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Current Progress in Proton Radiotherapy of Cancer

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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: 30 June 2024 | Viewed by 12819

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Dr. Carla Hajj

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1. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center [MSKCC], 1275 York Avenue, New York, NY 10065, USA
2. Department of Radiation Oncology, New York Proton Cancer Center [NYPC], 225 E 126th St., New York, NY 10035, USA
Interests: radiation therapy; protons; IMRT; SBRT; image guidance; motion management; gastrointestinal; lymphoma; liver cancer; pancreatic cancer; rectal cancer; anal cancer; multiple myeloma; cholangiocarcinoma; hepatocellular carcinoma

Special Issue Information

Dear Colleagues,

Proton beam radiotherapy is an advanced cancer treatment that involves the use of charged particles called protons, rather than high-energy X-rays. Proton beams deliver a high dose of radiation to a very precise target. This is due to the rapid deceleration of the protons, which leads to energy deposition that culminates in what is known as the Bragg peak. However, the inherent uncertainties in linear stopping power of protons lead to range uncertainties, which could theoretically lead to targeting undercover or unanticipated toxicity. With more sophisticated treatment planning techniques, beam delivery (pencil beam scanning technology), motion management and image-guidance techniques, proton beam therapy’s precision has significantly improved.

In this Special Issue, we would like to highlight the new technologies used in protons beam planning and delivery and highlight the recent advancements achieved in this field. We welcome case reports of unforeseen or unanticipated toxicities associated with proton radiation therapy, in addition to studies looking at the clinical efficacy, toxicities (in the acute, subacute, and long-term settings) and dosimetric comparisons of proton beam radiotherapy to X-ray radiation therapy. Finally, we would like to shed light on the growing number of indications of proton beam radiotherapy across different disease sites.

Dr. Carla Hajj
Guest Editor

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 short 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

proton
safety
efficacy
motion management
radiobiology
physics
planning
dosimetry
toxicity
outcomes
radiation therapy
image guidance
pencil beam

Published Papers (9 papers)

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Research

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10 pages, 750 KiB

Open AccessArticle

Treatment Outcomes of Proton Beam Therapy for Esophageal Squamous Cell Carcinoma at a Single Institute

by Eun Sang Oh, Sung Ho Moon, Youngjoo Lee, Beung-Chul Ahn, Jong Yeul Lee, Yang-Gun Suh, Joo-Hyun Chung, Moon Soo Kim, Jong Mog Lee, Jin-Ho Choi and Tae Hyun Kim

Cancers 2023, 15(23), 5524; https://doi.org/10.3390/cancers15235524 - 22 Nov 2023

Viewed by 760

Abstract

Recently, proton beam therapy (PBT) has gathered attention for improving outcomes and reducing toxicities in various cancers; however, the evidence for esophageal squamous cell carcinoma (ESCC) is lacking. Our study retrospectively evaluated the outcomes of PBT for ESCC patients at a single institute. The patients treated with PBT between November 2015 and February 2022 were included in the study, excluding those with distant metastases or those that had undertaken prior treatment for esophageal cancer (EC). The 3 year overall survival (OS) and progression-free survival (PFS) rates were calculated based on stage grouping. The patterns of failure, salvage treatment outcomes, and toxicity profiles were analyzed. The median follow-up was 35.1 months, and 132 patients were analyzed. The 3 year OS and PFS rates for the stages I, II, and III disease cases were 81.0%, 62.9%, and 51.3%; and 70.6%, 71.8%, and 39.8%, respectively. Nineteen patients presented isolated local progression, ten patients underwent appropriate salvage procedures, and nine were successfully salvaged. One patient with isolated regional progression was also salvaged. No cases of grade ≥ 4 lymphopenia were observed. One patient had grade 4 pericardial effusion and esophageal fistula. For the patients with ESCC, PBT is an effective treatment in terms of the survival outcomes and toxicities. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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13 pages, 1026 KiB

Open AccessArticle

Clinical Outcomes in AYAs (Adolescents and Young Adults) Treated with Proton Therapy for Uveal Melanoma: A Comparative Matching Study with Elder Adults

by Alessia Pica, Damien C. Weber, Claude Schweizer, Aziz Chaouch, Leonidas Zografos and Ann Schalenbourg

Cancers 2023, 15(18), 4652; https://doi.org/10.3390/cancers15184652 - 20 Sep 2023

Viewed by 802

Abstract

Objective: The aim of this study was to compare the clinical outcomes of adolescents and young adults (AYAs) with those of elder adult patients treated with proton therapy (PT) for uveal melanoma (UM). Material and Methods: A retrospective, comparative study was conducted in UM patients who underwent PT at the Ocular Oncology Unit of the Jules-Gonin Eye Hospital (University of Lausanne, Lausanne, Switzerland) and the Paul Scherrer Institute (PSI); (Villigen, Switzerland) between January 1997 and December 2007. Propensity score matching (PSM) was used to select for each AYA (between 15–39 years old) an elder adult patient (≥40 years) with similar characteristics. We assessed ocular follow-up, local tumor control, metastasis incidence, and overall and relative survival (OS and RS). Non-terminal outcomes were then compared between the two groups using competing risk survival analysis. Results: Out of a total of 2261 consecutive UM patients, after excluding 4 children (<15 years) and 6 patients who were metastatic at presentation, we identified 272 AYA patients and matched 270 of them with 270 elder adult patients. Before PSM, the AYA patients had a higher incidence of primary iris melanoma (4.0% vs. 1.4%; p = 0.005), while the elder patients were more likely to have other neoplastic diseases at presentation (9% vs. 3.7%; p = 0.004). Ocular outcomes and local tumor control were similar in both groups. Cumulative metastasis incidence for the AYA and elder adult groups was 13% and 7.9% at 5 years and 19.7% and 12.7% at 10 years, respectively, which was not significantly different between the groups (p = 0.214). The OS was similar in the two groups (p = 0.602), with estimates in the AYA and elder adult groups of 95.5% and 96.6% at 5 years and 94.6% and 91.4% at 10 years, respectively. However, the relative survival (RS) estimation was worse in the AYA group than the elder group (p = 0.036). Conclusion: While AYAs treated with PT for UM have similar ocular outcomes and present the same metastasis incidence and OS as elder adults, their RS is worse than that in elder adults, when compared with the population in general. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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13 pages, 1749 KiB

Open AccessArticle

Proton Bragg Peak FLASH Enables Organ Sparing and Ultra-High Dose-Rate Delivery: Proof of Principle in Recurrent Head and Neck Cancer

by Michael Pennock, Shouyi Wei, Chingyun Cheng, Haibo Lin, Shaakir Hasan, Arpit M. Chhabra, J. Isabelle Choi, Richard L. Bakst, Rafi Kabarriti, Charles B. Simone II, Nancy Y. Lee, Minglei Kang and Robert H. Press

Cancers 2023, 15(15), 3828; https://doi.org/10.3390/cancers15153828 - 28 Jul 2023

Cited by 4 | Viewed by 1778

Abstract

Proton pencil-beam scanning (PBS) Bragg peak FLASH combines ultra-high dose rate delivery and organ-at-risk (OAR) sparing. This proof-of-principle study compared dosimetry and dose rate coverage between PBS Bragg peak FLASH and PBS transmission FLASH in head and neck reirradiation. PBS Bragg peak FLASH plans were created via the highest beam single energy, range shifter, and range compensator, and were compared to PBS transmission FLASH plans for 6 GyE/fraction and 10 GyE/fraction in eight recurrent head and neck patients originally treated with quad shot reirradiation (14.8/3.7 CGE). The 6 GyE/fraction and 10 GyE/fraction plans were also created using conventional-rate intensity-modulated proton therapy techniques. PBS Bragg peak FLASH, PBS transmission FLASH, and conventional plans were compared for OAR sparing, FLASH dose rate coverage, and target coverage. All FLASH OAR V40 Gy/s dose rate coverage was 90–100% at 6 GyE and 10 GyE for both FLASH modalities. PBS Bragg peak FLASH generated dose volume histograms (DVHs) like those of conventional therapy and demonstrated improved OAR dose sparing over PBS transmission FLASH. All the modalities had similar CTV coverage. PBS Bragg peak FLASH can deliver conformal, ultra-high dose rate FLASH with a two-millisecond delivery of the minimum MU per spot. PBS Bragg peak FLASH demonstrated similar dose rate coverage to PBS transmission FLASH with improved OAR dose-sparing, which was more pronounced in the 10 GyE/fraction than in the 6 GyE/fraction. This feasibility study generates hypotheses for the benefits of FLASH in head and neck reirradiation and developing biological models. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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15 pages, 3154 KiB

Open AccessArticle

Comparative In Silico Analysis of Ultra-Hypofractionated Intensity-Modulated Photon Radiotherapy (IMRT) Versus Intensity-Modulated Proton Therapy (IMPT) in the Pre-Operative Treatment of Retroperitoneal Sarcoma

by Emile Gogineni, Hao Chen, Alexandra C. Istl, Fabian M. Johnston, Amol Narang and Curtiland Deville, Jr.

Cancers 2023, 15(13), 3482; https://doi.org/10.3390/cancers15133482 - 04 Jul 2023

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Abstract

Background: While pre-operative radiation did not improve abdominal recurrence-free survival for retroperitoneal sarcoma (RPS) in the randomized STRASS trial, it did reduce rates of local recurrence. However, the risk of toxicity was substantial and the time to surgery was prolonged. A combination of hypofractionation and proton therapy may reduce delays from the initiation of radiation to surgery and limit the dose to surrounding organs at risk (OARs). We conducted a dosimetric comparison of the pre-operative ultra-hypofractionated intensity-modulated photon (IMRT) and proton radiotherapy (IMPT). Methods: Pre-operative IMRT and IMPT plans were generated on 10 RPS patients. The prescription was 25 Gy radiobiological equivalents (GyEs) (radiobiological effective dose of 1.1) to the clinical target volume and 30 GyEs to the margin at risk, all in five fractions. Comparisons were made using student T-tests. Results: The following endpoints were significantly lower with IMPT than with IMRT: mean doses to liver, bone, and all genitourinary and gastrointestinal OARs; bowel, kidney, and bone V5–V20; stomach V15; liver V5; maximum doses to stomach, spinal canal, and body; and whole-body integral dose. Conclusions: IMPT maintained target coverage while significantly reducing the dose to adjacent OARs and integral dose compared to IMRT. A prospective trial treating RPS with pre-operative ultra-hypofractionated IMPT at our institution is currently being pursued. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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15 pages, 1451 KiB

Open AccessArticle

Single Ultra-High Dose Rate Proton Transmission Beam for Whole Breast FLASH-Irradiation: Quantification of FLASH-Dose and Relation with Beam Parameters

by Patricia van Marlen, Steven van de Water, Max Dahele, Berend J. Slotman and Wilko F. A. R. Verbakel

Cancers 2023, 15(9), 2579; https://doi.org/10.3390/cancers15092579 - 30 Apr 2023

Cited by 2 | Viewed by 1487

Abstract

Healthy tissue-sparing effects of FLASH (≥40 Gy/s, ≥4–8 Gy/fraction) radiotherapy (RT) make it potentially useful for whole breast irradiation (WBI), since there is often a lot of normal tissue within the planning target volume (PTV). We investigated WBI plan quality and determined FLASH-dose for various machine settings using ultra-high dose rate (UHDR) proton transmission beams (TBs). While five-fraction WBI is commonplace, a potential FLASH-effect might facilitate shorter treatments, so hypothetical 2- and 1-fraction schedules were also analyzed. Using one tangential 250 MeV TB delivering 5 × 5.7 Gy, 2 × 9.74 Gy or 1 × 14.32 Gy, we evaluated: (1) spots with equal monitor units (MUs) in a uniform square grid with variable spacing; (2) spot MUs optimized with a minimum MU-threshold; and (3) splitting the optimized TB into two sub-beams: one delivering spots above an MU-threshold, i.e., at UHDRs; the other delivering the remaining spots necessary to improve plan quality. Scenarios 1–3 were planned for a test case, and scenario 3 was also planned for three other patients. Dose rates were calculated using the pencil beam scanning dose rate and the sliding-window dose rate. Various machine parameters were considered: minimum spot irradiation time (minST): 2 ms/1 ms/0.5 ms; maximum nozzle current (maxN): 200 nA/400 nA/800 nA; two gantry-current (GC) techniques: energy-layer and spot-based. For the test case (PTV = 819 cc) we found: (1) a 7 mm grid achieved the best balance between plan quality and FLASH-dose for equal-MU spots; (2) near the target boundary, lower-MU spots are necessary for homogeneity but decrease FLASH-dose; (3) the non-split beam achieved >95% FLASH for favorable (not clinically available) machine parameters (SB GC, low minST, high maxN), but <5% for clinically available settings (EB GC, minST = 2 ms, maxN = 200 nA); and (4) splitting gave better plan quality and higher FLASH-dose (~50%) for available settings. The clinical cases achieved ~50% (PTV = 1047 cc) or >95% (PTV = 477/677 cc) FLASH after splitting. A single UHDR-TB for WBI can achieve acceptable plan quality. Current machine parameters limit FLASH-dose, which can be partially overcome using beam-splitting. WBI FLASH-RT is technically feasible. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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15 pages, 986 KiB

Open AccessArticle

The Feasibility of Stereotactic Body Proton Beam Therapy for Pancreatic Cancer

by Hyunju Shin, Jeong Il Yu, Hee Chul Park, Gyu Sang Yoo, Sungkoo Cho, Joon Oh Park, Kyu Taek Lee, Kwang Hyuck Lee, Jong Kyun Lee, Joo Kyung Park, Jin Seok Heo, In Woong Han and Sang Hyun Shin

Cancers 2022, 14(19), 4556; https://doi.org/10.3390/cancers14194556 - 20 Sep 2022

Cited by 1 | Viewed by 1586

Abstract

Background/Purpose: This study aimed to evaluate the clinical outcomes of stereotactic body proton beam therapy (SBPT) for pancreatic cancer. Methods: This retrospective study included 49 patients who underwent SBPT for pancreatic cancer between 2017 and 2020. Survival outcomes, bowel-related toxicities, and failure patterns were analysed. SBPT was performed after induction chemotherapy in 44 (89.8%) patients. The dose-fractionation scheme included 60 gray (Gy) relative biological effectiveness (RBE) in five fractions (n = 42, 85.7%) and 50 GyRBE in five fractions (n = 7, 14.3%). The median follow-up was 16.3 months (range, 1.8–45.0 months). Results: During follow-up, the best responses were complete response, partial response, and stable disease in four (8.2%), 13 (26.5%), and 31 (63.3%) patients, respectively. The 2-year overall survival, progression-free survival, and local control (LC) rates were 67.6%, 38.0%, and 73.0%, respectively. Grade ≥ 3 gastroduodenal (GD) toxicity occurred in three (6.1%) patients. Among them, one patient underwent endoscopic haemostasis. The other two patients received surgical management. They were followed up without disease progression for >30 months after SBPT. Overall, there was no significant dosimetric difference between the grade ≥ 2 and lower toxicity groups. Conclusions: SBPT provides relatively high LC rates with acceptable toxicities in pancreatic cancer. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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Review

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15 pages, 929 KiB

Open AccessReview

Proton Reirradiation for High-Risk Recurrent or New Primary Breast Cancer

by Molly A. Chakraborty, Atif J. Khan, Oren Cahlon, Amy J. Xu, Lior Z. Braunstein, Simon N. Powell and J. Isabelle Choi

Cancers 2023, 15(24), 5722; https://doi.org/10.3390/cancers15245722 - 06 Dec 2023

Viewed by 1076

Abstract

Radiotherapy is an integral component of multidisciplinary breast cancer care. Given how commonly radiotherapy is used in the treatment of breast cancer, many patients with recurrences have received previous radiotherapy. Patients with new primary breast cancer may also have received previous radiotherapy to the thoracic region. Curative doses and comprehensive field photon reirradiation (reRT) have often been avoided in these patients due to concerns for severe toxicities to organs-at-risk (OARs), such as the heart, lungs, brachial plexus, and soft tissue. However, many patients may benefit from definitive-intent reRT, such as patients with high-risk disease features such as lymph node involvement and dermal/epidermal invasion. Proton therapy is a potentially advantageous treatment option for delivery of reRT due to its lack of exit dose and greater conformality that allow for enhanced non-target tissue sparing of previously irradiated tissues. In this review, we discuss the clinical applications of proton therapy for patients with breast cancer requiring reRT, the currently available literature and how it compares to historical photon reRT outcomes, treatment planning considerations, and questions in this area warranting further study. Given the dosimetric advantages of protons and the data reported to date, proton therapy is a promising option for patients who would benefit from the added locoregional disease control provided by reRT for recurrent or new primary breast cancer. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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22 pages, 3333 KiB

Open AccessReview

Innate Immune System in the Context of Radiation Therapy for Cancer

by Ettickan Boopathi, Robert B. Den and Chellappagounder Thangavel

Cancers 2023, 15(15), 3972; https://doi.org/10.3390/cancers15153972 - 04 Aug 2023

Cited by 1 | Viewed by 1767

Abstract

Radiation therapy (RT) remains an integral component of modern oncology care, with most cancer patients receiving radiation as a part of their treatment plan. The main goal of ionizing RT is to control the local tumor burden by inducing DNA damage and apoptosis within the tumor cells. The advancement in RT, including intensity-modulated RT (IMRT), stereotactic body RT (SBRT), image-guided RT, and proton therapy, have increased the efficacy of RT, equipping clinicians with techniques to ensure precise and safe administration of radiation doses to tumor cells. In this review, we present the technological advancement in various types of RT methods and highlight their clinical utility and associated limitations. This review provides insights into how RT modulates innate immune signaling and the key players involved in modulating innate immune responses, which have not been well documented earlier. Apoptosis of cancer cells following RT triggers immune systems that contribute to the eradication of tumors through innate and adoptive immunity. The innate immune system consists of various cell types, including macrophages, dendritic cells, and natural killer cells, which serve as key mediators of innate immunity in response to RT. This review will concentrate on the significance of the innate myeloid and lymphoid lineages in anti-tumorigenic processes triggered by RT. Furthermore, we will explore essential strategies to enhance RT efficacy. This review can serve as a platform for researchers to comprehend the clinical application and limitations of various RT methods and provides insights into how RT modulates innate immune signaling. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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16 pages, 859 KiB

Open AccessReview

Quality of Life and Patient-Reported Outcomes Following Proton Therapy for Oropharyngeal Carcinoma: A Systematic Review

by Noorazrul Yahya and Hanani Abdul Manan

Cancers 2023, 15(8), 2252; https://doi.org/10.3390/cancers15082252 - 12 Apr 2023

Viewed by 1429

Abstract

Background: Complex anatomy surrounding the oropharynx makes proton therapy (PT), especially intensity-modulated PT (IMPT), a potentially attractive option due to its ability to reduce the volume of irradiated healthy tissues. Dosimetric improvement may not translate to clinically relevant benefits. As outcome data are emerging, we aimed to evaluate the evidence of the quality of life (QOL) and patient-reported outcomes (PROs) following PT for oropharyngeal carcinoma (OC). Materials and Methods: We searched PubMed and Scopus electronic databases (date: 15 February 2023) to identify original studies on QOL and PROs following PT for OC. We employed a fluid strategy in the search strategy by tracking citations of the initially selected studies. Reports were extracted for information on demographics, main results, and clinical and dose factor correlates. Quality assessment was performed using the NIH’s Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The PRISMA guidelines were followed in the preparation of this report. Results: Seven reports were selected, including one from a recently published paper captured from citation tracking. Five compared PT and photon-based therapy, although none were randomized controlled trials. Most endpoints with significant differences favored PT, including xerostomia, cough, need for nutritional supplements, dysgeusia, food taste, appetite, and general symptoms. However, some endpoints favored photon-based therapy (sexual symptoms) or showed no significant difference (e.g., fatigue, pain, sleep, mouth sores). The PROs and QOL improve following PT but do not appear to return to baseline. Conclusion: Evidence suggests that PT causes less QOL and PRO deterioration than photon-based therapy. Biases due to the non-randomized study design remain obstacles to a firm conclusion. Whether or not PT is cost-effective should be the subject of further investigation. Full article

(This article belongs to the Special Issue Current Progress in Proton Radiotherapy of Cancer)

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