A review on proton therapy of cancer
Abstract
Proton therapy has emerged as an advanced form of external beam radiotherapy that exploits the unique physical property of the Bragg peak to deliver high radiation doses to tumours while minimizing exit dose to surrounding normal tissues. This dosimetrist advantage is particularly relevant in paediatric cancers, central nervous system tumours, head and neck malignancies, and situations requiring re-irradiation, where reduction in late toxicities and preservation of organ function are critical. Clinical evidence demonstrates reduced acute and long-term complications, especially in children, though survival benefits over state-of-the-art photon techniques are less consistently established in adults. Modern intensity-modulated proton therapy (IMPT) enhances conformality but introduces uncertainties such as range variation and variable relative biological effectiveness, which necessitate robust treatment planning. While cost and limited accessibility remain barriers to widespread adoption, health-economic analyses suggest proton therapy may be cost-effective in select patient populations with long life expectancy or high risk of treatment-related morbidity. Emerging directions include adaptive strategies, biological optimization, and ultra-high dose-rate “FLASH” proton therapy, which show promise for further widening the therapeutic window. Overall, proton therapy represents a valuable and evolving modality in cancer management, with strongest justification in pediatric and anatomically complex tumors , and ongoing trials are expected to better define its role across common adult cancers.
Keywords:
Proton Therapy, Proton Beam Therapy, Bragg Peak, Cancer Treatment
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References
1. Yuan TZ. New frontiers in proton therapy: applications in cancers. Cancer Commun (Lond). 2019;39(61):61. doi:10.1186/s40880-019-0407-3. PMID: 31640788; PMCID: PMC6805548.
2. Loeffler JS, Durante M. Charged particle therapy—optimization, challenges and future directions. Nat Rev Clin Oncol. 2013;10(7):411–424.
3. Durante M, Loeffler JS. Charged particles in radiation oncology. Nat Rev Clin Oncol. 2010;7(1):37–43.
4. Togno M, et al. Advances in intensity-modulated proton therapy: Current status and future directions. Front Oncol. 2020;10:770.
5. Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–491. doi:10.1148/47.5.487.
6. Tobias CA, Lawrence JH, Born JL, et al. Pituitary irradiation with high-energy proton beams: a preliminary report. Cancer Res. 1958;18.
7. Goitein M, Koehler AM. Treatment planning for proton therapy. Int J Radiat Oncol Biol Phys. 1975;2(8):789–798.
8. Suit HD, Urie M, Goitein M, et al. Evaluation of proton beams for carcinoma therapy. Cancer. 1992;59(12):2249–2253.
9. Newhauser WD, Zhang R. The physics of proton therapy. Phys Med Biol. 2015;60(8):R155–R209. doi:10.1088/0031-9155/60/8/R155.
10. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol. 2012;57(11):R99–R117.
11. International Commission on Radiation Units and Measurements (ICRU). ICRU Report 78: Prescribing, Recording, and Reporting Proton-Beam Therapy. J ICRU. 2007.
12. Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment uncertainties 1: the potential effects of calculational uncertainties. Phys Med Biol. 2014;53:1027–1042.
13. Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–491.
14. Delaney TF, Kooy HM, editors. Proton and Charged Particle Radiotherapy. Philadelphia: Lippincott Williams & Wilkins; 2008.
15. Chhabra A. Two common methods are available for the delivery of proton therapy: passive scattering and active scanning. 2016.
16. Quan EM, Liu W, Wu R, et al. Preliminary evaluation of multifield and single-field optimization for the treatment planning of spot-scanning proton therapy of head and neck cancer. Med Phys. 2013;40:081709.
17. Mohan R. Spreading and shaping can be achieved by passively-scattered proton therapy (PSPT) or using magnetic scanning of thin beamlets in optimized intensity modulated proton therapy (IMPT). 2022.
18. Lühr A, et al. Relative biological effectiveness in proton beam therapy. Phys Med Biol. 2018;63(1). PMCID: PMC5862688.
19. Chen YL, Liebsch N, Kobayashi W. Definitive high-dose photon/proton radiotherapy for unresected mobile spine and sacral chordomas. Spine (Phila Pa 1976). 2013;38:E930–E936. doi:10.1097/BRS.0b013e318296e7d7.
20. Holtzman AL, et al. Impact of relative biologic effectiveness for proton therapy. Cancer. 2024. PMCID: PMC11171304.
21. Press RH, et al. Current status and technological advancements in proton therapy. 2024.
22. Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer. 2005;93(8):849–854. doi:10.1038/sj.bjc.6602754. PMID: 16189526; PMCID: PMC2361650.
23. Pedroni E, Bohringer T, Coray A, et al. Initial experience of using an active beam delivery technique at PSI. Strahlenther Onkol. 1999;175 Suppl 2:18–20. PMID: 10394388.
24. Lomax A. Intensity modulation methods for proton radiotherapy. Phys Med Biol. 1999;44:185–205. PMID: 10071883.
25. Ahern V. Selecting patients for proton beam therapy. J Med Radiat Sci. 2020.
26. Zientara N, et al. A scoping review of patient selection methods for proton therapy. Radiother Oncol. 2021.
27. Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer. 2005;93(8):849–854. doi:10.1038/sj.bjc.6602754.
28. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol. 2012;57(11):R99–R117. doi:10.1088/0031-9155/57/11/R99.
29. Smith AR. Proton therapy. Phys Med Biol. 2006;51(13):R491–R504. doi:10.1088/0031-9155/51/13/R26.
30. Smith AR. 2006; Paganetti H. 2012; Lomax AJ. 2008; Mailhot Vega RB. 2020.
31. Newhauser WD, Zhang R. The physics of proton therapy. Phys Med Biol. 2015;60:R155–R209. doi:10.1088/0031-9155/60/8/R155.
32. Newhauser WD, Zhang R. Phys Med Biol. 2015;60:R155–R209.
33. Smith AR. Proton therapy. Phys Med Biol. 2006;51:R491–R504.
34. Mailhot Vega RB, et al. Quality of life and patient-reported outcomes in proton therapy. Cancer. 2020;126(12):2636–2645.
35. International Agency for Research on Cancer. Estimated number of new cases in 2020, world, both sexes, all ages (excluding NMSC). Available from: https://gco.iarc.fr/today/online-analysis-table Accessed 6 March 2023.
36. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics. CA Cancer J Clin. 2012;2015:87–108.
37. Sax Institute. Rapid review: Evidence summary on proton beam therapy. 2024.
38. Jimenez RB, Sethi R, Depauw N, et al. Proton radiation therapy for pediatric medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very young children treated with upfront chemotherapy. Int J Radiat Oncol Biol Phys. 2013;21:017.
39. Ladra MM, Szymonifka JD, Mahajan A, et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol. 2014;32:3762–3770. doi:10.1200/JCO.2014.56.1548.
40. Blanchard P, et al. Proton therapy: assessment of clinical evidence. Radiother Oncol. 2016;119(2):195–201.
41. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol. 2012;57(11):R99–R117.
42. Astrahan MA. Some dosimetric aspects of proton radiotherapy. Radiat Oncol. 2008;3(1):35.
43. Hyer DE, Hill PM, Wang D, et al. A dynamic collimation system for penumbra reduction in spot-scanning proton therapy: proof of concept. Med Phys. 2014;41:091701. PMID: 25186376.
44. Hyer DE, Hill PM, Wang D, et al. Effects of spot size and spot spacing on lateral penumbra reduction when using a dynamic collimation system for spot scanning proton therapy. Phys Med Biol. 2014;59:N187–N196. PMID: 25330783.
45. Paganetti H. Proton beam therapy. Phys Med Biol. 2016;61(15):R75–R116.
46. Verburg JM, et al. Image-guided proton therapy: advances and challenges. Br J Radiol. 2018;91(1081):20180276.
47. Paganetti H, van Luijk P. Biological considerations when comparing proton therapy with photon therapy. Semin Radiat Oncol. 2013;23(2):77–87.
48. Verma V, et al. Cancer. 2016;122(10):1483–1501.
49. Lomax AJ. Phys Med Biol. 2016;61(13):R75–R109.
50. Wong W, Yim YM, Kim A, et al. Assessment of costs associated with adverse events in patients with cancer. PLoS One. 2018;13(4):e0196007. doi:10.1371/journal.pone.0196007.
51. Deutsch E, Le Péchoux C, Faivre L, et al. Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer. Ann Oncol. 2015;26(6):1223–1229. doi:10.1093/annonc/mdv105.
52. Sacher AG, Le LW, Leighl NB, Coate LE. Elderly patients with advanced NSCLC in phase III clinical trials: are the elderly excluded from practice-changing trials in advanced NSCLC? J Thorac Oncol. 2013;8(3):366–368. doi:10.1097/JTO.0b013e31827e2145.
2. Loeffler JS, Durante M. Charged particle therapy—optimization, challenges and future directions. Nat Rev Clin Oncol. 2013;10(7):411–424.
3. Durante M, Loeffler JS. Charged particles in radiation oncology. Nat Rev Clin Oncol. 2010;7(1):37–43.
4. Togno M, et al. Advances in intensity-modulated proton therapy: Current status and future directions. Front Oncol. 2020;10:770.
5. Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–491. doi:10.1148/47.5.487.
6. Tobias CA, Lawrence JH, Born JL, et al. Pituitary irradiation with high-energy proton beams: a preliminary report. Cancer Res. 1958;18.
7. Goitein M, Koehler AM. Treatment planning for proton therapy. Int J Radiat Oncol Biol Phys. 1975;2(8):789–798.
8. Suit HD, Urie M, Goitein M, et al. Evaluation of proton beams for carcinoma therapy. Cancer. 1992;59(12):2249–2253.
9. Newhauser WD, Zhang R. The physics of proton therapy. Phys Med Biol. 2015;60(8):R155–R209. doi:10.1088/0031-9155/60/8/R155.
10. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol. 2012;57(11):R99–R117.
11. International Commission on Radiation Units and Measurements (ICRU). ICRU Report 78: Prescribing, Recording, and Reporting Proton-Beam Therapy. J ICRU. 2007.
12. Lomax AJ. Intensity modulated proton therapy and its sensitivity to treatment uncertainties 1: the potential effects of calculational uncertainties. Phys Med Biol. 2014;53:1027–1042.
13. Wilson RR. Radiological use of fast protons. Radiology. 1946;47:487–491.
14. Delaney TF, Kooy HM, editors. Proton and Charged Particle Radiotherapy. Philadelphia: Lippincott Williams & Wilkins; 2008.
15. Chhabra A. Two common methods are available for the delivery of proton therapy: passive scattering and active scanning. 2016.
16. Quan EM, Liu W, Wu R, et al. Preliminary evaluation of multifield and single-field optimization for the treatment planning of spot-scanning proton therapy of head and neck cancer. Med Phys. 2013;40:081709.
17. Mohan R. Spreading and shaping can be achieved by passively-scattered proton therapy (PSPT) or using magnetic scanning of thin beamlets in optimized intensity modulated proton therapy (IMPT). 2022.
18. Lühr A, et al. Relative biological effectiveness in proton beam therapy. Phys Med Biol. 2018;63(1). PMCID: PMC5862688.
19. Chen YL, Liebsch N, Kobayashi W. Definitive high-dose photon/proton radiotherapy for unresected mobile spine and sacral chordomas. Spine (Phila Pa 1976). 2013;38:E930–E936. doi:10.1097/BRS.0b013e318296e7d7.
20. Holtzman AL, et al. Impact of relative biologic effectiveness for proton therapy. Cancer. 2024. PMCID: PMC11171304.
21. Press RH, et al. Current status and technological advancements in proton therapy. 2024.
22. Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer. 2005;93(8):849–854. doi:10.1038/sj.bjc.6602754. PMID: 16189526; PMCID: PMC2361650.
23. Pedroni E, Bohringer T, Coray A, et al. Initial experience of using an active beam delivery technique at PSI. Strahlenther Onkol. 1999;175 Suppl 2:18–20. PMID: 10394388.
24. Lomax A. Intensity modulation methods for proton radiotherapy. Phys Med Biol. 1999;44:185–205. PMID: 10071883.
25. Ahern V. Selecting patients for proton beam therapy. J Med Radiat Sci. 2020.
26. Zientara N, et al. A scoping review of patient selection methods for proton therapy. Radiother Oncol. 2021.
27. Levin WP, Kooy H, Loeffler JS, DeLaney TF. Proton beam therapy. Br J Cancer. 2005;93(8):849–854. doi:10.1038/sj.bjc.6602754.
28. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol. 2012;57(11):R99–R117. doi:10.1088/0031-9155/57/11/R99.
29. Smith AR. Proton therapy. Phys Med Biol. 2006;51(13):R491–R504. doi:10.1088/0031-9155/51/13/R26.
30. Smith AR. 2006; Paganetti H. 2012; Lomax AJ. 2008; Mailhot Vega RB. 2020.
31. Newhauser WD, Zhang R. The physics of proton therapy. Phys Med Biol. 2015;60:R155–R209. doi:10.1088/0031-9155/60/8/R155.
32. Newhauser WD, Zhang R. Phys Med Biol. 2015;60:R155–R209.
33. Smith AR. Proton therapy. Phys Med Biol. 2006;51:R491–R504.
34. Mailhot Vega RB, et al. Quality of life and patient-reported outcomes in proton therapy. Cancer. 2020;126(12):2636–2645.
35. International Agency for Research on Cancer. Estimated number of new cases in 2020, world, both sexes, all ages (excluding NMSC). Available from: https://gco.iarc.fr/today/online-analysis-table Accessed 6 March 2023.
36. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics. CA Cancer J Clin. 2012;2015:87–108.
37. Sax Institute. Rapid review: Evidence summary on proton beam therapy. 2024.
38. Jimenez RB, Sethi R, Depauw N, et al. Proton radiation therapy for pediatric medulloblastoma and supratentorial primitive neuroectodermal tumors: outcomes for very young children treated with upfront chemotherapy. Int J Radiat Oncol Biol Phys. 2013;21:017.
39. Ladra MM, Szymonifka JD, Mahajan A, et al. Preliminary results of a phase II trial of proton radiotherapy for pediatric rhabdomyosarcoma. J Clin Oncol. 2014;32:3762–3770. doi:10.1200/JCO.2014.56.1548.
40. Blanchard P, et al. Proton therapy: assessment of clinical evidence. Radiother Oncol. 2016;119(2):195–201.
41. Paganetti H. Range uncertainties in proton therapy and the role of Monte Carlo simulations. Phys Med Biol. 2012;57(11):R99–R117.
42. Astrahan MA. Some dosimetric aspects of proton radiotherapy. Radiat Oncol. 2008;3(1):35.
43. Hyer DE, Hill PM, Wang D, et al. A dynamic collimation system for penumbra reduction in spot-scanning proton therapy: proof of concept. Med Phys. 2014;41:091701. PMID: 25186376.
44. Hyer DE, Hill PM, Wang D, et al. Effects of spot size and spot spacing on lateral penumbra reduction when using a dynamic collimation system for spot scanning proton therapy. Phys Med Biol. 2014;59:N187–N196. PMID: 25330783.
45. Paganetti H. Proton beam therapy. Phys Med Biol. 2016;61(15):R75–R116.
46. Verburg JM, et al. Image-guided proton therapy: advances and challenges. Br J Radiol. 2018;91(1081):20180276.
47. Paganetti H, van Luijk P. Biological considerations when comparing proton therapy with photon therapy. Semin Radiat Oncol. 2013;23(2):77–87.
48. Verma V, et al. Cancer. 2016;122(10):1483–1501.
49. Lomax AJ. Phys Med Biol. 2016;61(13):R75–R109.
50. Wong W, Yim YM, Kim A, et al. Assessment of costs associated with adverse events in patients with cancer. PLoS One. 2018;13(4):e0196007. doi:10.1371/journal.pone.0196007.
51. Deutsch E, Le Péchoux C, Faivre L, et al. Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer. Ann Oncol. 2015;26(6):1223–1229. doi:10.1093/annonc/mdv105.
52. Sacher AG, Le LW, Leighl NB, Coate LE. Elderly patients with advanced NSCLC in phase III clinical trials: are the elderly excluded from practice-changing trials in advanced NSCLC? J Thorac Oncol. 2013;8(3):366–368. doi:10.1097/JTO.0b013e31827e2145.
Published
06/11/2025
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I, P. D., A. P. SK, P. C. Yadala, and S. M. “A Review on Proton Therapy of Cancer”. International Journal of Health Care and Biological Sciences, Vol. 6, no. 4, Nov. 2025, pp. 13-24, doi:10.46795/ijhcbs.v6i4.765.
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