Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2011;12:127–36. https://doi.org/10.1016/S1470-2045(10)70290-4.

Article  Google Scholar 

Peng G, Wang T, Yang K-Y, Zhang S, Zhang T, Li Q, et al. A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2012;104:286–93. https://doi.org/10.1016/j.radonc.2012.08.013.

Article  Google Scholar 

Gomez DR, Tang C, Zhang J, Blumenschein GRJ, Hernandez M, Lee JJ, et al. Local consolidative therapy Vs. maintenance Therapy or Observation for patients with Oligometastatic Non-small-cell Lung Cancer: long-term results of a multi-institutional, phase II, Randomized Study. J Clin Oncol off J Am Soc Clin Oncol. 2019;37:1558–65. https://doi.org/10.1200/JCO.19.00201.

Article  Google Scholar 

Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, et al. Stereotactic ablative radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol off J Am Soc Clin Oncol. 2020;38:2830–8. https://doi.org/10.1200/JCO.20.00818.

Article  Google Scholar 

Macchia G, Lazzari R, Colombo N, Laliscia C, Capelli G, D’Agostino GR, et al. A large, Multicenter, Retrospective Study on Efficacy and Safety of Stereotactic Body Radiotherapy (SBRT) in Oligometastatic Ovarian Cancer (MITO RT1 Study): a collaboration of MITO, AIRO GYN, and MaNGO groups. Oncologist. 2020;25:e311–20. https://doi.org/10.1634/theoncologist.2019-0309.

Article  Google Scholar 

Macchia G, Pezzulla D, Campitelli M, Laliscia C, Fodor A, Bonome P, et al. Efficacy and safety of stereotactic body Radiation Therapy in Oligometastatic Uterine Cancer (MITO-RT2/RAD): a large, real-world study in Collaboration with Italian Association of Radiation Oncology, Multicenter Italian trials in Ovarian Cancer, and Mari. Int J Radiat Oncol Biol Phys. 2023;117:321–32. https://doi.org/10.1016/j.ijrobp.2023.04.025.

Article  Google Scholar 

Beddok A, Vela A, Calugaru V, Tessonnier T, Kubes J, Dutheil P, et al. Proton therapy for head and neck squamous cell carcinomas: a review of the physical and clinical challenges. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2020;147:30–9. https://doi.org/10.1016/j.radonc.2020.03.006.

Article  Google Scholar 

Tinganelli W, Durante M. Carbon Ion Radiobiology. Cancers (Basel). 2020;12. https://doi.org/10.3390/cancers12103022.

Lin SH, Willers H, Krishnan S, Sarkaria JN, Baumann M, Lawrence TS. Moving beyond the Standard of Care: accelerate testing of Radiation-Drug combinations. Int J Radiat Oncol Biol Phys. 2021;111:1131–9. https://doi.org/10.1016/j.ijrobp.2021.08.018.

Article  Google Scholar 

Sokol O, Durante M. Carbon ions for hypoxic tumors: are we making the most of them? Cancers (Basel). 2023;15. https://doi.org/10.3390/cancers15184494.

Galeaz C, Totis C, Bisio A, Radiation Resistance. A matter of transcription factors. Front Oncol. 2021;11:662840. https://doi.org/10.3389/fonc.2021.662840.

Article  Google Scholar 

Olivares-Urbano MA, Griñán-Lisón C, Marchal JA, Núñez MI. CSC Radioresistance: a therapeutic challenge to improve Radiotherapy Effectiveness in Cancer. Cells 2020;9. https://doi.org/10.3390/cells9071651.

Tinganelli W, Durante M. Tumor Hypoxia and circulating Tumor cells. Int J Mol Sci. 2020;21. https://doi.org/10.3390/ijms21249592.

Choudhry H, Harris AL. Advances in Hypoxia-Inducible factor Biology. Cell Metab. 2018;27:281–98. https://doi.org/10.1016/j.cmet.2017.10.005.

Article  Google Scholar 

Charalampopoulou A, Barcellini A, Frittitta GE, Fulgini G, Ivaldi GB, Magro G et al. In Vitro effects of Photon Beam and Carbon Ion Radiotherapy on the Perineural Invasion of Two Cell Lines of Neurotropic Tumours. Life 2023;13. https://doi.org/10.3390/life13030794.

Facoetti A, Di Gioia C, Pasi F, Di Liberto R, Corbella F, Nano R, et al. Morphological analysis of amoeboid-mesenchymal transition plasticity after low and high LET Radiation on migrating and invading pancreatic Cancer cells. Anticancer Res. 2018;38:4585–91. https://doi.org/10.21873/anticanres.12763.

Article  Google Scholar 

Charalampopoulou A, Barcellini A, Ciocca M, Di Liberto R, Pasi F, Pullia MG, et al. Factors released by low and high-LET irradiated fibroblasts modulate migration and invasiveness of pancreatic cancer cells. Front Oncol. 2022;12:1003494. https://doi.org/10.3389/fonc.2022.1003494.

Article  Google Scholar 

Subtil FSB, Wilhelm J, Bill V, Westholt N, Rudolph S, Fischer J, et al. Carbon ion radiotherapy of human lung cancer attenuates HIF-1 signaling and acts with considerably enhanced therapeutic efficiency. FASEB J off Publ Fed Am Soc Exp Biol. 2014;28:1412–21. https://doi.org/10.1096/fj.13-242230.

Article  Google Scholar 

Valable S, Gérault AN, Lambert G, Leblond MM, Anfray C, Toutain J, et al. Impact of Hypoxia on Carbon Ion Therapy in Glioblastoma cells: modulation by LET and Hypoxia-Dependent genes. Cancers (Basel). 2020;12. https://doi.org/10.3390/cancers12082019.

Wozny A-S, Lauret A, Battiston-Montagne P, Guy J-B, Beuve M, Cunha M, et al. Differential pattern of HIF-1α expression in HNSCC cancer stem cells after carbon ion or photon irradiation: one molecular explanation of the oxygen effect. Br J Cancer. 2017;116:1340–9. https://doi.org/10.1038/bjc.2017.100.

Article  Google Scholar 

Furusawa Y, Fukutsu K, Aoki M, Itsukaichi H, Eguchi-Kasai K, Ohara H, et al. Inactivation of aerobic and hypoxic cells from three different cell lines by accelerated (3)He-, (12)C- and (20)Ne-ion beams. Radiat Res. 2000;154:485–96. https://doi.org/10.1667/0033-7587(2000)154[0485:ioaahc]2.0.co;2.

Article  Google Scholar 

Wenzl T, Wilkens JJ. Theoretical analysis of the dose dependence of the oxygen enhancement ratio and its relevance for clinical applications. Radiat Oncol. 2011;6:171. https://doi.org/10.1186/1748-717X-6-171.

Article  Google Scholar 

Nakano T, Suzuki Y, Ohno T, Kato S, Suzuki M, Morita S, et al. Carbon Beam therapy overcomes the radiation resistance of uterine cervical cancer originating from hypoxia. Clin Cancer Res off J Am Assoc Cancer Res. 2006;12:2185–90. https://doi.org/10.1158/1078-0432.CCR-05-1907.

Article  Google Scholar 

Pompos A, Foote RL, Koong AC, Le QT, Mohan R, Paganetti H, et al. National Effort to Re-establish Heavy Ion Cancer Therapy in the United States. Front Oncol. 2022;12:880712. https://doi.org/10.3389/fonc.2022.880712.

Article  Google Scholar 

Glowa C, Karger CP, Brons S, Zhao D, Mason RP, Huber PE, et al. Carbon ion radiotherapy decreases the impact of tumor heterogeneity on radiation response in experimental prostate tumors. Cancer Lett. 2016;378:97–103. https://doi.org/10.1016/j.canlet.2016.05.013.

Article  Google Scholar 

Glowa C, Peschke P, Brons S, Neels OC, Kopka K, Debus J, et al. Carbon ion radiotherapy: impact of tumor differentiation on local control in experimental prostate carcinomas. Radiat Oncol. 2017;12:174. https://doi.org/10.1186/s13014-017-0914-9.

Article  Google Scholar 

Glowa C, Peschke P, Brons S, Debus J, Karger CP. Intrinsic and extrinsic tumor characteristics are of minor relevance for the efficacy of split-dose carbon ion irradiation in three experimental prostate tumors. Radiother Oncol J Eur Soc Ther Radiol Oncol. 2019;133:120–4. https://doi.org/10.1016/j.radonc.2018.12.017.

Article  Google Scholar 

Huang Y, Huang Q, Zhao J, Dong Y, Zhang L, Fang X, et al. The impacts of different types of Radiation on the CRT and PDL1 expression in Tumor cells under Normoxia and Hypoxia. Front Oncol. 2020;10:1610. https://doi.org/10.3389/fonc.2020.01610.

Article  Google Scholar 

Iijima M, Okonogi N, Nakajima NI, Morokoshi Y, Kanda H, Yamada T, et al. Significance of PD-L1 expression in carbon-ion radiotherapy for uterine cervical adeno/adenosquamous carcinoma. J Gynecol Oncol. 2020;31:e19. https://doi.org/10.3802/jgo.2020.31.e19.

Article  Google Scholar 

Zhou H, Tu C, Yang P, Li J, Kepp O, Li H, et al. Carbon ion radiotherapy triggers immunogenic cell death and sensitizes melanoma to anti-PD-1 therapy in mice. Oncoimmunology. 2022;11:2057892. https://doi.org/10.1080/2162402X.2022.2057892.

Article  Google Scholar 

Helm A, Tinganelli W, Simoniello P, Kurosawa F, Fournier C, Shimokawa T, et al. Reduction of lung metastases in a mouse osteosarcoma model treated with Carbon ions and Immune Checkpoint inhibitors. Int J Radiat Oncol Biol Phys. 2021;109:594–602. https://doi.org/10.1016/j.ijrobp.2020.09.041.

Article  Google Scholar 

Shimokawa T, Ma L, Ando K, Sato K, Imai T. The future of combining Carbon-Ion Radiotherapy with Immunotherapy: evidence and progress in mouse models. Int J Part Ther. 2016;3:61–70. https://doi.org/10.14338/IJPT-15-00023.1.

Article  Google Scholar 

Durante M, Brenner DJ, Formenti SC. Does Heavy Ion Therapy Work through the Immune System? Int J Radiat Oncol Biol Phys. 2016;96:934–6. https://doi.org/10.1016/j.ijrobp.2016.08.037.

Article  Google Scholar 

Durante M, Formenti S. Harnessing radiation to improve immunotherapy: better with particles? Br J Radiol. 2020;93:20190224. https://doi.org/10.1259/bjr.20190224.

Article  Google Scholar 

Tubin S, Yan W, Mourad WF, Fossati P, Khan MK. The future of radiation-induced abscopal response: beyond conventional radiotherapy approaches. Future Oncol. 2020;16:1137–51. https://doi.org/10.2217/fon-2020-0063.

Article  Google Scholar 

Cavalieri S, Vitolo V, Barcellini A, Ronchi S, Facoetti A, Campo C, et al. Immune checkpoint inhibitors and Carbon iON radiotherapy in solid cancers with stable disease (ICONIC). Future Oncol. 2023;19:193–203. https://doi.org/10.2217/fon-2022-0503.

Article  Google Scholar 

Paganetti H. Relative biological effectiveness (RBE) values for proton beam therapy. Variations as a function of biological endpoint, dose, and linear energy transfer. Phys Med Biol. 2014;59:R419–72. https://doi.org/10.1088/0031-9155/59/22/R419.

Article  Google Scholar 

Riva G, Cavallo I, Gandini S, Ingargiola R, Pecorilla M, Imparato S, et al. Particle Radiotherapy for Skull Base Chondrosarcoma: a clinical series from Italian National Center for Oncological Hadrontherapy. Cancers (Basel). 2021;13. https://doi.org/10.3390/cancers13174423.

Mizoe J-E, Hasegawa A, Takagi R, Bessho H, Onda T, Tsujii H. Carbon ion radiotherapy for skull base chordoma. Skull Base. 2009;19:219–24. https://doi.org/10.1055/s-0028-1114295.

Article  Google Scholar 

Cuccia F, Fiore MR, Barcellini A, Iannalfi A, Vischioni B, Ronchi S, et al. Outcome and Toxicity of Carbon Ion Radiotherapy for Axial Bone and Soft tissue sarcomas. Anticancer Res. 2020;40. https://doi.org/10.21873/anticanres.14260.

Vischioni B, Dhanireddy B, Severo C, Bonora M, Ronchi S, Vitolo V, et al. Reirradiation of salivary gland tumors with carbon ion radiotherapy at CNAO. Radiother Oncol. 2020;145. https://doi.org/10.1016/j.radonc.2020.01.004.

Held T, Windisch P, Akbaba S, Lang K, El Shafie R, Bernhardt D, et al. Carbon Ion Reirradiation for Recurrent Head and Neck Cancer: a single-institutional experience. Int J Radiat Oncol Biol Phys. 2019;105:803–11. https://doi.org/10.1016/j.ijrobp.2019.07.021.

Article  Google Scholar 

Bhattacharyya T, Koto M, Windisch P, Ikawa H, Hagiwara Y, Tsuji H, et al. Emerging role of Carbon Ion Radiotherapy in Reirradiation of Recurrent Head and Neck cancers: what have we achieved so far? Front Oncol. 2022;12:888446. https://doi.org/10.3389/fonc.2022.888446.

Article  Google Scholar 

Yamada S, Takiyama H, Isozaki Y, Shinoto M, Ebner DK, Koto M, et al. Carbon Ion Radiotherapy for locally recurrent rectal Cancer of patients with prior pelvic irradiation. Ann Surg Oncol. 2022;29:99–106. https://doi.org/10.1245/s10434-021-10876-4.

Article  Google Scholar 

Barcellini A, Vitolo V, Cobianchi L, Peloso A, Vanoli A, Mirandola A, et al. Re-irradiation with Carbon Ion Radiotherapy for pelvic rectal Cancer recurrences in patients previously irradiated to the Pelvis. Vivo (Brooklyn). 2020;34:1547–53. https://doi.org/10.21873/invivo.11944.

Article  Google Scholar 

Shiba S, Okonogi N, Kato S, Wakatsuki M, Kobayashi D, Kiyohara H, et al. Clinical impact of re-irradiation with Carbon-ion Radiotherapy for Lymph Node Recurrence of Gynecological Cancers. Anticancer Res. 2017;37:5577–83. https://doi.org/10.21873/anticanres.11991.

Article  Google Scholar 

Barcellini A, Vitolo V, Mastella E, Mirandola A, Valvo F. Letter to the editor concerning re-irradiation in gynaecological cancers, present experiences and future hopes. J Radiat Oncol. 2019;8:355–6. https://doi.org/10.1007/s13566-019-00396-w.