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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 30764

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Dr. Andrea Mairani

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Guest Editor

Heidelberg Ion Beam Therapy Center (HIT), Heidelberg, Germany
Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany
National Center of Oncological Hadrontherapy, Pavia, Italy
Interests: Monte Carlo; fast computing; treatment planning; biophysical modelling; novel particle therapy modalities

Dr. Ivana Dokic

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Guest Editor

National Center for Tumor Diseases (NCT); Heidelberg Ion-Beam Therapy Center (HIT); Heidelberg University Hospital (UKHD), Heidelberg, Germany
Interests: particle radiobiology; radiotherapy; cancer research; immunotherapy; personalized cancer treatment
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Dr. Semi B. Harrabi

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Guest Editor

Heidelberg Ion Beam Therapy Center (HIT), Department of Radiation Oncology, University Hospital of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
Interests: pediatric oncology; pediatric brain tumors; neuro-oncology; proton beam therapy; ion beam therapy; high-precision radiotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues

Charged particle therapy (CPT) is an emerging field in cancer therapy, and with recent technological advances, cutting-edge modalities are more accessible to the general public than ever. As opposed to conventional photon-based radiotherapy, light and heavy ion beams promise more favorable therapeutic properties for cancer therapy, affording clinicians the power to deliver radiation doses to tumors with high precision and conformity while significantly sparing surrounding healthy tissues and critical anatomic structures. Through application of state-of-the-art delivery systems, such as intensity modulated particle therapy, radio-resistant diseases with poor prognosis using standard care can be effectively treated.

To fully exploit CPT with the utmost precision, modeling and predicting biophysical processes elicited from particle beam interactions within the human body must be performed on both macroscopic and microscopic scales. Moreover, with numerous proton facilities sprouting worldwide, recent reports emphasize the urgency of improving current clinical practices in handling biological effect uncertainty. To this end, we believe developing and integrating advanced computational methods and biological perspectives for CPT into clinical environments is vital.

In this Special Issue, we welcome submissions from the following categories:

Novel particle therapy modalities such as helium, oxygen ion beams, combined ion treatments, FLASH, etc.;
Advanced computation and optimization techniques in particle therapy (e.g. analytical, Monte Carlo, machine learning);
Breakthroughs in patient-specific particle therapy treatments;
Novel insights in biological response of tumors and normal tissues to particle therapy;
Expansion and evolution of fundamental biophysical knowledge of radiation induced effects using particle beams through biological experimental study and/or implementing sophisticated models to describe biological phenomena;
Assessment and interpretation of clinical data to link physical, biological, and clinical endpoints to treatment outcome in CPT.

Dr. Andrea Mairani
Dr. Dokic Ivana
Dr. Semi B. Harrabi
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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 2900 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

particle therapy
treatment planning
Monte Carlo
fast computing
biophysical models
quality assurance
patients’ outcome
normal tissue reaction
radiobiology

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Published Papers (9 papers)

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Research

Jump to: Review

18 pages, 4457 KiB

Open AccessArticle

Novel Carbon Ion and Proton Partial Irradiation of Recurrent Unresectable Bulky Tumors (Particle-PATHY): Early Indication of Effectiveness and Safety

by Slavisa Tubin, Piero Fossati, Antonio Carlino, Giovanna Martino, Joanna Gora, Markus Stock and Eugen Hug

Cancers 2022, 14(9), 2232; https://doi.org/10.3390/cancers14092232 - 29 Apr 2022

Cited by 13 | Viewed by 3008

Abstract

Background: We present the early results of a novel partial bulky-tumor irradiation using particles for patients with recurrent unresectable bulky tumors who failed previous state-of-the-art treatments. Methods: First, eleven consecutive patients were treated from March 2020 until December 2021. The targeted Bystander Tumor Volume (BTV) was created by subtracting 1 cm from Gross Tumor Volume (GTV) surface. It reflected approximately 30% of the central GTV volume and was irradiated with 30–45 Gy RBE (Relative Biological Effectiveness) in three consecutive fractions. The Peritumoral Immune Microenvironment (PIM) surrounding the GTV, containing nearby tissues, blood-lymphatic vessels and lymph nodes, was considered an organ at risk (OAR) and protected by highly conservative constraints. Results: With the median follow up of 6.3 months, overall survival was 64% with a median survival of 6.7 months; 46% of patients were progression-free. The average tumor volume regression was 61% from the initial size. The symptom control rate was 91%, with an average increase of the Karnofsky Index of 20%. The abscopal effect has been observed in 60% of patients. Conclusions: Partial bulky-tumor irradiation is an effective, safe and well tolerated treatment for patients with unresectable recurrent bulky disease. Abscopal effects elucidate an immunogenic pathway contribution. Extensive tumor shrinkage in some patients might permit definitive treatment—otherwise previously impossible. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

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13 pages, 951 KiB

Open AccessArticle

Prospective Study of Proton Therapy for Lung Cancer Patients with Poor Lung Function or Pulmonary Fibrosis

by Jae Myoung Noh, Hongseok Yoo, Woojin Lee, Hye Yun Park, Sun Hye Shin and Hongryull Pyo

Cancers 2022, 14(6), 1445; https://doi.org/10.3390/cancers14061445 - 11 Mar 2022

Cited by 3 | Viewed by 2565

Abstract

PBT has a unique depth–dose curve with a Bragg peak that enables one to reduce the dose to normal lung tissue. We prospectively enrolled 54 patients with non-small cell lung cancer treated with definitive PBT. The inclusion criteria were forced expiratory volume in 1 s (FEV1) ≤ 1.0 L or FEV1 ≤ 50% of predicted or diffusing capacity of the lungs for carbon monoxide (DLco) ≤ 50%, or pulmonary fibrosis. The primary endpoint was grade ≥ 3 pulmonary toxicity, and secondary endpoints were changes in pulmonary function and quality of life. The median age was 71.5 years (range, 57–87). Fifteen (27.8%) and fourteen (25.9%) patients had IPF and combined pulmonary fibrosis and emphysema, respectively. The median predicted forced vital capacity (FVC), FEV1, and DLco were 77% (range, 42–104%), 66% (range, 31–117%), and 46% (range, 23–94%), respectively. During the follow-up (median, 14.7 months), seven (13.0%) patients experienced grade ≥ 3 pulmonary toxicity. Seven months after the completion of PBT, patients with IPF or non-IPF interstitial lung disease (ILD) experienced a decrease in the FVC but the decrease in DLco was not significant. Under careful monitoring by pulmonologists, PBT could be a useful treatment modality for lung cancer patients with poor lung function or pulmonary fibrosis. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

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13 pages, 659 KiB

Open AccessArticle

Particle Beam Therapy Tolerance and Outcome on Patients with Autoimmune Diseases: A Single Institution Matched Case–Control Study

by Giulia Riva, Barbara Vischioni, Sara Gandini, Stefano Cavalieri, Sara Ronchi, Amelia Barcellini, Maria Bonora, Agnieszka Chalaszczyk, Rossana Ingargiola, Viviana Vitolo, Maria Rosaria Fiore, Alberto Iannalfi and Ester Orlandi

Cancers 2021, 13(20), 5183; https://doi.org/10.3390/cancers13205183 - 15 Oct 2021

Cited by 2 | Viewed by 1447

Abstract

It is unclear whether autoimmune diseases (ADs) may predispose patients to higher radiation-induced toxicity, and no data are available regarding particle therapy. Our objective was to determine if cancer patients with ADs have a higher incidence of complications after protons (PT) or carbon ion (CIRT) therapy. METHODS. In our retrospective monocentric study, 38 patients with ADs over 1829 patients were treated with particle therapy between 2011 and 2020. Thirteen patients had collagen vascular disease (CVD), five an inflammatory bowel disease (IBD) and twenty patients an organ-specific AD. Each patient was matched with two control patients without ADs on the basis of type/site of cancer, type of particle treatment, age, sex, hypertension and/or diabetes and previous surgery. RESULTS. No G4–5 complications were reported. In the AD group, the frequency of acute grade 3 (G3) toxicity was higher than in the control group (15.8% vs. 2.6%, p = 0.016). Compared to their matched controls, CVD–IBD patients had a higher frequency of G3 acute complications (27.7 vs. 2.6%, p = 0.002). There was no difference between AD patients (7.9%) and controls (2.6%) experiencing late G3 toxicity (p = 0.33). The 2 years disease-free survival was lower in AD patients than in controls (74% vs. 91%, p = 0.01), although the differences in terms of survival were not significant. CONCLUSIONS. G3 acute toxicity was more frequently reported in AD patients after PT or CIRT. Since no severe G4–G5 events were reported and in consideration of the benefit of particle therapy for selected cancers, we conclude that particle therapy should be not discouraged for patients with ADs. Further prospective studies are warranted to gain insight into toxicity in cancer patients with ADs enrolled for particle therapy. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

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14 pages, 4099 KiB

Open AccessArticle

Mapping the Relative Biological Effectiveness of Proton, Helium and Carbon Ions with High-Throughput Techniques

by Lawrence Bronk, Fada Guan, Darshana Patel, Duo Ma, Benjamin Kroger, Xiaochun Wang, Kevin Tran, Joycelyn Yiu, Clifford Stephan, Jürgen Debus, Amir Abdollahi, Oliver Jäkel, Radhe Mohan, Uwe Titt and David R. Grosshans

Cancers 2020, 12(12), 3658; https://doi.org/10.3390/cancers12123658 - 5 Dec 2020

Cited by 21 | Viewed by 3290

Abstract

Large amounts of high quality biophysical data are needed to improve current biological effects models but such data are lacking and difficult to obtain. The present study aimed to more efficiently measure the spatial distribution of relative biological effectiveness (RBE) of charged particle beams using a novel high-accuracy and high-throughput experimental platform. Clonogenic survival was selected as the biological endpoint for two lung cancer cell lines, H460 and H1437, irradiated with protons, carbon, and helium ions. Ion-specific multi-step microplate holders were fabricated such that each column of a 96-well microplate is spatially situated at a different location along a particle beam path. Dose, dose-averaged linear energy transfer (LET_d), and dose-mean lineal energy (y_d) were calculated using an experimentally validated Geant4-based Monte Carlo system. Cells were irradiated at the Heidelberg Ion Beam Therapy Center (HIT). The experimental results showed that the clonogenic survival curves of all tested ions were y_d-dependent. Both helium and carbon ions achieved maximum RBEs within specific y_d ranges before biological efficacy declined, indicating an overkill effect. For protons, no overkill was observed, but RBE increased distal to the Bragg peak. Measured RBE profiles strongly depend on the physical characteristics such as y_d and are ion specific. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

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8 pages, 1473 KiB

Open AccessArticle

Kinetics of Prostate-Specific Antigen after Carbon Ion Radiotherapy for Prostate Cancer

by Narisa Dewi Maulany Darwis, Takahiro Oike, Hidemasa Kawamura, Masahiro Kawahara, Nobuteru Kubo, Hiro Sato, Yuhei Miyasaka, Hiroyuki Katoh, Hitoshi Ishikawa, Hiroshi Matsui, Yoshiyuki Miyazawa, Kazuto Ito, Kazuhiro Suzuki, Soehartati Gondhowiardjo, Takashi Nakano and Tatsuya Ohno

Cancers 2020, 12(3), 589; https://doi.org/10.3390/cancers12030589 - 4 Mar 2020

Cited by 4 | Viewed by 3710

Abstract

This study aimed to first elucidate prostate-specific antigen (PSA) kinetics in prostate cancer patients treated with carbon ion radiotherapy (CIRT). From 2010 to 2015, 131 patients with prostate adenocarcinoma treated with CIRT (57.6 Gy relative biological effectiveness (RBE) in 16 fractions) alone were recruited. PSA was measured at 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54, and 60 months post-CIRT. PSA bounce was defined as PSA increase over a cutoff followed by spontaneous decrease to or below the pre-bounce nadir. PSA failure was determined using the Phoenix criteria (nadir + 2.0 ng/mL). As a result, non-failure-associated temporary increase in PSA exhibited two distinct patterns, namely a classical bounce and a surge at one month. PSA bounce of ≥0.2 ng/mL was observed in 55.7% of the patients. Bounce amplitude was <2.0 ng/mL in 97.6% of cases. Bounce occurred significantly earlier than PSA failure. Younger age was a significant predictor of bounce occurrence. Bounce positivity was a significant predictor of favorable 5-year PSA failure-free survival. Meanwhile, a PSA surge of ≥0.2 ng/mL was observed in 67.9% of patients. Surge amplitude was significantly larger than bounce amplitude. Larger prostate volume was a significant predictor of PSA surge occurrence. PSA surge positivity did not significantly predict PSA failure. In summary, PSA bounce was distinguishable from PSA failure with regard to timing of occurrence and amplitude (earlier and lower for bounce, respectively). These data are useful for post-CIRT surveillance of prostate cancer patients. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

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17 pages, 2840 KiB

Open AccessArticle

Personalized Assessment of Normal Tissue Radiosensitivity via Transcriptome Response to Photon, Proton and Carbon Irradiation in Patient-Derived Human Intestinal Organoids

by Ali Nowrouzi, Mathieu G. Sertorio, Mahdi Akbarpour, Maximillian Knoll, Damir Krunic, Matthew Kuhar, Christian Schwager, Stephan Brons, Jürgen Debus, Susanne I. Wells, James M. Wells and Amir Abdollahi

Cancers 2020, 12(2), 469; https://doi.org/10.3390/cancers12020469 - 18 Feb 2020

Cited by 13 | Viewed by 4713

Abstract

Radiation-induced normal tissue toxicity often limits the curative treatment of cancer. Moreover, normal tissue relative biological effectiveness data for high-linear energy transfer particles are urgently needed. We propose a strategy based on transcriptome analysis of patient-derived human intestinal organoids (HIO) to determine molecular surrogates for radioresponse of gastrointestinal (GI) organs at risk in a personalized manner. HIO were generated from induced pluripotent stem cells (iPSC), which were derived from skin biopsies of three patients, including two patients with FANCA deficiency as a paradigm for enhanced radiosensitivity. For the two Fanconi anemia (FA) patients (HIO-104 and 106, previously published as FA-A#1 IND-iPS1 and FA-A#2 IND-iPS3), FANCA expression was reconstituted as a prerequisite for generation of HIO via lentiviral expression of a doxycycline inducible construct. For radiosensitivity analysis, FANCA deficient and FANCA rescued as well as wtHIO were sham treated or irradiated with 4Gy photon, proton or carbon ions at HIT, respectively. Immunofluorescence staining of HIO for 53BP1-foci was performed 1 h post IR and gene expression analyses was performed 12 and 48 h post IR. 53BP1-foci numbers and size correlated with the higher RBE of carbon ions. A FANCA dependent differential gene expression in response to radiation was found (p < 0.01, ANOVA; n = 1071 12 h; n = 1100 48 h). Pathways associated with FA and DNA-damage repair i.e., transcriptional coupled nucleotide excision repair, homology-directed repair and translational synthesis were found to be differentially regulated in FANCA deficient HIO. Next, differential regulated genes were investigated as a function of radiation quality (RQ, p < 0.05, ANOVA; n = 742 12 h; n = 553 48 h). Interestingly, a gradual increase or decrease of gene expression was found to correlate with the three main qualities, from photon to proton and carbon irradiation. Clustering separated high-linear energy transfer irradiation with carbons from proton and photon irradiation. Genes associated with dual incision steps of TC-NER were differentially regulated in photon vs. proton and carbon irradiation. Consequently, SUMO3, ALC1, POLE4, PCBP4, MUTYH expression correlated with the higher RBE of carbon ions. An interaction between the two studied parameters FA and RQ was identified (p < 0.01, 2-way ANOVA n = 476). A comparison of genes regulated as a function of FA, RQ and RBE suggest a role for p53 interacting genes BRD7, EWSR1, FBXO11, FBXW8, HMGB1, MAGED2, PCBP4, and RPS27 as modulators of FA in response to radiation. This proof of concept study demonstrates that patient tailored evaluation of GI response to radiation is feasible via generation of HIO and comparative transcriptome profiling. This methodology can now be further explored for a personalized assessment of GI radiosensitivity and RBE estimation. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

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12 pages, 2886 KiB

Open AccessArticle

Rectum Dose Constraints for Carbon Ion Therapy: Relative Biological Effectiveness Model Dependence in Relation to Clinical Outcomes

by Kyungdon Choi, Silvia Molinelli, Stefania Russo, Alfredo Mirandola, Maria Rosaria Fiore, Barbara Vischioni, Piero Fossati, Rachele Petrucci, Irene Turturici, Jon Espen Dale, Francesca Valvo, Mario Ciocca and Andrea Mairani

Cancers 2020, 12(1), 46; https://doi.org/10.3390/cancers12010046 - 21 Dec 2019

Cited by 14 | Viewed by 3050

Abstract

The clinical application of different relative biological effectiveness (RBE) models for carbon ion RBE-weighted dose calculation hinders a global consensus in defining normal tissue constraints. This work aims to update the local effect model (LEM)-based constraints for the rectum using microdosimetric kinetic model (mMKM)-defined values, relying on RBE translation and the analysis of long-term clinical outcomes. LEM-optimized plans of treated patients, having suffered from prostate adenocarcinoma (n = 22) and sacral chordoma (n = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (D_LEM|v and D_MKM|v) was fitted to translate new LEM-based constraints. Normal tissue complication probability (NTCP) values, predicting late rectal toxicity, were obtained by applying published parameters. No late rectal toxicity events were reported within the patient cohort. The rectal toxicity outcome was confirmed using dosimetric analysis: D_MKMVHs lay largely below original constraints; the translated D_LEM|v values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal D_MKM|v of the rectum volume, v—1%, 5%, 10% and 20%. The average NTCP value ranged from 5% for the prostate adenocarcinoma, to 0% for the sacral chordoma group. The redefined constraints, to be confirmed prospectively with clinical data, are D_LEM|5cc ≤ 61 Gy(RBE) and D_LEM|1cc ≤ 66 Gy(RBE). Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

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10 pages, 228 KiB

Open AccessArticle

Dose-Limiting Organs at Risk in Carbon Ion Re-Irradiation of Head and Neck Malignancies: An Individual Risk-Benefit Tradeoff

by Thomas Held, Semi B. Harrabi, Kristin Lang, Sati Akbaba, Paul Windisch, Denise Bernhardt, Stefan Rieken, Klaus Herfarth, Jürgen Debus and Sebastian Adeberg

Cancers 2019, 11(12), 2016; https://doi.org/10.3390/cancers11122016 - 13 Dec 2019

Cited by 7 | Viewed by 2613

Abstract

Background: Carbon ion re-irradiation (CIR) was evaluated to investigate treatment planning and the consequences of individual risk-benefit evaluations concerning dose-limiting organs at risk (OAR). Methods: A total of 115 consecutive patients with recurrent head and neck cancer (HNC) were analyzed after initial radiotherapy and CIR at the same anatomical site. Toxicities were evaluated in line with the Common Terminology Criteria for Adverse Events 4.03. Results: The median maximum cumulative equivalent doses applied in fractions of 2 Gy (EQD2) to the brainstem, optic chiasm, ipsilateral optic nerve, and spinal cord were 56.8 Gy (range 0.94–103.9), 51.4 Gy (range 0–120.3 Gy), 63.6 Gy (range 0–146.1 Gy), and 28.8 Gy (range 0.2–87.7 Gy). The median follow up after CIR was 24.0 months (range 2.5–72.0 months). The cumulative rates of acute and late severe (≥grade III) side effects after CIR were 1.8% and 14.3%. Conclusion: In recurrent HNC, an individual risk-benefit tradeoff is frequently inevitable due to unfavorable location of tumors in close proximity to vital OAR. There are uncertainties about the dose tolerance of OAR after CIR, which warrant increased awareness about the potential treatment toxicity and further studies on heavy ion re-irradiation. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

Review

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14 pages, 688 KiB

Open AccessReview

Exploring the Biological and Physical Basis of Boron Neutron Capture Therapy (BNCT) as a Promising Treatment Frontier in Breast Cancer

by Danushka Seneviratne, Pooja Advani, Daniel M. Trifiletti, Saranya Chumsri, Chris J. Beltran, Aaron F. Bush and Laura A. Vallow

Cancers 2022, 14(12), 3009; https://doi.org/10.3390/cancers14123009 - 18 Jun 2022

Cited by 14 | Viewed by 4540

Abstract

BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states. Full article

(This article belongs to the Special Issue New Horizons in Particle Therapy)

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