{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:24:22Z","timestamp":1760145862799,"version":"build-2065373602"},"reference-count":56,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2024,8,31]],"date-time":"2024-08-31T00:00:00Z","timestamp":1725062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Conventional radiotherapies used in the current management of rectal cancer commonly cause iatrogenic radiotoxicity. Proton beam therapy has emerged as an alternative to conventional radiotherapy with the aim of improving tumour control and reducing off-set radiation exposure to surrounding tissue. However, the real-world treatment and oncological outcomes associated with the use of proton beam therapy in rectal cancer remain poorly characterised. This systematic review seeks to evaluate the radiation dosages and safety of proton beam therapy compared to conventional radiotherapy in patients with non-metastatic rectal cancer. Materials and Methods: A computer-assisted search was performed on the Medline, Embase and Cochrane Central databases. Studies that evaluated the adverse effects and oncological outcomes of proton beam therapy and conventional radiotherapy in adult patients with non-metastatic rectal cancer were included. Results: Eight studies were included in this review. There was insufficient evidence to determine the adverse treatment outcomes of proton beam therapy versus conventional radiotherapy. No current studies assessed radiotoxicities nor oncological outcomes. Pooled dosimetric comparisons between proton beam therapy and various conventional radiotherapies were associated with reduced radiation exposure to the pelvis, bowel and bladder. Conclusions: This systematic review demonstrates a significant paucity of evidence in the current literature surrounding adverse effects and oncological outcomes related to proton beam therapy compared to conventional radiotherapy for non-metastatic rectal cancer. Pooled analyses of dosimetric studies highlight greater predicted radiation-sparing effects with proton beam therapy in this setting. This evidence, however, is based on evidence at a moderate risk of bias and clinical heterogeneity. Overall, more robust, prospective clinical trials are required.<\/jats:p>","DOI":"10.3390\/medicina60091426","type":"journal-article","created":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T03:45:21Z","timestamp":1725248721000},"page":"1426","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluating the Effectiveness of Proton Beam Therapy Compared to Conventional Radiotherapy in Non-Metastatic Rectal Cancer: A Systematic Review of Clinical Outcomes"],"prefix":"10.3390","volume":"60","author":[{"given":"Kelvin","family":"Le","sequence":"first","affiliation":[{"name":"Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James Norton","family":"Marchant","sequence":"additional","affiliation":[{"name":"Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3052, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4532-8248","authenticated-orcid":false,"given":"Khang Duy Ricky","family":"Le","sequence":"additional","affiliation":[{"name":"Department of General Surgical Specialties, The Royal Melbourne Hospital, Melbourne, VIC 3052, Australia"},{"name":"Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia"},{"name":"Geelong Clinical School, Deakin University, Geelong, VIC 3220, Australia"},{"name":"Department of Medical Education, Melbourne Medical School, The University of Melbourne, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101174","DOI":"10.1016\/j.tranon.2021.101174","article-title":"Global colorectal cancer burden in 2020 and projections to 2040","volume":"14","author":"Xi","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s11864-022-00961-5","article-title":"The Evolving Neoadjuvant Treatment Paradigm for Patients with Locoregional mismatch Repair Proficient Rectal Cancer","volume":"23","author":"Bhudia","year":"2022","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S1470-2045(11)70097-3","article-title":"Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial","volume":"12","author":"Marijnen","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/S0140-6736(09)60484-0","article-title":"Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): A multicentre, randomised trial","volume":"373","author":"Stephens","year":"2009","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1016\/S1470-2045(14)70377-8","article-title":"Oxaliplatin, fluorouracil, and leucovorin versus fluorouracil and leucovorin as adjuvant chemotherapy for locally advanced rectal cancer after preoperative chemoradiotherapy (ADORE): An open-label, multicentre, phase 2, randomised controlled trial","volume":"15","author":"Hong","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1002\/1097-0142(20010815)92:4<896::AID-CNCR1398>3.0.CO;2-R","article-title":"The Stockholm II trial on preoperative radiotherapy in rectal carcinoma: Long-term follow-up of a population-based study","volume":"92","author":"Martling","year":"2001","journal-title":"Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.ejso.2018.01.088","article-title":"Delaying surgery after neoadjuvant chemoradiotherapy in rectal cancer has no influence in surgical approach or short-term clinical outcomes","volume":"44","author":"Figueiredo","year":"2018","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1016\/S1470-2045(15)00120-5","article-title":"High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: A prospective observational study","volume":"16","author":"Appelt","year":"2015","journal-title":"Lancet Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1097\/01.sla.0000141194.27992.32","article-title":"Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: Long-term results","volume":"240","author":"Perez","year":"2004","journal-title":"Ann. Surg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1056\/NEJMoa040694","article-title":"Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer","volume":"351","author":"Sauer","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101638","DOI":"10.1016\/j.suronc.2021.101638","article-title":"Proton beam therapy in rectal cancer: A systematic review and meta-analysis","volume":"38","author":"Fok","year":"2021","journal-title":"Surg. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1016\/j.ijrobp.2010.07.007","article-title":"Late Patient-Reported Toxicity after Preoperative Radiotherapy or Chemoradiotherapy in Nonresectable Rectal Cancer: Results From a Randomized Phase III Study","volume":"81","author":"Tveit","year":"2011","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1111\/codi.13381","article-title":"Oxaliplatin\/fluorouracil-based adjuvant chemotherapy for locally advanced rectal cancer after neoadjuvant chemoradiotherapy and surgery: A systematic review and meta-analysis of randomized controlled trials","volume":"18","author":"Zhao","year":"2016","journal-title":"Color. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.ejca.2003.09.032","article-title":"Preoperative chemoradiotherapy versus preoperative radiotherapy in rectal cancer patients: Assessment of acute toxicity and treatment compliance: Report of the 22921 randomised trial conducted by the EORTC Radiotherapy Group","volume":"40","author":"Bosset","year":"2004","journal-title":"Eur. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1200\/JCO.21.01667","article-title":"Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR)","volume":"40","author":"Jin","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/ans.18059","article-title":"Long-term adverse effects and healthcare burden of rectal cancer radiotherapy: Systematic review and meta-analysis","volume":"93","author":"Morton","year":"2023","journal-title":"ANZ J. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1002\/pro6.1149","article-title":"A review of proton therapy\u2014Current status and future directions","volume":"6","author":"Mohan","year":"2022","journal-title":"Precis. Radiat. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e528","DOI":"10.1016\/j.clon.2023.05.014","article-title":"Assessing Equity of Access to Proton Beam Therapy: A Literature Review","volume":"35","author":"Gaito","year":"2023","journal-title":"Clin. Oncol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Vitti, E.T., and Parsons, J.L. (2019). The Radiobiological Effects of Proton Beam Therapy: Impact on DNA Damage and Repair. Cancers, 11.","DOI":"10.3390\/cancers11070946"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1038\/sj.bjc.6602754","article-title":"Proton beam therapy","volume":"93","author":"Levin","year":"2005","journal-title":"Br. J. Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1186\/s13045-018-0683-4","article-title":"Proton beam therapy for cancer in the era of precision medicine","volume":"11","author":"Hu","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"187","DOI":"10.21037\/jgo.2019.09.03","article-title":"Proton beam re-irradiation for gastrointestinal malignancies: A systematic review","volume":"11","author":"Barsky","year":"2020","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e254","DOI":"10.1016\/S1470-2045(17)30179-1","article-title":"Proton therapy for head and neck cancer: Expanding the therapeutic window","volume":"18","author":"Leeman","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"176","DOI":"10.21037\/jgo.2019.04.03","article-title":"Proton beam radiotherapy for anal and rectal cancers","volume":"11","author":"Vaios","year":"2020","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.ijrobp.2013.02.026","article-title":"Spot-Scanning Proton Radiation Therapy for Pediatric Chordoma and Chondrosarcoma: Clinical Outcome of 26 Patients Treated at Paul Scherrer Institute","volume":"86","author":"Rombi","year":"2013","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.ijrobp.2023.08.058","article-title":"Severe Lymphopenia During Chemoradiation Therapy for Esophageal Cancer: Comprehensive Analysis of Randomized Phase 2B Trial of Proton Beam Therapy Versus Intensity Modulated Radiation Therapy","volume":"118","author":"Wang","year":"2024","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"109971","DOI":"10.1016\/j.radonc.2023.109971","article-title":"Comparing the oncologic outcomes of proton therapy and intensity-modulated radiation therapy for head and neck squamous cell carcinoma","volume":"190","author":"Chang","year":"2024","journal-title":"Radiother. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1136\/bmj.n71","article-title":"The Prisma 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_30","first-page":"iv22","article-title":"Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"28","author":"Wyrwicz","year":"2017","journal-title":"Ann. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"i4919","DOI":"10.1136\/bmj.i4919","article-title":"ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions","volume":"355","author":"Sterne","year":"2016","journal-title":"BMJ"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wan, X., Wang, W., Liu, J., and Tong, T. (2014). Estimating the sample mean and standard deviation from the sample size, median, range and\/or interquartile range. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-135"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis","volume":"21","author":"Higgins","year":"2002","journal-title":"Stat. Med."},{"key":"ref_34","first-page":"388","article-title":"Protons offer reduced bone marrow, small bowel, and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer","volume":"5","author":"Colaco","year":"2014","journal-title":"J. Gastrointest. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S0167-8140(96)01851-8","article-title":"Comparative treatment planning between proton and X-ray therapy in locally advanced rectal cancer","volume":"41","author":"Isacsson","year":"1996","journal-title":"Radiother. Oncol."},{"key":"ref_36","first-page":"72","article-title":"Pelvic insufficiency fractures, dose volume parameters and plan optimization after radiotherapy for rectal cancer","volume":"19","author":"Kronborg","year":"2019","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_37","first-page":"59","article-title":"Definitive hyperfractionated, accelerated proton reirradiation for patients with pelvic malignancies","volume":"19","author":"Moningi","year":"2019","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_38","first-page":"100562","article-title":"Preoperative short-course radiation therapy with PROtons compared to photons in high-risk RECTal cancer (PRORECT): Initial dosimetric experience","volume":"39","author":"Pedone","year":"2023","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"528","DOI":"10.3109\/0284186X.2012.737022","article-title":"Integrated peripheral boost in preoperative radiotherapy for the locally most advanced non-resectable rectal cancer patients","volume":"52","author":"Radu","year":"2013","journal-title":"Acta Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1080\/0284186X.2021.1953139","article-title":"Intensity modulated proton therapy planning study for organ at risk sparing in rectal cancer re-irradiation","volume":"60","author":"Kallehauge","year":"2021","journal-title":"Acta Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.radonc.2011.10.018","article-title":"Irradiation with protons for the individualized treatment of patients with locally advanced rectal cancer: A planning study with clinical implications","volume":"102","author":"Wolff","year":"2012","journal-title":"Radiother. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.6004\/jnccn.2022.0051","article-title":"Rectal cancer, version 2.2022, NCCN clinical practice guidelines in oncology","volume":"20","author":"Benson","year":"2022","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2","DOI":"10.14338\/IJPT.13-00002.1","article-title":"Proton Reirradiation of Recurrent Rectal Cancer: Dosimetric Comparison, Toxicities, and Preliminary Outcomes","volume":"1","author":"Berman","year":"2014","journal-title":"Int. J. Part. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/j.adro.2020.05.004","article-title":"Clinical Implementation of Preoperative Short-Course Pencil Beam Scanning Proton Therapy for Patients with Rectal Cancer","volume":"5","author":"Jeans","year":"2020","journal-title":"Adv. Radiat. Oncol."},{"key":"ref_45","first-page":"17","article-title":"Systematic review of methodology used in clinical studies evaluating the benefits of proton beam therapy","volume":"19","author":"Ofuya","year":"2019","journal-title":"Clin. Transl. Radiat. Oncol."},{"key":"ref_46","first-page":"891067","article-title":"Intensity-Modulated Radiation Therapy for Rectal Carcinoma Can Reduce Treatment Breaks and Emergency Department Visits","volume":"2012","author":"Jabbour","year":"2012","journal-title":"Int. J. Surg. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/j.ijrobp.2011.01.051","article-title":"Reduced Acute Bowel Toxicity in Patients Treated With Intensity-Modulated Radiotherapy for Rectal Cancer","volume":"82","author":"Samuelian","year":"2012","journal-title":"Int. J. Radiat. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1007\/s00384-020-03595-x","article-title":"Late gastrointestinal toxicity after radiotherapy for rectal cancer: A systematic review","volume":"35","author":"Sipaviciute","year":"2020","journal-title":"Int. J. Color. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"100595","DOI":"10.1016\/j.adro.2020.10.008","article-title":"Reirradiation for Rectal Cancer Using Pencil Beam Scanning Proton Therapy: A Single Institutional Experience","volume":"6","author":"Koroulakis","year":"2021","journal-title":"Adv. Radiat. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3589","DOI":"10.21873\/anticanres.15147","article-title":"Proton Beam Therapy for Local Recurrence of Rectal Cancer","volume":"41","author":"Hiroshima","year":"2021","journal-title":"Anticancer Res"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"825","DOI":"10.5114\/aoms.2020.94330","article-title":"Overall treatment outcome\u2014Analysis of long-term results of rectal cancer treatment on the basis of a new parameter","volume":"16","author":"Jankowski","year":"2020","journal-title":"Arch. Med. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/jrr\/rrae019","article-title":"Proton beam reirradiation for locally recurrent rectal cancer patients with prior pelvic irradiation","volume":"65","author":"Takagawa","year":"2024","journal-title":"J. Radiat. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.radonc.2021.12.004","article-title":"Current practice in proton therapy delivery in adult cancer patients across Europe","volume":"167","author":"Tambas","year":"2022","journal-title":"Radiother. Oncol."},{"key":"ref_54","first-page":"438","article-title":"Patient characterization and usage trends of proton beam therapy for localized prostate cancer in the United States: A study of the National Cancer Database","volume":"35","author":"Amini","year":"2017","journal-title":"Urol. Oncol. Semin. Orig. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Willmann, J., Leiser, D., and Weber, D.C. (2023). Oncological Outcomes, Long-Term Toxicities, Quality of Life and Sexual Health after Pencil-Beam Scanning Proton Therapy in Patients with Low-Grade Glioma. Cancers, 15.","DOI":"10.3390\/cancers15215287"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Khong, J., Tee, H., Gorayski, P., Le, H., Penniment, M., Jessop, S., Hansford, J., Penfold, M., Green, J., and Skelton, K. (2023). Proton beam therapy in paediatric cancer: Anticipating the opening of the Australian Bragg Centre for Proton Therapy and Research. J. Med. Imaging Radiat. Oncol.","DOI":"10.1111\/1754-9485.13614"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/9\/1426\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:46:22Z","timestamp":1760111182000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/60\/9\/1426"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,31]]},"references-count":56,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["medicina60091426"],"URL":"https:\/\/doi.org\/10.3390\/medicina60091426","relation":{},"ISSN":["1648-9144"],"issn-type":[{"type":"electronic","value":"1648-9144"}],"subject":[],"published":{"date-parts":[[2024,8,31]]}}}