Cancers

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15 pages, 1952 KiB

Open AccessArticle

Potential for Improvements in Robustness and Optimality of Intensity-Modulated Proton Therapy for Lung Cancer with 4-Dimensional Robust Optimization

by Shuaiping Ge, Xiaochun Wang, Zhongxing Liao, Lifei Zhang, Narayan Sahoo, Jinzhong Yang, Fada Guan and Radhe Mohan

Cancers 2019, 11(1), 35; https://doi.org/10.3390/cancers11010035 - 1 Jan 2019

Cited by 27 | Viewed by 3953

Abstract

Background: Major challenges in the application of intensity-modulated proton therapy (IMPT) for lung cancer patients include the uncertainties associated with breathing motion, its mitigation and its consideration in IMPT optimization. The primary objective of this research was to evaluate the potential of four-dimensional [...] Read more.

Background: Major challenges in the application of intensity-modulated proton therapy (IMPT) for lung cancer patients include the uncertainties associated with breathing motion, its mitigation and its consideration in IMPT optimization. The primary objective of this research was to evaluate the potential of four-dimensional robust optimization (4DRO) methodology to make IMPT dose distributions resilient to respiratory motion as well as to setup and range uncertainties; Methods: The effect of respiratory motion, characterized by different phases of 4D computed tomography (4DCT), was incorporated into an in-house 4DRO system. Dose distributions from multiple setup and range uncertainty scenarios were calculated for each of the ten phases of CT datasets. The 4DRO algorithm optimizes dose distributions to achieve target dose coverage and normal tissue sparing for multiple setup and range uncertainty scenarios as well as for all ten respiratory phases simultaneously. IMPT dose distributions of ten lung cancer patients with different tumor sizes and motion magnitudes were optimized to illustrate our approach and its potential; Results: Compared with treatment plans generated using the conventional planning target volume (PTV)-based optimization and 3D robust optimization (3DRO), plans generated by 4DRO were found to have superior clinical target volume coverage and dose robustness in the face of setup and range uncertainties as well as for respiratory motion. In most of the cases we studied, 4DRO also resulted in more homogeneous target dose distributions. Interestingly, such improvements were found even for cases in which moving diaphragms intruded into the proton beam paths; Conclusion: The incorporation of respiratory motion, along with setup and range uncertainties, into robust optimization, has the potential to improve the resilience of target and normal tissue dose distributions in IMPT plans in the face of the uncertainties considered. Moreover, it improves the optimality of plans compared to PTV-based optimization as well as 3DRO. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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18 pages, 16820 KiB

Open AccessArticle

Antrocin Sensitizes Prostate Cancer Cells to Radiotherapy through Inhibiting PI3K/AKT and MAPK Signaling Pathways

by Yu-An Chen, David T. W. Tzeng, Yi-Ping Huang, Chun-Jung Lin, U-Ging Lo, Chia-Lin Wu, Ho Lin, Jer-Tsong Hsieh, Chih-Hsin Tang and Chih-Ho Lai

Cancers 2019, 11(1), 34; https://doi.org/10.3390/cancers11010034 - 31 Dec 2018

Cited by 37 | Viewed by 5514

Abstract

Radiotherapy is one of the most common treatment options for local or regional advanced prostate cancer (PCa). Importantly, PCa is prone to radioresistance and often develops into malignancies after long-term radiotherapy. Antrocin, a sesquiterpene lactone isolated from Antrodia cinnamomea, possesses pharmacological efficacy [...] Read more.

Radiotherapy is one of the most common treatment options for local or regional advanced prostate cancer (PCa). Importantly, PCa is prone to radioresistance and often develops into malignancies after long-term radiotherapy. Antrocin, a sesquiterpene lactone isolated from Antrodia cinnamomea, possesses pharmacological efficacy against various cancer types; however, its therapeutic potential requires comprehensive exploration, particularly in radioresistant PCa cells. In this study, we emphasized the effects of antrocin on radioresistant PCa cells and addressed the molecular mechanism underlying the radiosensitization induced by antrocin. Our results showed that a combination treatment with antrocin and ionizing radiation (IR) synergistically inhibited cell proliferation and induced apoptosis in radioresistant PCa cells. We further demonstrated that antrocin downregulated PI3K/AKT and MAPK signaling pathways as well as suppressed type 1 insulin-like growth factor 1 receptor (IGF-1R)-mediated induction of β-catenin to regulate cell cycle and apoptosis. Using xenograft mouse models, we showed that antrocin effectively enhanced radiotherapy in PCa. Our study demonstrates that antrocin sensitizes PCa to radiation through constitutive suppression of IGF-1R downstream signaling, revealing that it can be developed as a potent therapeutic agent to overcome radioresistant PCa. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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13 pages, 850 KiB

Open AccessArticle

Intensity Modulated Radiotherapy (IMRT) + Carbon Ion Boost for Adenoid Cystic Carcinoma of the Minor Salivary Glands in the Oral Cavity

by Kristin Lang, Melissa Baur, Sati Akbaba, Thomas Held, Steffen Kargus, Nina Bougatf, Denise Bernhardt, Kolja Freier, Peter K. Plinkert, Stefan Rieken, Jürgen Debus and Sebastian Adeberg

Cancers 2018, 10(12), 488; https://doi.org/10.3390/cancers10120488 - 4 Dec 2018

Cited by 15 | Viewed by 4193

Abstract

Background: Adenoid cystic carcinoma (ACC) are more common in the minor salivary glands (MiSGs) than the major salivary glands, and are characterized by slow tumor progression and frequently local recurrence. The main treatment option is surgery followed by combined radiotherapy. Methods: A retrospective [...] Read more.

Background: Adenoid cystic carcinoma (ACC) are more common in the minor salivary glands (MiSGs) than the major salivary glands, and are characterized by slow tumor progression and frequently local recurrence. The main treatment option is surgery followed by combined radiotherapy. Methods: A retrospective analysis contained 67 patients with ACC of MiSGs in the oral cavity who underwent surgery followed by radiotherapy. The median cumulative IMRT dose was 50 Gy followed by 24 Gy for carbon ion (C12) boost. Median follow-up was 40 months. Results: Median 5-years overall survival (OS), progression-free survival (PFS) and local disease-free survival (LDFS) rates were 85.5%, 57.4% and 74.9%. Median time until progression was detected was 32 months (range: 2–205 months). Early grade ≥3 mucositis, dermatitis, and dysphagia were detected in 52.2%, 7.5% and 11.9% respectively. Besides common toxicities, two patients (3.0%) developed grade 3 toxicities with osteoradionecrosis of the jaw after 18 and 66 months. Higher-grade late toxicity (CTCAE grade 4) was not detected. No treatment-related death was detected. Conclusions: Our results demonstrate that postoperative combined radiotherapy with IMRT plus C12 boost seems to be a feasible and effective treatment method in ACC of MiSGs in the oral cavity, with good control and survival rates and adequate toxicity. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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11 pages, 3398 KiB

Open AccessArticle

Advanced Radiation Techniques in the Treatment of Esthesioneuroblastoma: A 7-Year Single-Institution’s Clinical Experience

by Jakob Liermann, Mustafa Syed, Thomas Held, Denise Bernhardt, Peter Plinkert, Christine Jungk, Andreas Unterberg, Stefan Rieken, Jürgen Debus, Klaus Herfarth and Sebastian Adeberg

Cancers 2018, 10(11), 457; https://doi.org/10.3390/cancers10110457 - 20 Nov 2018

Cited by 13 | Viewed by 4587

Abstract

(1) Background: Esthesioneuroblastoma (ENB) is a rare tumor entity originating from the olfactory neuroepithelium. There is a scarcity of data about different treatment strategies. Intensity modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) are advanced radiation techniques that might improve local tumor control. [...] Read more.

(1) Background: Esthesioneuroblastoma (ENB) is a rare tumor entity originating from the olfactory neuroepithelium. There is a scarcity of data about different treatment strategies. Intensity modulated radiotherapy (IMRT) and carbon ion radiotherapy (CIRT) are advanced radiation techniques that might improve local tumor control. (2) Methods: This retrospective analysis contained 17 patients with ENB (Kadish stage ≥ C: 88%; n = 15). Four patients had already undergone previous radiotherapy (RT). The treatment consisted of either IMRT (n = 5), CIRT (n = 4) or a combination of both techniques (n = 8). Median follow-up was 29 months. (3) Results: In patients that had not been irradiated before (n = 13), calculated overall survival (OS) and progression free survival (PFS) rates after 48 months were 100% and 81% respectively (Kaplan-Meier estimates). Two of four patients that underwent reirradiation died after RT, presumably due to tumor progression. Besides common toxicities, five patients (30%) showed mostly asymptomatic radiation-induced brain changes, most likely due to a disturbance of the blood-brain barrier. (4) Conclusions: Our results demonstrate that IMRT, CIRT, a combined approach of IMRT and CIRT as well as reirradiation with CIRT seem to be feasible and effective treatment methods in ENB. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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15 pages, 3543 KiB

Open AccessArticle

Automated Knowledge-Based Intensity-Modulated Proton Planning: An International Multicenter Benchmarking Study

by Alexander R. Delaney, Lei Dong, Anthony Mascia, Wei Zou, Yongbin Zhang, Lingshu Yin, Sara Rosas, Jan Hrbacek, Antony J. Lomax, Ben J. Slotman, Max Dahele and Wilko F. A. R. Verbakel

Cancers 2018, 10(11), 420; https://doi.org/10.3390/cancers10110420 - 2 Nov 2018

Cited by 23 | Viewed by 3693

Abstract

Background: Radiotherapy treatment planning is increasingly automated and knowledge-based planning has been shown to match and sometimes improve upon manual clinical plans, with increased consistency and efficiency. In this study, we benchmarked a novel prototype knowledge-based intensity-modulated proton therapy (IMPT) planning solution, against [...] Read more.

Background: Radiotherapy treatment planning is increasingly automated and knowledge-based planning has been shown to match and sometimes improve upon manual clinical plans, with increased consistency and efficiency. In this study, we benchmarked a novel prototype knowledge-based intensity-modulated proton therapy (IMPT) planning solution, against three international proton centers. Methods: A model library was constructed, comprising 50 head and neck cancer (HNC) manual IMPT plans from a single center. Three external-centers each provided seven manual benchmark IMPT plans. A knowledge-based plan (KBP) using a standard beam arrangement for each patient was compared with the benchmark plan on the basis of planning target volume (PTV) coverage and homogeneity and mean organ-at-risk (OAR) dose. Results: PTV coverage and homogeneity of KBPs and benchmark plans were comparable. KBP mean OAR dose was lower in 32/54, 45/48 and 38/53 OARs from center-A, -B and -C, with 23/32, 38/45 and 23/38 being >2 Gy improvements, respectively. In isolated cases the standard beam arrangement or an OAR not being included in the model or being contoured differently, led to higher individual KBP OAR doses. Generating a KBP typically required <10 min. Conclusions: A knowledge-based IMPT planning solution using a single-center model could efficiently generate plans of comparable quality to manual HNC IMPT plans from centers with differing planning aims. Occasional higher KBP OAR doses highlight the need for beam angle optimization and manual review of KBPs. The solution furthermore demonstrated the potential for robust optimization. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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15 pages, 4486 KiB

Open AccessArticle

Dosimetric Comparison of Proton Radiation Therapy, Volumetric Modulated Arc Therapy, and Three-Dimensional Conformal Radiotherapy Based on Intracranial Tumor Location

by Sebastian Adeberg, Semi B. Harrabi, Nina Bougatf, Vivek Verma, Paul Windisch, Denise Bernhardt, Stephanie E. Combs, Klaus Herfarth, Juergen Debus and Stefan Rieken

Cancers 2018, 10(11), 401; https://doi.org/10.3390/cancers10110401 - 26 Oct 2018

Cited by 41 | Viewed by 4301

Abstract

(1) Background: Selecting patients that will benefit the most from proton radiotherapy (PRT) is of major importance. This study sought to assess dose reductions to numerous organs-at-risk (OARs) with PRT, as compared to three-dimensional conformal radiotherapy (3DCRT) and volumetric-modulated arc therapy (VMAT), as [...] Read more.

(1) Background: Selecting patients that will benefit the most from proton radiotherapy (PRT) is of major importance. This study sought to assess dose reductions to numerous organs-at-risk (OARs) with PRT, as compared to three-dimensional conformal radiotherapy (3DCRT) and volumetric-modulated arc therapy (VMAT), as a function of tumor location. (2) Materials/Methods: Patients with intracranial neoplasms (all treated with PRT) were stratified into five location-based groups (frontal, suprasellar, temporal, parietal, posterior cranial fossa; n = 10 per group). Each patient was re-planned for 3DCRT and intensity-modulated radiotherapy (IMRT) using similar methodology, including the originally planned target and organ-at-risk (OAR) dose constraints. (3) Results: In parietal tumors, PRT showed the most pronounced dose reductions. PRT lowered doses to nearly every OAR, most notably the optical system and several contralateral structures (subventricular zone, thalamus, hippocampus). For frontal lobe cases, the greatest relative dose reductions in mean dose (D_mean) with PRT were to the infratentorial normal brain, contralateral hippocampus, brainstem, pituitary gland and contralateral optic nerve. For suprasellar lesions, PRT afforded the greatest relative D_mean reductions to the infratentorial brain, supratentorial brain, and the whole brain. Similar results could be observed in temporal and posterior cranial fossa disease. (4) Conclusions: The effectiveness and degree of PRT dose-sparing to various OARs depends on intracranial tumor location. These data will help to refine selection of patients receiving PRT, cost-effectiveness, and future clinical toxicity assessment. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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12 pages, 594 KiB

Open AccessFeature PaperArticle

Accelerated Hypofractionated Active Raster-Scanned Carbon Ion Radiotherapy (CIRT) for Laryngeal Malignancies: Feasibility and Safety

by Sati Akbaba, Kristin Lang, Thomas Held, Olcay Cem Bulut, Matthias Mattke, Matthias Uhl, Alexandra Jensen, Peter Plinkert, Stefan Rieken, Klaus Herfarth, Juergen Debus and Sebastian Adeberg

Cancers 2018, 10(10), 388; https://doi.org/10.3390/cancers10100388 - 18 Oct 2018

Cited by 9 | Viewed by 3390

Abstract

(1) Background: The authors present the first results of active raster-scanned carbon ion radiotherapy (CIRT) for radioresistant laryngeal malignancies regarding efficacy and toxicity. (2) Methods: 15 patients with laryngeal adenoid cystic carcinoma (ACC; n = 8; 53.3%) or chondrosarcoma (CS; n = 7; [...] Read more.

(1) Background: The authors present the first results of active raster-scanned carbon ion radiotherapy (CIRT) for radioresistant laryngeal malignancies regarding efficacy and toxicity. (2) Methods: 15 patients with laryngeal adenoid cystic carcinoma (ACC; n = 8; 53.3%) or chondrosarcoma (CS; n = 7; 46.7%) who underwent radiotherapy with carbon ions (C12) at the Heidelberg Ion Beam Therapy Center (HIT) between 2013 and 2018 were identified retrospectively and analyzed for local control (LC), overall survival (OS), and distant progression-free survival using the Kaplan–Meier method. CIRT was applied either alone (n = 7, 46.7%) or in combination with intensity modulated radiotherapy (IMRT) (n = 8, 53.3%). The toxicity was assessed according to the Common Toxicity Terminology Criteria for Adverse Events (CTCAE) v4.03. (3). Results: the median follow-up was 24 months (range 5–61 months). Overall, the therapy was tolerated very well. No grade >3 acute and chronic toxicity could be identified. The most reported acute grade 3 side effects were acute dysphagia (n = 2; 13%) and acute odynophagia (n = 3; 20%), making supportive nutrition via gastric tube (n = 2; 13.3%) and via high caloric drinks (n = 1; 6.7%) necessary due to swallowing problems (n = 4; 27%). Overall, chronic grade 3 toxicity in the form of chronic hoarseness occurred in 7% of the patients (n = 1; 7%). At the last follow-up, all the patients were alive. No local or locoregional recurrence could be identified. Only one patient with laryngeal ACC developed lung metastases three years after the first diagnosis. (4) Conclusions: the accelerated hypofractionated active raster-scanned carbon ion radiotherapy for radioresistant laryngeal malignancies is feasible in practice with excellent local control rates and moderate acute and late toxicity. Further follow-ups are necessary to evaluate the long-term clinical outcome. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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13 pages, 1753 KiB

Open AccessArticle

Phase I Study of Carbon Ion Radiotherapy and Image-Guided Brachytherapy for Locally Advanced Cervical Cancer

by Tatsuya Ohno, Shin-ei Noda, Kazutoshi Murata, Yuya Yoshimoto, Noriyuki Okonogi, Ken Ando, Tomoaki Tamaki, Shingo Kato, Takashi Hirakawa, Tatsuya Kanuma, Takashi Minegishi, Takashi Nakano and On behalf of the Working Group for Gynecologic Cancer

Cancers 2018, 10(9), 338; https://doi.org/10.3390/cancers10090338 - 18 Sep 2018

Cited by 20 | Viewed by 5130

Abstract

A phase I study was performed to determine the recommended dose of carbon ion radiotherapy and 3D image-guided brachytherapy for histologically confirmed stage II (≥4 cm), III, or IVA cervical cancer. Dose-limiting toxicities (treatment-related toxicities occurring within three months from the start of [...] Read more.

A phase I study was performed to determine the recommended dose of carbon ion radiotherapy and 3D image-guided brachytherapy for histologically confirmed stage II (≥4 cm), III, or IVA cervical cancer. Dose-limiting toxicities (treatment-related toxicities occurring within three months from the start of carbon ion radiotherapy) included Grade 3 non-hematological toxicity, Grade 4 hematological toxicity, or interruption of treatment for more than two weeks due to treatment-related toxicities. Carbon ion radiotherapy consisted of whole-pelvic irradiation with 36.0 Gy (relative biological effectiveness) in 12 fractions and local boost with 19.2 Gy in four fractions for the primary site, and for positive lymph nodes. Three sessions of three-dimensional (3D) image-guided brachytherapy were administered after completion of carbon ion radiotherapy. Weekly cisplatin at a dose of 40 mg/m² was given concurrently. At a dose level of one, a total rectosigmoid D2cc dose between 67.2 Gy and 71.3 Gy at a biological equivalent dose of 2 Gy per fraction from carbon ion radiotherapy and 3D image-guided brachytherapy was prescribed. Six patients were enrolled into this dose level. No patients developed the pre-defined dose-limiting toxicities. For late toxicities, however, one patient developed Grade 3 rectal hemorrhage requiring transfusion at 10 months after treatment. The median survival time was 50.0 months for the five surviving patients. No further dose escalation was performed, and we determined the dose of level one as the recommended rectosigmoid dose. Although our results are preliminary, the study regimen encourages further investigation (registration: UMIN000013340). Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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12 pages, 1260 KiB

Open AccessArticle

High-Dose-Rate Brachytherapy Monotherapy versus Image-Guided Intensity-Modulated Radiotherapy with Helical Tomotherapy for Patients with Localized Prostate Cancer

by Hideya Yamazaki, Koji Masui, Gen Suzuki, Satoaki Nakamura, Daisuke Shimizu, Tatsuyuki Nishikawa, Haruumi Okabe, Ken Yoshida, Tadayuki Kotsuma, Eiichi Tanaka, Keisuke Otani, Yasuo Yoshioka and Kazuhiko Ogawa

Cancers 2018, 10(9), 322; https://doi.org/10.3390/cancers10090322 - 10 Sep 2018

Cited by 6 | Viewed by 3835

Abstract

The aim of this paper is to compare outcomes between high-dose-rate interstitial brachytherapy (HDR-BT) monotherapy and image-guided intensity-modulated radiotherapy (IG-IMRT) for localized prostate cancer. We examined 353 HDR-BT and 270 IG-IMRT patients. To reduce background selection bias, we used the method of inverse [...] Read more.

The aim of this paper is to compare outcomes between high-dose-rate interstitial brachytherapy (HDR-BT) monotherapy and image-guided intensity-modulated radiotherapy (IG-IMRT) for localized prostate cancer. We examined 353 HDR-BT and 270 IG-IMRT patients. To reduce background selection bias, we used the method of inverse probability treatment weighting (IPTW) with propensity scores. The actuarial five-year biochemical failure-free survival rates were 92.9% and 96.7% (p = 0.1847; p = 0.077 in IPTW) for HDR-BT and IG-IMRT, respectively; they were 100% and 95.8% (p = 0.286) for the low-risk group, 95.6% and 92% (p = 0.42) for the intermediate-risk group, 90.4% and 84.9% (p = 0.1059; p = 0.04 in IPTW) for the high-risk group, and 87.1% and 89.2% (p = 0.3816) for the very-high-risk group. In the assessment of accumulated incidences of grade ≥ 2 toxicity (Common Terminology Criteria for Adverse Events version 4.0) at five years, HDR-BT monotherapy showed higher genitourinary toxicity (11.9%) than IG-IMRT (3.3%) (p < 0.0001). The gastrointestinal toxicity was equivalent for HDR-BT (2.3%) and IG-IMRT (5.5%) (p = 0.063). No Grade 4 or 5 toxicity was detected in either modality. HDR-BT showed higher genitourinary toxicity than IG-IMRT. HDR-BT and IG-IMRT showed equivalent outcomes in low-, intermediate-, and very-high-risk groups. For high-risk patients, HDR-BT showed potential to improve prostate-specific antigen (PSA) control rate compared to IG-IMRT. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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13 pages, 1432 KiB

Open AccessFeature PaperArticle

The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation

by Fiona K. Middleton, John R. Pollard and Nicola J. Curtin

Cancers 2018, 10(8), 275; https://doi.org/10.3390/cancers10080275 - 20 Aug 2018

Cited by 30 | Viewed by 5610

Abstract

Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. Mutations in p53, critical for G1 checkpoint control, are common in cancer and predicted to confer vulnerability to ATR inhibitors. [...] Read more.

Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. Mutations in p53, critical for G1 checkpoint control, are common in cancer and predicted to confer vulnerability to ATR inhibitors. Reported data on the impact of p53 status are variable possibly because of the use of unmatched cells and surrogate endpoints of survival. The cytotoxicity of VE-821 alone and its ability to potentiate radiation and gemcitabine cytotoxicity was determined in isogenic and unmatched p53 wild-type (wt) and null/mutant cells, as well as immortalised nonmalignant MCF10 (immortalised non-neoplastic) cells, by colony-forming assay. The effect on cell cycle checkpoints was determined by flow cytometry. The isogenic p53 defective cells were not more sensitive to VE-821 alone. Defective p53 consistently conferred greater chemo- and radiosensitisation, particularly at high dose levels in isogenic cells but not unmatched cells. VE-821 did not sensitise MCF10 cells. We conclude that p53 status is just one factor contributing to chemo- and radiosensitisation by ATR inhibition, the lack of chemo- or radiosensitisation in the noncancerous cells suggests an element of tumour-specificity that warrants further investigation. The greater sensitisation at high-dose irradiation suggests that ATR inhibitors may be most effective with hypofractionated radiotherapy. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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Review

Jump to: Research

15 pages, 805 KiB

Open AccessReview

The Radiobiological Effects of Proton Beam Therapy: Impact on DNA Damage and Repair

by Eirini Terpsi Vitti and Jason L Parsons

Cancers 2019, 11(7), 946; https://doi.org/10.3390/cancers11070946 - 5 Jul 2019

Cited by 85 | Viewed by 8247

Abstract

Proton beam therapy (PBT) offers significant benefit over conventional (photon) radiotherapy for the treatment of a number of different human cancers, largely due to the physical characteristics. In particular, the low entrance dose and maximum energy deposition in depth at a well-defined region, [...] Read more.

Proton beam therapy (PBT) offers significant benefit over conventional (photon) radiotherapy for the treatment of a number of different human cancers, largely due to the physical characteristics. In particular, the low entrance dose and maximum energy deposition in depth at a well-defined region, the Bragg peak, can spare irradiation of proximal healthy tissues and organs at risk when compared to conventional radiotherapy using high-energy photons. However, there are still biological uncertainties reflected in the relative biological effectiveness that varies along the track of the proton beam as a consequence of the increases in linear energy transfer (LET). Furthermore, the spectrum of DNA damage induced by protons, particularly the generation of complex DNA damage (CDD) at high-LET regions of the distal edge of the Bragg peak, and the specific DNA repair pathways dependent on their repair are not entirely understood. This knowledge is essential in understanding the biological impact of protons on tumor cells, and ultimately in devising optimal therapeutic strategies employing PBT for greater clinical impact and patient benefit. Here, we provide an up-to-date review on the radiobiological effects of PBT versus photon radiotherapy in cells, particularly in the context of DNA damage. We also review the DNA repair pathways that are essential in the cellular response to PBT, with a specific focus on the signaling and processing of CDD induced by high-LET protons. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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13 pages, 1871 KiB

Open AccessReview

Value of Three-Dimensional Imaging Systems for Image-Guided Carbon Ion Radiotherapy

by Yang Li, Yoshiki Kubota, Mutsumi Tashiro and Tatsuya Ohno

Cancers 2019, 11(3), 297; https://doi.org/10.3390/cancers11030297 - 2 Mar 2019

Cited by 17 | Viewed by 4213

Abstract

Carbon ion radiotherapy (C-ion RT) allows excellent dose distribution because of the Bragg Peak. Compared with conventional radiotherapy, it delivers a higher dose with a smaller field. However, the dose distribution is sensitive to anatomical changes. Imaging technologies are necessary to reduce uncertainties [...] Read more.

Carbon ion radiotherapy (C-ion RT) allows excellent dose distribution because of the Bragg Peak. Compared with conventional radiotherapy, it delivers a higher dose with a smaller field. However, the dose distribution is sensitive to anatomical changes. Imaging technologies are necessary to reduce uncertainties during treatment, especially for hypofractionated and adaptive radiotherapy (ART). In-room computed tomography (CT) techniques, such as cone-beam CT (CBCT) and CT-on-rails are routinely used in photon centers and play a key role in improving treatment accuracy. For C-ion RT, there is an increasing demand for a three-dimensional (3D) image-guided system because of the limitations of the present two-dimensional (2D) imaging verification technology. This review discusses the current imaging system used in carbon ion centers and the potential benefits of a volumetric image-guided system. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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12 pages, 244 KiB

Open AccessReview

Targeted Radionuclide Therapy: New Advances for Improvement of Patient Management and Response

by Javian Malcolm, Nadia Falzone, Boon Q. Lee and Katherine A. Vallis

Cancers 2019, 11(2), 268; https://doi.org/10.3390/cancers11020268 - 25 Feb 2019

Cited by 39 | Viewed by 5725

Abstract

Compared to external beam radiotherapy, targeted radionuclide therapy (TRT) allows for systemic radiation treatment of metastatic lesions. Published work on recent strategies to improve patient management and response to TRT through individualising patient treatment, modifying treatment pharmacokinetics and increasing anticancer potency are discussed [...] Read more.

Compared to external beam radiotherapy, targeted radionuclide therapy (TRT) allows for systemic radiation treatment of metastatic lesions. Published work on recent strategies to improve patient management and response to TRT through individualising patient treatment, modifying treatment pharmacokinetics and increasing anticancer potency are discussed in this review, with a special focus on the application of clinically evaluated radiolabelled ligands and peptides in the treatment of neuroendocrine and prostate cancers. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

23 pages, 1536 KiB

Open AccessFeature PaperReview

Mechanistic Modelling of Radiation Responses

by Stephen J. McMahon and Kevin M. Prise

Cancers 2019, 11(2), 205; https://doi.org/10.3390/cancers11020205 - 10 Feb 2019

Cited by 58 | Viewed by 6810

Abstract

Radiobiological modelling has been a key part of radiation biology and therapy for many decades, and many aspects of clinical practice are guided by tools such as the linear-quadratic model. However, most of the models in regular clinical use are abstract and empirical, [...] Read more.

Radiobiological modelling has been a key part of radiation biology and therapy for many decades, and many aspects of clinical practice are guided by tools such as the linear-quadratic model. However, most of the models in regular clinical use are abstract and empirical, and do not provide significant scope for mechanistic interpretation or making predictions in novel cell lines or therapies. In this review, we will discuss the key areas of ongoing mechanistic research in radiation biology, including physical, chemical, and biological steps, and review a range of mechanistic modelling approaches which are being applied in each area, highlighting the possible opportunities and challenges presented by these techniques. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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15 pages, 1180 KiB

Open AccessReview

Integrating Small Animal Irradiators with Functional Imaging for Advanced Preclinical Radiotherapy Research

by Mihaela Ghita, Kathryn H. Brown, Olivia J. Kelada, Edward E. Graves and Karl T. Butterworth

Cancers 2019, 11(2), 170; https://doi.org/10.3390/cancers11020170 - 1 Feb 2019

Cited by 23 | Viewed by 4451

Abstract

Translational research aims to provide direct support for advancing novel treatment approaches in oncology towards improving patient outcomes. Preclinical studies have a central role in this process and the ability to accurately model biological and physical aspects of the clinical scenario in radiation [...] Read more.

Translational research aims to provide direct support for advancing novel treatment approaches in oncology towards improving patient outcomes. Preclinical studies have a central role in this process and the ability to accurately model biological and physical aspects of the clinical scenario in radiation oncology is critical to translational success. The use of small animal irradiators with disease relevant mouse models and advanced in vivo imaging approaches offers unique possibilities to interrogate the radiotherapy response of tumors and normal tissues with high potential to translate to improvements in clinical outcomes. The present review highlights the current technology and applications of small animal irradiators, and explores how these can be combined with molecular and functional imaging in advanced preclinical radiotherapy research. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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13 pages, 1582 KiB

Open AccessReview

Stereotactic Radiotherapy for Oligometastasis

by Sotaro Otake and Taichiro Goto

Cancers 2019, 11(2), 133; https://doi.org/10.3390/cancers11020133 - 23 Jan 2019

Cited by 46 | Viewed by 6563

Abstract

Oligometastatic disease is defined as “a condition with a few metastases arising from tumors that have not acquired a potential for widespread metastases.” Its behavior suggests a transitional malignant state somewhere between localized and metastatic cancer. Treatment of oligometastatic disease is expected to [...] Read more.

Oligometastatic disease is defined as “a condition with a few metastases arising from tumors that have not acquired a potential for widespread metastases.” Its behavior suggests a transitional malignant state somewhere between localized and metastatic cancer. Treatment of oligometastatic disease is expected to achieve long-term local control and to improve survival. Historically, patients with oligometastases have often undergone surgical resection since it was anecdotally believed that surgical resection could result in progression-free or overall survival benefits. To date, no prospective randomized trials have demonstrated surgery-related survival benefits. Short courses of highly focused, extremely high-dose radiotherapies (e.g., stereotactic radiosurgery and stereotactic ablative body radiotherapy (SABR)) have frequently been used as alternatives to surgery for treatment of oligometastasis. A randomized study has demonstrated the overall survival benefits of stereotactic radiosurgery for solitary brain metastasis. Following the success of stereotactic radiosurgery, SABR has been widely accepted for treating extracranial metastases, considering its efficacy and minimum invasiveness. In this review, we discuss the history of and rationale for the local treatment of oligometastases and probe into the implementation of SABR for oligometastatic disease. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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23 pages, 5131 KiB

Open AccessReview

Emerging Functional Imaging Biomarkers of Tumour Responses to Radiotherapy

by Alan Campbell, Laura M. Davis, Sophie K. Wilkinson and Richard L. Hesketh

Cancers 2019, 11(2), 131; https://doi.org/10.3390/cancers11020131 - 23 Jan 2019

Cited by 8 | Viewed by 4337

Abstract

Tumour responses to radiotherapy are currently primarily assessed by changes in size. Imaging permits non-invasive, whole-body assessment of tumour burden and guides treatment options for most tumours. However, in most tumours, changes in size are slow to manifest and can sometimes be difficult [...] Read more.

Tumour responses to radiotherapy are currently primarily assessed by changes in size. Imaging permits non-invasive, whole-body assessment of tumour burden and guides treatment options for most tumours. However, in most tumours, changes in size are slow to manifest and can sometimes be difficult to interpret or misleading, potentially leading to prolonged durations of ineffective treatment and delays in changing therapy. Functional imaging techniques that monitor biological processes have the potential to detect tumour responses to treatment earlier and refine treatment options based on tumour biology rather than solely on size and staging. By considering the biological effects of radiotherapy, this review focusses on emerging functional imaging techniques with the potential to augment morphological imaging and serve as biomarkers of early response to radiotherapy. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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20 pages, 1913 KiB

Open AccessReview

Hyperthermia: The Optimal Treatment to Overcome Radiation Resistant Hypoxia

by Pernille B. Elming, Brita S. Sørensen, Arlene L. Oei, Nicolaas A.P. Franken, Johannes Crezee, Jens Overgaard and Michael R. Horsman

Cancers 2019, 11(1), 60; https://doi.org/10.3390/cancers11010060 - 9 Jan 2019

Cited by 157 | Viewed by 8710

Abstract

Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been [...] Read more.

Regions of low oxygenation (hypoxia) are a characteristic feature of solid tumors, and cells existing in these regions are a major factor influencing radiation resistance as well as playing a significant role in malignant progression. Consequently, numerous pre-clinical and clinical attempts have been made to try and overcome this hypoxia. These approaches involve improving oxygen availability, radio-sensitizing or killing the hypoxic cells, or utilizing high LET (linear energy transfer) radiation leading to a lower OER (oxygen enhancement ratio). Interestingly, hyperthermia (heat treatments of 39–45 °C) induces many of these effects. Specifically, it increases blood flow thereby improving tissue oxygenation, radio-sensitizes via DNA repair inhibition, and can kill cells either directly or indirectly by causing vascular damage. Combining hyperthermia with low LET radiation can even result in anti-tumor effects equivalent to those seen with high LET. The various mechanisms depend on the time and sequence between radiation and hyperthermia, the heating temperature, and the time of heating. We will discuss the role these factors play in influencing the interaction between hyperthermia and radiation, and summarize the randomized clinical trials showing a benefit of such a combination as well as suggest the potential future clinical application of this combination. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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23 pages, 1475 KiB

Open AccessReview

Glioblastoma’s Next Top Model: Novel Culture Systems for Brain Cancer Radiotherapy Research

by Seamus Caragher, Anthony J. Chalmers and Natividad Gomez-Roman

Cancers 2019, 11(1), 44; https://doi.org/10.3390/cancers11010044 - 4 Jan 2019

Cited by 62 | Viewed by 10826

Abstract

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research [...] Read more.

Glioblastoma (GBM), the most common and aggressive primary brain tumor in adults, remains one of the least treatable cancers. Current standard of care—combining surgical resection, radiation, and alkylating chemotherapy—results in a median survival of only 15 months. Despite decades of investment and research into the development of new therapies, most candidate anti-glioma compounds fail to translate into effective treatments in clinical trials. One key issue underlying this failure of therapies that work in pre-clinical models to generate meaningful improvement in human patients is the profound mismatch between drug discovery systems—cell cultures and mouse models—and the actual tumors they are supposed to imitate. Indeed, current strategies that evaluate the effects of novel treatments on GBM cells in vitro fail to account for a wide range of factors known to influence tumor growth. These include secreted factors, the brain’s unique extracellular matrix, circulatory structures, the presence of non-tumor brain cells, and nutrient sources available for tumor metabolism. While mouse models provide a more realistic testing ground for potential therapies, they still fail to account for the full complexity of tumor-microenvironment interactions, as well as the role of the immune system. Based on the limitations of current models, researchers have begun to develop and implement novel culture systems that better recapitulate the complex reality of brain tumors growing in situ. A rise in the use of patient derived cells, creative combinations of added growth factors and supplements, may provide a more effective proving ground for the development of novel therapies. This review will summarize and analyze these exciting developments in 3D culturing systems. Special attention will be paid to how they enhance the design and identification of compounds that increase the efficacy of radiotherapy, a bedrock of GBM treatment. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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24 pages, 716 KiB

Open AccessReview

Radiotherapy as a New Player in Immuno-Oncology

by Shang-Jui Wang and Bruce Haffty

Cancers 2018, 10(12), 515; https://doi.org/10.3390/cancers10120515 - 14 Dec 2018

Cited by 22 | Viewed by 5022

Abstract

Recent development in radiation biology has revealed potent immunogenic properties of radiotherapy in cancer treatments. However, antitumor immune effects of radiotherapy are limited by the concomitant induction of radiation-dependent immunosuppressive effects. In the growing era of immunotherapy, combining radiotherapy with immunomodulating agents has [...] Read more.

Recent development in radiation biology has revealed potent immunogenic properties of radiotherapy in cancer treatments. However, antitumor immune effects of radiotherapy are limited by the concomitant induction of radiation-dependent immunosuppressive effects. In the growing era of immunotherapy, combining radiotherapy with immunomodulating agents has demonstrated enhancement of radiation-induced antitumor immune activation that correlated with improved treatment outcomes. Yet, how to optimally deliver combination therapy regarding dose-fractionation and timing of radiotherapy is largely unknown. Future prospective testing to fine-tune this promising combination of radiotherapy and immunotherapy is warranted. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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15 pages, 735 KiB

Open AccessReview

Developments in Stereotactic Body Radiotherapy

by Anoop Haridass

Cancers 2018, 10(12), 497; https://doi.org/10.3390/cancers10120497 - 7 Dec 2018

Cited by 15 | Viewed by 4690

Abstract

Stereotactic body radiotherapy is the technique of accurately delivering high doses of radiotherapy to small volume targets in a single or small number of sessions. The high biological effective dose of this treatment is reflected in the high rates of local control achieved [...] Read more.

Stereotactic body radiotherapy is the technique of accurately delivering high doses of radiotherapy to small volume targets in a single or small number of sessions. The high biological effective dose of this treatment is reflected in the high rates of local control achieved across multiple tumour sites. Toxicity of the treatment can be significant and ongoing prospective trials will help define the utility of this treatment as an alternative to surgery in treating primary tumours and oligometastatic disease. Longer follow-up and survival data from prospective trials will be essential in determining the value of this resource-intensive treatment. The opportunity to combine this treatment with systemic therapies and its potential synergy with immunotherapy opens up interesting avenues for research in the future. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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18 pages, 1532 KiB

Open AccessReview

Focal Salvage Treatment of Radiorecurrent Prostate Cancer: A Narrative Review of Current Strategies and Future Perspectives

by Marieke Van Son, Max Peters, Marinus Moerland, Linda Kerkmeijer, Jan Lagendijk and Jochem Van der Voort van Zyp

Cancers 2018, 10(12), 480; https://doi.org/10.3390/cancers10120480 - 3 Dec 2018

Cited by 24 | Viewed by 4310

Abstract

Over the last decades, primary prostate cancer radiotherapy saw improving developments, such as more conformal dose administration and hypofractionated treatment regimens. Still, prostate cancer recurrences after whole-gland radiotherapy remain common, especially in patients with intermediate- to high-risk disease. The vast majority of these [...] Read more.

Over the last decades, primary prostate cancer radiotherapy saw improving developments, such as more conformal dose administration and hypofractionated treatment regimens. Still, prostate cancer recurrences after whole-gland radiotherapy remain common, especially in patients with intermediate- to high-risk disease. The vast majority of these patients are treated palliatively with androgen deprivation therapy (ADT), which exposes them to harmful side-effects and is only effective for a limited amount of time. For patients with a localized recurrent tumor and no signs of metastatic disease, local treatment with curative intent seems more rational. However, whole-gland salvage treatments such as salvage radiotherapy or salvage prostatectomy are associated with significant toxicity and are, therefore, uncommonly performed. Treatments that are solely aimed at the recurrent tumor itself, thereby better sparing the surrounding organs at risk, potentially provide a safer salvage treatment option in terms of toxicity. To achieve such tumor-targeted treatment, imaging developments have made it possible to better exclude metastatic disease and accurately discriminate the tumor. Currently, focal salvage treatment is being performed with different modalities, including brachytherapy, cryotherapy, high-intensity focused ultrasound (HIFU), and stereotactic body radiation therapy (SBRT). Oncologic outcomes seem comparable to whole-gland salvage series, but with much lower toxicity rates. In terms of oncologic control, these results will improve further with better understanding of patient selection. Other developments, such as high-field diagnostic MRI and live adaptive MRI-guided radiotherapy, will further improve precision of the treatment. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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13 pages, 673 KiB

Open AccessReview

Human Glioma Migration and Infiltration Properties as a Target for Personalized Radiation Medicine

by Michaela Wank, Daniela Schilling, Thomas E. Schmid, Bernhard Meyer, Jens Gempt, Melanie Barz, Jürgen Schlegel, Friederike Liesche, Kerstin A. Kessel, Benedikt Wiestler, Stefanie Bette, Claus Zimmer and Stephanie E. Combs

Cancers 2018, 10(11), 456; https://doi.org/10.3390/cancers10110456 - 20 Nov 2018

Cited by 41 | Viewed by 4159

Abstract

Gliomas are primary brain tumors that present the majority of malignant adult brain tumors. Gliomas are subdivided into low- and high-grade tumors. Despite extensive research in recent years, the prognosis of malignant glioma patients remains poor. This is caused by naturally highly infiltrative [...] Read more.

Gliomas are primary brain tumors that present the majority of malignant adult brain tumors. Gliomas are subdivided into low- and high-grade tumors. Despite extensive research in recent years, the prognosis of malignant glioma patients remains poor. This is caused by naturally highly infiltrative capacities as well as high levels of radio- and chemoresistance. Additionally, it was shown that low linear energy transfer (LET) irradiation enhances migration and invasion of several glioma entities which might counteract today’s treatment concepts. However, this finding is discussed controversially. In the era of personalized medicine, this controversial data might be attributed to the patient-specific heterogeneity that ultimately could be used for treatment. Thus, current developments in glioma therapy should be seen in the context of intrinsic and radiation-enhanced migration and invasion. Due to the natural heterogeneity of glioma cells and different radiation responses, a personalized radiation treatment concept is suggested and alternative radiation concepts are discussed. Full article

(This article belongs to the Special Issue New Developments in Radiotherapy)

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