Special Issue "Proton Therapy For Cancers"

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 June 2021).

Special Issue Editor

Prof. Dr. Hitoshi Ishikawa
E-Mail Website
Guest Editor
Department of Radiation Oncology and Proton Medical Research Center, University of Tsukuba, 2-1-1, Amakubo, Tsukuba, Ibaraki 305-8576, Japan
Interests: radiation oncology; particle therapy using protons and carbon ions; radiation-induced immune reaction; combination therapy of chemotherapy; molecular targeted therapy; immune checkpoint inhibitors with radiation therapy

Special Issue Information

Dear Colleagues,

Although it is well known that dose escalation is one of methods to successfully control many cancers by radiation therapy (RT), dose–volume effects on late toxicities in at-risk organs have been also observed. Protons offer advantageous physical properties for RT, as they can create favorable dose distributions to the target volume using fewer portals compared with photon-based RT. Thus, dose escalation using protons is a reasonable approach to improve cancer control and reduce short- and long-term complications, including the risk of secondary cancers. However, due to limited clinical evidence, proton therapy has long been regarded as a costly RT from an economic point of view. Particle Therapy Co-Operative Group (PTCOG) was founded in 1985 to promote the science, technology, and practical application of particle therapy and, step by step, clinical advantages of proton therapy have been shown through prospective studies.

Recent advances in molecular biology and immunology have allowed us to understand the mechanisms of induction of systemic antitumor effects via radiation-induced cell death, and the combination of immune checkpoint inhibitors with irradiation is of primary focus in radiation oncology. In actuality, there is an abundance of prospective studies of combination therapy. On the other hand, some investigators have revealed that radiation-associated lymphopenia during therapy is associated with poor prognosis, and proton therapy is expected to be a lymphocyte-sparing RT, especially in chemoradiation for esophageal cancer and stage III non-small cell lung cancer.

Based on the accumulation of evidence that demonstrates the efficacy of proton therapy in various cancer treatments, the number of proton therapy facilities has been increasing worldwide. This is in spite of the fact that there still exists the important question regarding whether it provides an overall advantage compared to photon-based RT, which is still under discussion. We are currently facing an important point at which proton therapy can be compared directly with not only other RTs, but also surgery or pharmacotherapy, from several points of view, such as survival, adverse events, QOL, and cost. The Special Issue will highlight the perspective of proton therapy in cancer treatment, covering biology, physics, and economic studies as well as clinical trials.

Prof. Dr. Hitoshi Ishikawa
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Proton therapy
  • Dose escalation
  • Toxicity
  • Quality of life
  • Radiation-induced immune reaction
  • Image-guided radiation therapy
  • Multimodal treatment

Published Papers (9 papers)

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Research

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Article
Particle Radiotherapy for Skull Base Chondrosarcoma: A Clinical Series from Italian National Center for Oncological Hadrontherapy
Cancers 2021, 13(17), 4423; https://doi.org/10.3390/cancers13174423 - 02 Sep 2021
Viewed by 442
Abstract
Background: The standard treatment for skull base chondrosarcoma (SB-CHS) consists of surgery and high-dose radiation therapy. Our aim was to evaluate outcome in terms of local control (LC) and toxicity of proton therapy (PT) and carbon ion (CIRT) after surgery. Materials and methods: [...] Read more.
Background: The standard treatment for skull base chondrosarcoma (SB-CHS) consists of surgery and high-dose radiation therapy. Our aim was to evaluate outcome in terms of local control (LC) and toxicity of proton therapy (PT) and carbon ion (CIRT) after surgery. Materials and methods: From September 2011 to July 2020, 48 patients underwent particle therapy (67% PT, 33% CIRT) for SB-CHS. PT and CIRT total dose was 70 GyRBE (relative biological effectiveness) in 35 fractions and 70.4 GyRBE in 16 fractions, respectively. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5). Results: After a median follow-up time of 38 months, one local failure (2%) was documented and the patient died for progressive disease. Overall, 3-year LC was 98%. One (2%) and 4 (8%) patients experienced G3 acute and late toxicity, respectively. White-matter brain changes were documented in 22 (46%) patients, but only 7 needed steroids (G2). No patients had G3 brain toxicity. No G4–5 complications were reported. We did not find any correlation between high-grade toxicity or white-matter changes and characteristics of patients, disease and surgery. Conclusions: PT and CIRT appeared to be effective and safe treatments for patients with SB-CHS, resulting in high LC rates and an acceptable toxicity profile. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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Article
Clinical Outcomes of Pencil Beam Scanning Proton Therapy in Locally Advanced Non-Small Cell Lung Cancer: Propensity Score Analysis
Cancers 2021, 13(14), 3497; https://doi.org/10.3390/cancers13143497 - 13 Jul 2021
Cited by 1 | Viewed by 549
Abstract
This study compared the efficacy and safety of pencil beam scanning proton therapy (PBSPT) versus intensity-modulated (photon) radiotherapy (IMRT) in patients with stage III non-small cell lung cancer (NSCLC). We retrospectively reviewed 219 patients with stage III NSCLC who received definitive concurrent chemoradiotherapy [...] Read more.
This study compared the efficacy and safety of pencil beam scanning proton therapy (PBSPT) versus intensity-modulated (photon) radiotherapy (IMRT) in patients with stage III non-small cell lung cancer (NSCLC). We retrospectively reviewed 219 patients with stage III NSCLC who received definitive concurrent chemoradiotherapy between November 2016 and December 2018. Twenty-five patients (11.4%) underwent PBSPT (23 with single-field optimization) and 194 patients (88.6%) underwent IMRT. Rates of locoregional control (LRC), overall survival, and acute/late toxicities were compared between the groups using propensity score-adjusted analyses. Patients treated with PBSPT were older (median: 67 vs. 62 years) and had worse pulmonary function at baseline (both FEV1 and DLCO) compared to those treated with IMRT. With comparable target coverage, PBSPT exhibited superior sparing of the lung, heart, and spinal cord to radiation exposure compared to IMRT. At a median follow-up of 21.7 (interquartile range: 16.8–26.8) months, the 2-year LRC rates were 72.1% and 84.1% in the IMRT and PBSPT groups, respectively (p = 0.287). The rates of grade ≥ 3 esophagitis were 8.2% and 20.0% after IMRT and PBSPT (p = 0.073), respectively, while corresponding rates of grade ≥ 2 radiation pneumonitis were 28.9% and 16.0%, respectively (p = 0.263). PBSPT appears to be an effective and safe treatment technique even for patients with poor lung function, and it does not jeopardize LRC. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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Article
Early Clinical Outcomes of Intensity Modulated Radiation Therapy/Intensity Modulated Proton Therapy Combination in Comparison with Intensity Modulated Radiation Therapy Alone in Oropharynx Cancer Patients
Cancers 2021, 13(7), 1549; https://doi.org/10.3390/cancers13071549 - 27 Mar 2021
Cited by 2 | Viewed by 801
Abstract
Purpose: To report the early clinical outcomes of combining intensity-modulated radiation therapy (IMRT) and intensity-modulated proton therapy (IMPT) in comparison with IMRT alone in treating oropharynx cancer (OPC) patients. Materials and Methods: The medical records of 148 OPC patients who underwent definitive radiotherapy [...] Read more.
Purpose: To report the early clinical outcomes of combining intensity-modulated radiation therapy (IMRT) and intensity-modulated proton therapy (IMPT) in comparison with IMRT alone in treating oropharynx cancer (OPC) patients. Materials and Methods: The medical records of 148 OPC patients who underwent definitive radiotherapy (RT) with concurrent systemic therapy, from January 2016 till December 2019 at Samsung Medical Center, were retrospectively reviewed. During the 5.5 weeks’ RT course, the initial 16 (or 18) fractions were delivered by IMRT in all patients, and the subsequent 12 (or 10) fractions were either by IMRT in 81 patients (IMRT only) or by IMPT in 67 (IMRT/IMPT combination), respectively, based on comparison of adaptive re-plan profiles and availability of equipment. Propensity-score matching (PSM) was done on 76 patients (38 from each group) for comparative analyses. Results: With the median follow-up of 24.7 months, there was no significant difference in overall survival and progression free survival between groups, both before and after PSM. Before PSM, the IMRT/IMPT combination group experienced grade ≥ 3 acute toxicities less frequently: mucositis in 37.0% and 13.4% (p < 0.001); and analgesic quantification algorithm (AQA) in 37.0% and 19.4% (p = 0.019), respectively. The same trends were observed after PSM: mucositis in 39.5% and 15.8% (p = 0.021); and AQA in 47.4% and 21.1% (p = 0.016), respectively. In multivariate logistic regression, grade ≥ 3 mucositis was significantly less frequent in the IMRT/IMPT combination group, both before and after PSM (p = 0.027 and 0.024, respectively). AQA score ≥ 3 was also less frequent in the IMRT/IMPT combination group, both before and after PSM (p = 0.085 and 0.018, respectively). Conclusions: In treating the OPC patients, with comparable early oncologic outcomes, more favorable acute toxicity profiles were achieved following IMRT/IMPT combination than IMRT alone. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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Article
Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation
Cancers 2021, 13(3), 527; https://doi.org/10.3390/cancers13030527 - 30 Jan 2021
Cited by 1 | Viewed by 957
Abstract
Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with [...] Read more.
Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p < 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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Article
An Analysis of Vertebral Body Growth after Proton Beam Therapy for Pediatric Cancer
Cancers 2021, 13(2), 349; https://doi.org/10.3390/cancers13020349 - 19 Jan 2021
Viewed by 670
Abstract
Impairment of bone growth after radiotherapy for pediatric bone cancer is a well-known adverse event. However, there is limited understanding of the relationship between bone growth and irradiation dose. In this study, we retrospectively analyzed bone growth impairment after proton beam therapy for [...] Read more.
Impairment of bone growth after radiotherapy for pediatric bone cancer is a well-known adverse event. However, there is limited understanding of the relationship between bone growth and irradiation dose. In this study, we retrospectively analyzed bone growth impairment after proton beam therapy for pediatric cancer. A total of 353 vertebral bodies in 23 patients under 12 years old who received proton beam therapy were evaluated. Compared to the non-irradiated vertebral body growth rate, the irradiated vertebral body rate (%/year) was significantly lower: 77.2%, 57.6%, 40.8%, 26.4%, and 14.1% at 10, 20, 30, 40, and 50 Gy (RBE) irradiation, respectively. In multivariate analysis, radiation dose was the only factor correlated with vertebral body growth. Age, gender, and vertebral body site were not significant factors. These results suggest that the growth rate of the vertebral body is dose-dependent and decreases even at a low irradiated dose. This is the first report to show that proton beam therapy has the same growth inhibitory effect as photon radiotherapy within the irradiated field. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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Article
Image-Guided Proton Therapy for Elderly Patients with Hepatocellular Carcinoma: High Local Control and Quality of Life Preservation
Cancers 2021, 13(2), 219; https://doi.org/10.3390/cancers13020219 - 09 Jan 2021
Cited by 1 | Viewed by 615
Abstract
This study retrospectively investigated the efficacy and safety of image-guided proton therapy (IGPT) for elderly (≥80 years old) hepatocellular carcinoma (HCC) patients. Proton therapy was performed using respiratory-gated and image-guided techniques. Seventy-one elderly HCC patients were treated using IGPT. The Child–Pugh score was [...] Read more.
This study retrospectively investigated the efficacy and safety of image-guided proton therapy (IGPT) for elderly (≥80 years old) hepatocellular carcinoma (HCC) patients. Proton therapy was performed using respiratory-gated and image-guided techniques. Seventy-one elderly HCC patients were treated using IGPT. The Child–Pugh score was A5 in 49 patients, A6 in 15, and B7-9 in 7. Forty-seven patients with a peripherally located tumor were administered 66 gray relative biological effectiveness (GyRBE) in 10 fractions, whereas 24 with a centrally located tumor received 72.6 GyRBE in 22 fractions. The median follow-up period of surviving patients was 33 months (range: 9–68). Two-year overall survival (OS) and local control (LC) rates estimated by the Kaplan–Meier method were 76% (95% confidence interval: 66–87%) and 88% (80–97%), respectively. According to the Common Terminology Criteria for Adverse Events version 4.0, no grade 2 or higher radiation-induced liver disease was observed, and only 1 patient developed grade 3 dermatitis. The quality of life score (European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0, QLQ-HCC18, and SF-36) did not change after 1 year, except for the three-mental component summary (SF-36, improvement). IGPT is a safe and effective treatment for HCC in elderly patients. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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Article
Optimal Androgen Deprivation Therapy Combined with Proton Beam Therapy for Prostate Cancer: Results from a Multi-Institutional Study of the Japanese Radiation Oncology Study Group
Cancers 2020, 12(6), 1690; https://doi.org/10.3390/cancers12061690 - 25 Jun 2020
Cited by 2 | Viewed by 835
Abstract
Background: Androgen deprivation therapy (ADT) combined with radiation therapy benefits intermediate- and high-risk prostate cancer (PC) patients. The optimal ADT duration in combination with high-dose proton beam therapy (PBT) remains unknown. Methods: Intermediate- and high-risk PC patients treated with PBT combined with ADT [...] Read more.
Background: Androgen deprivation therapy (ADT) combined with radiation therapy benefits intermediate- and high-risk prostate cancer (PC) patients. The optimal ADT duration in combination with high-dose proton beam therapy (PBT) remains unknown. Methods: Intermediate- and high-risk PC patients treated with PBT combined with ADT for various durations were analyzed retrospectively. To assess the relationship between ADT and biochemical relapse-free (bRF) rate, Cox proportional hazards models including T stage, prostate specific antigen (PSA) level, Gleason score (GS), and total radiation dose were used. Results: In the intermediate-risk PC patients (n = 520), ADT use improved bRF (HR 0.49, 95% CI 0.26–0.93; p = 0.029), especially in those with multiple intermediate-risk factors (T2b–2c, PSA 10–20 ng/mL, and GS 7). In the high-risk PC patients (n = 555), a longer ADT duration (>6 months) conferred a benefit for bRF (HR 0.54, 95% CI 0.32–0.90; p = 0.018), which was most apparent in patients with multiple high-risk factors (T3a–4, PSA > 20 ng/mL, and GS ≥ 8) treated with ADT for ≥21 months. Conclusions: Short-term (≤6 months) ADT is beneficial for intermediate-risk PC patients, but likely unnecessary for those with a single risk factor, whereas ADT for >6 months is necessary for high-risk PC patients and ADT for ≥21 months might be optimal for those with multiple risk factors in combination of high-dose PBT. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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Article
Inhibition of ATM Increases the Radiosensitivity of Uveal Melanoma Cells to Photons and Protons
Cancers 2020, 12(6), 1388; https://doi.org/10.3390/cancers12061388 - 28 May 2020
Cited by 3 | Viewed by 693
Abstract
Treatment of uveal melanoma (UM) is generally successful, with local primary tumour control being at 90%–95%. Localized radiotherapy in the form of plaque brachytherapy or proton beam radiotherapy is the most common treatment modality in the UK. However, the basic mechanisms of radiation [...] Read more.
Treatment of uveal melanoma (UM) is generally successful, with local primary tumour control being at 90%–95%. Localized radiotherapy in the form of plaque brachytherapy or proton beam radiotherapy is the most common treatment modality in the UK. However, the basic mechanisms of radiation response, DNA repair and tissue reactions in UM have not been well documented previously. We have investigated the comparative radiosensitivity of four UM cell lines in response to exogenous radiation sources (both X-rays and protons), and correlated this with DNA repair protein expression and repair efficiency. We observed a broad range of radiosensitivity of different UM cell lines to X-rays and protons, with increased radioresistance correlating with elevated protein expression of ataxia telangiectasia mutated (ATM), a protein kinase involved in the signaling and repair of DNA double strand breaks. The use of an ATM inhibitor in UM cell lines enhanced radiosensitivity following both X-ray and proton irradiation, particularly in cells that contained high levels of ATM protein which are otherwise comparatively radioresistant. In proton-irradiated compared with non-irradiated primary enucleated UM patient samples, there was no significant difference in ATM protein expression. Our study therefore suggests that ATM is a potential target for increasing the radiosensitivity of more resistant UM subgroups. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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Review

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Review
Models for Translational Proton Radiobiology—From Bench to Bedside and Back
Cancers 2021, 13(16), 4216; https://doi.org/10.3390/cancers13164216 - 22 Aug 2021
Viewed by 634
Abstract
The number of proton therapy centers worldwide are increasing steadily, with more than two million cancer patients treated so far. Despite this development, pending questions on proton radiobiology still call for basic and translational preclinical research. Open issues are the on-going discussion on [...] Read more.
The number of proton therapy centers worldwide are increasing steadily, with more than two million cancer patients treated so far. Despite this development, pending questions on proton radiobiology still call for basic and translational preclinical research. Open issues are the on-going discussion on an energy-dependent varying proton RBE (relative biological effectiveness), a better characterization of normal tissue side effects and combination treatments with drugs originally developed for photon therapy. At the same time, novel possibilities arise, such as radioimmunotherapy, and new proton therapy schemata, such as FLASH irradiation and proton mini-beams. The study of those aspects demands for radiobiological models at different stages along the translational chain, allowing the investigation of mechanisms from the molecular level to whole organisms. Focusing on the challenges and specifics of proton research, this review summarizes the different available models, ranging from in vitro systems to animal studies of increasing complexity as well as complementing in silico approaches. Full article
(This article belongs to the Special Issue Proton Therapy For Cancers)
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