Breakthroughs and challenges： clinical application and progress of proton and heavy ion radiotherapy for malignant tumors

Abstract

Abstract:

Particle beam radiation therapy （PBRT）， using proton and heavy ion （mainly carbon ion in clinical practice） beams， provides precise cancer treatment by targeting tumor sites while sparing healthy tissues， by leveraging the Bragg peak for superior dose distribution. Proton beams have a relative-biological-effectiveness （RBE） of 1.1， which is slightly higher than that of photon beams. And carbon ions have an RBE of 2-3 due to their high linear energy transfer， thus being more advantageous for radioresistant and hypoxic tumors. Treatment strategies include single-beam and mixed-beam approaches， the latter of which combines the advantages of different particles and is an important direction of cancer treatment research. PBRT faces challenges such as managing moving targets and dose uncertainties， requiring advanced techniques like respiratory gating and adaptive planning. Additionally， the scarcity of randomized clinical trials （RCTs） limits PBRT's clinical validation. Existing RCTs， such as those from MD Anderson， indicate the benefits， as well as the need for further studies to confirm PBRT's long-term efficacy and safety. Future research should compare PBRT to photon therapy and explore the therapeutic benefit of combining PBRT with systemic therapies like immunotherapy. Reviewing the clinical practice and research of PBRT， and further discussing its cost-effectiveness in tumor treatment， can provide readers with a comprehensive understanding and promote the development and application of PBRT in cancer treatment.

Key words:Proton therapy,Heavy ion radiotherapy,Clinical study,Cost-benefit analysis,Particle beam radiation therapy,Clinical application

Kong Lin, Lu Jiade. Breakthroughs and challenges： clinical application and progress of proton and heavy ion radiotherapy for malignant tumors[J]. Journal of International Oncology, 2024, 51(7): 417-423.

References33

[1]	Loeffler JS, Durante M. Charged particle therapy—optimization, challenges and future directions[J].Nat Rev Clin Oncol,2013,10(7): 411-424. DOI:10.1038/nrclinonc.2013.79. pmid:23689752
[2]	Vai A, Molinelli S, Rossi E, et al. Proton radiation therapy for nasopharyngeal cancer patients: dosimetric and NTCP evaluation supporting clinical decision[J].Cancers (Basel),2022,14(5): 1109. DOI:10.3390/cancers14051109.
[3]	Moreno AC, Frank SJ, Garden AS, et al. Intensity modulated proton therapy (IMPT)—the future of IMRT for head and neck cancer[J].Oral Oncol,2019,88: 66-74. DOI:10.1016/j.oraloncology.2018.11.015. pmid:30616799
[4]	Doyen J, Falk AT, Floquet V, et al. Proton beams in cancer treatments: clinical outcomes and dosimetric comparisons with photon therapy[J].Cancer Treat Rev,2016,43: 104-112. DOI:10.1016/j.ctrv.2015.12.007. pmid:26827698
[5]	Ma N, Ming X, Chen J, et al. Dosimetric rationale and preliminary experience in proton plus carbon-ion radiotherapy for esophageal carcinoma: a retrospective analysis[J].Radiat Oncol,2023,18(1): 195. DOI:10.1186/s13014-023-02371-9. pmid:38041122
[6]	Huang H, Gao X, Li Q, et al. Dosimetric comparison between stereotactic body radiotherapy and carbon-ion radiation therapy for prostate cancer[J].Quant Imaging Med Surg,2023,13(10): 6965-6978. DOI:10.21037/qims-23-340.
[7]	Byun HK, Han MC, Yang K, et al. Physical and biological characteristics of particle therapy for oncologists[J].Cancer Res Treat,2021,53(3): 611-620. DOI:10.4143/crt.2021.066. pmid:34139805
[8]	Engwall E, Glimelius L, Hynning E. Effectiveness of different rescanning techniques for scanned proton radiotherapy in lung cancer patients[J].Phys Med Biol,2018,63(9): 095006. DOI:10.1088/1361-6560/aabb7b.
[9]	Paganetti H, Botas P, Sharp GC, et al. Adaptive proton therapy[J].Phys Med Biol,2021,66(22): 10. DOI:10.1088/1361-6560/ac344f.
[10]	Hagiwara Y, Bhattacharyya T, Matsufuji N, et al. Influence of dose-averaged linear energy transfer on tumour control after carbon-ion radiation therapy for pancreatic cancer[J].Clin Transl Radiat Oncol,2019,21: 19-24. DOI:10.1016/j.ctro.2019.11.002.
[11]	Matsumoto S, Lee SH, Imai R, et al. Unresectable chondrosarcomas treated with carbon ion radiotherapy: relationship between dose-averaged linear energy transfer and local recurrence[J].Anticancer Res,2020,40(11): 6429-6435. DOI:10.21873/anticanres.14664. pmid:33109581
[12]	Molinelli S, Magro G, Mairani A, et al. How LEM-based RBE and dose-averaged LET affected clinical outcomes of sacral chordoma patients treated with carbon ion radiotherapy[J].Radiother Oncol,2021,163: 209-214. DOI:10.1016/j.radonc.2021.08.024. pmid:34506829
[13]	Bassler N, Jäkel O, Søndergaard CS, et al. Dose-and LET-painting with particle therapy[J].Acta Oncol,2010,49(7): 1170-1176. DOI:10.3109/0284186X.2010.510640. pmid:20831510
[14]	Malinen E, Søvik Å. Dose or 'LET' painting—what is optimal in particle therapy of hypoxic tumors?[J].Acta Oncol,2015,54(9): 1614-1622. DOI:10.3109/0284186X.2015.1062540. pmid:26198655
[15]	Hu J, Huang Q, Gao J, et al. Mixed photon and carbon-ion beam radiotherapy in the management of non-metastatic nasopharyngeal carcinoma[J].Front Oncol,2021,11: 653050. DOI:10.3389/fonc.2021.653050.
[16]	Liao Z, Lee JJ, Komaki R, et al. Bayesian adaptive randomization trial of passive scattering proton therapy and intensity-modulated photon radiotherapy for locally advanced non-small-cell lung cancer[J].J Clin Oncol,2018,36(18): 1813-1822. DOI:10.1200/JCO.2017.74.0720. pmid:29293386
[17]	Frank SJ, Busse P, Rosenthal DI, et al. Phase Ⅲ randomized trial of intensity-modulated proton therapy (IMPT) versus intensity-modulated photon therapy (IMRT) for the treatment of head and neck oropharyngeal carcinoma (OPC)[J].J Clin Oncol,2024,42(16 Suppl): 6006. DOI:10.1200/JCO.2024.42.16_suppl.6006.
[18]	Sokol O, Durante M. Carbon ions for hypoxic tumors: are we making the most of them?[J].Cancers (Basel),2023,15(18): 4494. DOI:10.3390/cancers15184494.
[19]	Helm A, Fournier C. High-LET charged particles: radiobiology and application for new approaches in radiotherapy[J].Strahlenther Onkol,2023,199(12): 1225-1241. DOI:10.1007/s00066-023-02158-7. pmid:37872399
[20]	Rodríguez-Ruiz ME, Vanpouille-Box C, Melero I, et al. Immunological mechanisms responsible for radiation-induced abscopal effect[J].Trends Immunol,2018,39(8): 644-655. DOI:10.1016/j.it.2018.06.001. pmid:30001871
[21]	Ngwa W, Irabor OC, Schoenfeld JD, et al. Using immunotherapy to boost the abscopal effect[J].Nat Rev Cancer,2018,18(5): 313-322. DOI:10.1038/nrc.2018.6. pmid:29449659
[22]	Zhang Z, Liu X, Chen D, et al. Radiotherapy combined with immunotherapy: the dawn of cancer treatment[J].Signal Transduct Target Ther,2022,7(1): 258. DOI:10.1038/s41392-022-01102-y.
[23]	Takahashi Y, Yasui T, Minami K, et al. Carbon ion irradiation enhances the antitumor efficacy of dual immune checkpoint blockade therapy both for local and distant sites in murine osteosarcoma[J].Oncotarget,2019,10(6): 633-646. DOI:10.18632/oncotarget.26551. pmid:30774761
[24]	Helm A, Tinganelli W, Simoniello P, et al. Reduction of lung metastases in a mouse osteosarcoma model treated with carbon ions and immune checkpoint inhibitors[J].Int J Radiat Oncol Biol Phys,2021,109(2): 594-602. DOI:10.1016/j.ijrobp.2020.09.041.
[25]	Nie M, Chen L, Zhang J, et al. Pure proton therapy for skull base chordomas and chondrosarcomas: a systematic review of clinical experience[J].Front Oncol,2022: 1016857. DOI:10.3389/fonc.2022.1016857.
[26]	Guan X, Gao J, Hu J, et al. The preliminary results of proton and carbon ion therapy for chordoma and chondrosarcoma of the skull base and cervical spine[J].Radiat Oncol,2019,14(1): 206. DOI:10.1186/s13014-019-1407-9. pmid:31752953
[27]	Ioakeim-Ioannidou M, Niemierko A, Kim DW, et al. Surgery and proton radiation therapy for pediatric base of skull chordomas: long-term clinical outcomes for 204 patients[J].Neuro Oncol,2023,25(9): 1686-1697. DOI:10.1093/neuonc/noad068.
[28]	Hu J, Huang Q, Gao J, et al. Clinical outcomes of carbon-ion radiotherapy for patients with locoregionally recurrent nasopharyngeal carcinoma[J].Cancer,2020,126(23): 5173-5183. DOI:10.1002/cncr.33197.
[29]	Greenberger BA, Yock TI. The role of proton therapy in pediatric malignancies: recent advances and future directions[J].Semin Oncol,2020,47(1): 8-22. DOI:10.1053/j.seminoncol.2020.02.002. pmid:32139101
[30]	Mohan R, Grosshans D. Proton therapy-present and future[J].Adv Drug Deliv Rev,2017,109: 26-44. DOI:10.1016/j.addr.2016.11.006.
[31]	Verma V, Mishra MV, Mehta MP. A systematic review of the cost and cost-effectiveness studies of proton radiotherapy[J].Cancer,2016,122(10): 1483-1501. DOI:10.1002/cncr.29882. pmid:26828647
[32]	Mailhot Vega RB, Ishaq O, Raldow A, et al. Establishing cost-effective allocation of proton therapy for breast irradiation[J].Int J Radiat Oncol Biol Phys,2016,95(1): 11-18. DOI:10.1016/j.ijrobp.2016.02.031.
[33]	Mutter RW, Choi JI, Jimenez RB, et al. Proton therapy for breast cancer: a consensus statement from the particle therapy cooperative group breast cancer subcommittee[J].Int J Radiat Oncol Biol Phys,2021,111(2): 337-359. DOI:10.1016/j.ijrobp.2021.05.110.