hasegawa
A,
Bessho
H,
Tsuji
H,
Kamada
T,
Yamada
S,
Tsujii
H.
Malignant mucosal melanoma treated with carbon ion radiotherapy with concurrent chemotherapy: prognostic value of pretreatment apparent diffusion coefficient (ADC)
.
Radiother Oncol
.
2011
;
98
:
68
73
.
23
Shinoto
M,
Yamada
S,
Yasuda
S,
Imada
H,
Shioyama
Y,
Honda
H,
Kamada
T,
Tsujii
H,
Saisho
H;
Working Group for Pancreas Cancer. Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer
.
Cancer
.
2013
;
119
:
45
51
.
24
Shinoto
M,
Yamada
S,
Terashima
K,
Yasuda
S,
Shioyama
Y,
Honda
H,
Kamada
T,
Tsujii
H,
Saisho
H;
Working Group for Pancreas Cancer. Carbon ion radiation therapy with concurrent gemcitabine for patients with locally advanced pancreatic cancer
.
Int J Radiat Oncol Biol Phys
.
2016
;
95
:
498
504
.
25
Imai
T.
Treatment with carbon-ion radiotherapy and its combinations: basic biological studies and investigations at the National Institute of Radiological Sciences
.
Gan To Kagaku Ryoho
.
2015
;
42
:
154
8
.
26
Combs
SE,
Zipp
L,
Rieken
S,
Habermehl
D,
Brons
S,
Winter
M,
Haberer
T,
Debus
J,
Weber
KJ.
In vitro evaluation of photon and carbon ion radiotherapy in combination with chemotherapy in glioblastoma cells
.
Radiat Oncol
.
2012
;
7
:
9
.
27
Barazzuol
L,
Jena
R,
Burnet
NG,
Jeynes
JC,
Merchant
MJ,
Kirkby
KJ,
Kirkby
NF.
In vitro evaluation of combined temozolomide and radiotherapy using X rays and high-linear energy transfer radiation for glioblastoma
.
Radiat Res
.
2012
;
177
:
651
62
.
28
Dehne
S,
Fritz
C,
Rieken
S,
Baris
D,
Brons
S,
Haberer
T,
Debus
J,
Weber
KJ,
Schmid
TE,
Combs
SE,
Habermehl
D.
Combination of photon and carbon ion irradiation with targeted therapy substances temsirolimus and gemcitabine in hepatocellular carcinoma cell lines
.
Front Oncol
.
2017
;
7
:
35
.
29
Sai
S,
Vares
G,
Kim
EH,
Karasawa
K,
Wang
B,
Nenoi
M,
Horimoto
Y,
Hayashi
M.
Carbon ion beam combined with cisplatin effectively disrupts triple negative breast cancer stem-like cells in vitro
.
Mol Cancer
.
2015
;
14
:
166
.
30
Sai
S,
Wakai
T,
Vares
G,
Yamada
S,
Kamijo
T,
Kamada
T,
Shirai
T.
Combination of carbon ion beam and gemcitabine causes irreparable DNA damage and death of radioresistant pancreatic cancer stem-like cells in vitro and in vivo
.
Oncotarget
.
2015
;
20;
6
:
5517
35
.
31
Hirakawa
H,
Fujisawa
H,
Masaoka
A,
Noguchi
M,
Hirayama
R,
Takahashi
M,
Fujimori
A,
Okayasu
R.
The combination of Hsp90 inhibitor 17AAG and heavy-ion irradiation provides effective tumor control in human lung cancer cells
.
Cancer Med
.
2015
;
4
:
426
36
.
32
Lee
Y,
Sunada
S,
Hirakawa
H,
Fujimori
A,
Nickoloff
JA,
Okayasu
R.
TAS-116, a novel Hsp90 inhibitor, selectively enhances radiosensitivity of human cancer cells to X-rays and carbon ion radiation
.
Mol Cancer Ther
.
2017
;
16
:
16
24
.
33
Ghorai
A,
Sarma
A,
Chowdhury
P,
Ghosh
U.
PARP-1 depletion in combination with carbon ion exposure significantly reduces MMPs activity and overall increases TIMPs expression in cultured HeLa cells
.
Radiat Oncol
.
2016
;
11
:
126
.
34
Formenti
SC,
Demaria
S.
Systemic effects of local radiotherapy
.
Lancet Oncol
.
2009
;
10
:
718
26
.
35
Scheithauer
H,
Belka
C,
Lauber
K,
Gaipl
US.
Immunological aspects of radiotherapy
.
Radiat Oncol
.
2014
;
9
:
185
.
36
Haikerwal
SJ,
Hagekyriakou
J,
MacManus
M,
Martin
OA,
Haynes
NM.
Building immunity to cancer with radiation therapy
.
Cancer Lett
.
2015
;
368
:
198
208
.
37
Grass
GD,
Krishna
N,
Kim
S.
The immune mechanisms of abscopal effect in radiation therapy
.
Curr Probl Cancer
.
2016
;
40
:
10
24
.
38
Galluzzi1 L, Buqué A, Kepp O, Zitvoge L, Kroemer G
.
Immunogenic cell death in cancer and infectious disease
.
Nat Rev Immunol
.
2017
;
17
:
97
111
.
39
Zenkoh
J,
Gerelchuluun
A,
Wang
Y,
Miwa
Y,
Ohno
T,
Tsuboi
K.
The abscopal effect induced by in situ-irradiated peripheral tumor cells in a murine GL261 brain tumor model
.
Transl Cancer Res
.
2017
;
6
:
136
48
.
40
Demaria
S,
Kawashima
N,
Yang
AM,
Devitt
ML,
Babb
JS,
Allison
JP,
Formenti
SC.
Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer
.
Clin Cancer Res
.
2005
;
11
:
728
34
.
41
Deng
L,
Liang
H,
Burnette
B,
Beckett
M,
Darga
T,
Weichselbaum
RR,
Fu
YX.
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice
.
J Clin Invest
.
2014
;
124
:
687
95
.
42
Ishihara
D,
Pop
L,
Takeshima
T,
Iyengar
P,
Hannan
R.
Rationale and evidence to combine radiation therapy and immunotherapy for cancer treatment: rationale and evidence to combine radiation therapy and immunotherapy for cancer treatment
.
Cancer Immunol Immunother
.
2017
;
66
:
281
98
.
43
Girdhani
S,
Lamont
C,
Hahnfeldt
P,
Abdollahi
A,
Hlatky
L.
Proton irradiation suppresses angiogenic genes and impairs cell invasion and tumor growth
.
Radiat Res
.
2012
;
178
:
33
45
.
44
Gameiro
SR,
Malamas
AS,
Bernstein
MB,
Tsang
KY,
Vassantachart
A,
Sahoo
N,
Tailor
R,
Pidikiti
R,
Guha
CP,
Hahn
SM,
Krishnan
S,
Hodge
JW.
Tumor cells surviving exposure to proton or photon radiation share a common immunogenic modulation signature, rendering them more sensitive to T cell-mediated killing
.
Int J Radiat Oncol Biol Phys
.
2016
;
95
:
120
30
.
45
Girdhani
S,
Sachs
R,
Hlatky
L.
Biological effects of proton radiation: what we know and don't know
.
Radiat Res
.
2013
;
179
:
257
72
.
46
Ebner
DK,
Tinganelli
W,
Helm
A,
Bisio
A,
Yamada
S,
Kamada
T,
Shimokawa
T,
Durante
M.
The immunoregulatory potential of particle radiation in cancer therapy
.
Front Immunol
.
2017
;
8
:
99
.
47
Fernandez-Gonzalo
R,
Baatout
S,
Moreels
M.
Impact of particle irradiation on the immune system: from the clinic to Mars
.
Front Immunol
.
2017
;
8
:
177
.
48
Abei
M,
Okumura
T,
Fukuda
K,
Hashimoto
T,
Araki
M,
Ishige
K,
Hyodo
I,
Kanemoto
A,
Numajiri
H,
Mizumoto
M,
Sakae
T,
Sakurai
H,
Zenkoh
J,
Ariungerel
G,
Sogo
Y,
Ito
A,
Ohno
T,
Tsuboi
K.
A phase I study on combined therapy with proton-beam radiotherapy and in situ tumor vaccination for locally advanced recurrent hepatocellular carcinoma
.
Radiat Oncol
.
2013
;
8
:
239
.
49
Ohkubo
Y,
Iwakawa
M,
Seino
K,
Nakawatari
M,
Wada
H,
Kamijuku
H,
Nakamura
E,
Nakano
T,
Imai
T.
Combining carbon ion radiotherapy and local injection of α-galactosylceramide-pulsed dendritic cells inhibits lung metastases in an in vivo murine model
.
Int J Radiat Oncol Biol Phys
.
2010
;
78
:
1524
31
.
50
Ando
K,
Fujita
H,
Hosoi
A,
Ma
L,
Wakatsuki
M,
Seino
KI,
Kakimi
K,
Imai
T,
Shimokawa
T,
Nakano
T.
Intravenous dendritic cell administration enhances suppression of lung metastasis induced by carbon-ion irradiation
.
J Radiat Res
.
2017
;
58
:
446
55
.
51
Ogata
T,
Teshima
T,
Kagawa
K,
Hishikawa
Y,
Takahashi
Y,
Kawaguchi
A,
et al.
Particle irradiation suppresses metastatic potential of cancer cells
.
Cancer Res
.
2005
;
65
:
113
20
.
52
Durante
M,
Brenner
DJ,
Formenti
SC.
Does heavy ion therapy work through the immune system?
Int J Radiat Oncol Biol Phys
.
2016
;
96
:
934
6
.
53
Durante
M,
Reppingen
N,
Held
KD.
Immunologically augmented cancer treatment using modern radiotherapy
.
Trends Mol Med
.
2013
;
19
:
565
82
.