Proton Beam Reirradiation

  • Mark W. McDonald
  • Kevin P. McMullen
Part of the Medical Radiology book series (MEDRAD)


Proton therapy is a modality of radiation therapy with unique physical properties relative to photon (X-ray) therapy. Each proton beam is modulated to deposit the maximum radiation dose in the target, with essentially no radiation to tissues beyond the target. Compared to photon treatments, highly conformal treatment plans can typically be developed with fewer proton beams, significantly reducing the overall exposure of nontarget tissues to radiation. Given the narrow therapeutic window of reirradiation, proton therapy is of great interest as a mechanism to potentially avoid or reduce toxicities of reirradiation by limiting the volume of nontarget tissues receiving additional radiation dose. In some diseases, proton reirradiation may improve outcomes by facilitating safer radiation dose escalation to recurrent and potentially radioresistant tumors or providing better target coverage while respecting constraints to critical normal structures. In uncommon cases, proton therapy may permit reirradiation when the dosimetry achieved with other modalities is felt to preclude safe reirradiation. Clinical experience with proton reirradiation is currently limited to relatively small patient series and is highly heterogeneous. To better understand the value of proton therapy in reirradiation relative to other radiation modalities, prospective evaluation with more homogenous patient populations is needed to evaluate predefined end points based on rational clinical hypotheses. In this chapter, the rationale and published clinical results of proton therapy for reirradiation are reviewed for a variety of disease sites, with case examples provided.


Stereotactic Body Radiation Therapy Concurrent Chemotherapy Radiation Necrosis Proton Therapy Proton Beam Therapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Andersson KM, Ahnesjo A, Vallhagen Dahlgren C (2014) Evaluation of a metal artifact reduction algorithm in CT studies used for proton radiotherapy treatment planning. J Appl Clin Med Phys 15(5):4857CrossRefPubMedGoogle Scholar
  2. Bassal M, Mertens AC, Taylor L, Neglia JP, Greffe BS, Hammond S, Ronckers CM, Friedman DL, Stovall M, Yasui YY, Robison LL, Meadows AT, Kadan-Lottick NS (2006) Risk of selected subsequent carcinomas in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol 24(3):476–483CrossRefPubMedGoogle Scholar
  3. Berman AT, Both S, Sharkoski T, Goldrath K, Tochner Z, Apisarnthanarax S, Metz JM, Plastaras JP (2014) Proton reirradiation of recurrent rectal cancer: dosimetric comparison, toxicities, and preliminary outcomes. Int J Particle Ther 1(1):2–13CrossRefGoogle Scholar
  4. Berrington de Gonzalez A, Curtis RE, Kry SF, Gilbert E, Lamart S, Berg CD, Stovall M, Ron E (2011) Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol 12(4):353–360CrossRefPubMedGoogle Scholar
  5. Bishop AJ, Gupta S, Cunningham MG, Tao R, Berner PA, Korpela SG, Ibbott GS, Lawyer AA, Crane CH (2015) Interstitial brachytherapy for the treatment of locally recurrent anorectal cancer. Ann Surg Oncol 22(S3):596–602Google Scholar
  6. Brown AP, Barney CL, Grosshans DR, McAleer MF, de Groot JF, Puduvalli VK, Tucker SL, Crawford CN, Khan M, Khatua S, Gilbert MR, Brown PD, Mahajan A (2013) Proton beam craniospinal irradiation reduces acute toxicity for adults with medulloblastoma. Int J Radiat Oncol Biol Phys 86(2):277–284CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chung CS, Yock TI, Nelson K, Xu Y, Keating NL, Tarbell NJ (2013) Incidence of second malignancies among patients treated with proton versus photon radiation. Int J Radiat Oncol Biol Phys 87(1):46–52CrossRefPubMedGoogle Scholar
  8. Combs SE, Burkholder I, Edler L, Rieken S, Habermehl D, Jakel O, Haberer T, Haselmann R, Unterberg A, Wick W, Debus J (2010) Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: the CINDERELLA trial. BMC Cancer 10:533CrossRefPubMedPubMedCentralGoogle Scholar
  9. De Ruysscher D, Sterpin E, Haustermans K, Depuydt T (2015) Tumour movement in proton therapy: solutions and remaining questions: a review. Cancers (Basel) 7(3):1143–1153CrossRefGoogle Scholar
  10. Defoe SG, Bernard ME, Rwigema JC, Heron DE, Ozhasoglu C, Burton S (2011) Stereotactic body radiotherapy for the treatment of presacral recurrences from rectal cancers. J Cancer Res Ther 7(4):408–411CrossRefPubMedGoogle Scholar
  11. Dendale R, Lumbroso-Le Rouic L, Noel G, Feuvret L, Levy C, Delacroix S, Meyer A, Nauraye C, Mazal A, Mammar H, Garcia P, D’Hermies F, Frau E, Plancher C, Asselain B, Schlienger P, Mazeron JJ, Desjardins L (2006) Proton beam radiotherapy for uveal melanoma: results of Curie Institut-Orsay proton therapy center (ICPO). Int J Radiat Oncol Biol Phys 65(3):780–787CrossRefPubMedGoogle Scholar
  12. Desjardins L, Lumbroso-Le Rouic L, Levy-Gabriel C, Cassoux N, Dendale R, Mazal A, Delacroix S, Sastre X, Plancher C, Asselain B (2012) Treatment of uveal melanoma by accelerated proton beam. Dev Ophthalmol 49:41–57CrossRefPubMedGoogle Scholar
  13. Diener-West M, Earle JD, Fine SL, Hawkins BS, Moy CS, Reynolds SM, Schachat AP, Straatsma BR, Collaborative Ocular Melanoma Study G (2001) The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18. Arch Ophthalmol 119(7):969–982CrossRefPubMedGoogle Scholar
  14. Eaton BR, Esiashvili N, Kim S, Patterson B, Weyman EA, Thornton LT, Mazewski C, MacDonald TJ, Ebb D, MacDonald SM, Tarbell NJ, Yock TI (2015) Endocrine outcomes with proton and photon radiotherapy for standard risk medulloblastoma. Neuro Oncol, available online ahead of printGoogle Scholar
  15. Fagundes MA, Hug EB, Liebsch NJ, Daly W, Efird J, Munzenrider JE (1995) Radiation therapy for chordomas of the base of skull and cervical spine: patterns of failure and outcome after relapse. Int J Radiat Oncol Biol Phys 33(3):579–584CrossRefPubMedGoogle Scholar
  16. Fernandes A, Berman AT, Mick R, Both S, Lelionis K, Lukens JN, Ben-Josef E, Metz JM, Plastaras JP (2016) A prospective study of proton beam reirradiation for esophageal cancer. Int J Radiat Oncol Biol Phys 95(1):483–487Google Scholar
  17. Fogh SE, Andrews DW, Glass J, Curran W, Glass C, Champ C, Evans JJ, Hyslop T, Pequignot E, Downes B, Comber E, Maltenfort M, Dicker AP, Werner-Wasik M (2010) Hypofractionated stereotactic radiation therapy: an effective therapy for recurrent high-grade gliomas. J Clin Oncol 28(18):3048–3053CrossRefPubMedPubMedCentralGoogle Scholar
  18. Galle JO, McDonald MW, Simoneaux V, Buchsbaum JC (2015) Reirradiation with proton therapy for recurrent gliomas. Int J Particle Ther 2(1):11–18CrossRefGoogle Scholar
  19. Hill-Kayser C, Kirk M (2015) Brainstem-sparing craniospinal irradiation delivered with pencil beam scanning proton therapy. Pediatr Blood Cancer 62(4):718–720CrossRefPubMedGoogle Scholar
  20. Hocht S, Stark R, Seiler F, Heufelder J, Bechrakis NE, Cordini D, Marnitz S, Kluge H, Foerster MH, Hinkelbein W (2005) Proton or stereotactic photon irradiation for posterior uveal melanoma? A planning intercomparison. Strahlenther Onkol 181(12):783–788CrossRefPubMedGoogle Scholar
  21. ICRU (2007) Prescribing, recording, and reporting proton-beam therapy: treatment planning. J ICRU 7(2):95–122Google Scholar
  22. Kano H, Iqbal FO, Sheehan J, Mathieu D, Seymour ZA, Niranjan A, Flickinger JC, Kondziolka D, Pollock BE, Rosseau G, Sneed PK, McDermott MW, Lunsford LD (2011) Stereotactic radiosurgery for chordoma: a report from the North American Gamma Knife Consortium. Neurosurgery 68(2):379–389CrossRefPubMedGoogle Scholar
  23. Kleinerman RA, Tucker MA, Tarone RE, Abramson DH, Seddon JM, Stovall M, Li FP, Fraumeni JF Jr (2005) Risk of new cancers after radiotherapy in long-term survivors of retinoblastoma: an extended follow-up. J Clin Oncol 23(10):2272–2279CrossRefPubMedGoogle Scholar
  24. Konski AA, Suh WW, Herman JM, Blackstock AW Jr, Hong TS, Poggi MM, Rodriguez-Bigas M, Small W Jr, Thomas CR Jr, Zook J (2012) ACR appropriateness criteria(R)-recurrent rectal cancer. Gastrointest Cancer Res 5(1):3–12PubMedPubMedCentralGoogle Scholar
  25. Kusters M, Dresen RC, Martijn H, Nieuwenhuijzen GA, van de Velde CJ, van den Berg HA, Beets-Tan RG, Rutten HJ (2009) Radicality of resection and survival after multimodality treatment is influenced by subsite of locally recurrent rectal cancer. Int J Radiat Oncol Biol Phys 75(5):1444–1449CrossRefPubMedGoogle Scholar
  26. Langer CJ, Harris J, Horwitz EM, Nicolaou N, Kies M, Curran W, Wong S, Ang K (2007) Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in recurrent squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Protocol 9911. J Clin Oncol 25(30):4800–4805CrossRefPubMedGoogle Scholar
  27. Li Z (2012) Toward robust proton therapy planning and delivery. Transl Cancer Res 1(3):217–226Google Scholar
  28. Lomax AJ (2009) Charged particle therapy: the physics of interaction. Cancer J 15(4):285–291CrossRefPubMedGoogle Scholar
  29. Lomax AJ, Bohringer T, Bolsi A, Coray D, Emert F, Goitein G, Jermann M, Lin S, Pedroni E, Rutz H, Stadelmann O, Timmermann B, Verwey J, Weber DC (2004) Treatment planning and verification of proton therapy using spot scanning: initial experiences. Med Phys 31(11):3150–3157CrossRefPubMedGoogle Scholar
  30. Mannina E Jr, Bartlett G, Wallace D, McMullen K (2014) Steroid-induced adaptive proton planning in a pediatric patient with low grade glioma: a case report and literature review. Pract Radiat Oncol 4(1):50–54CrossRefPubMedGoogle Scholar
  31. Marucci L, Lane AM, Li W, Egan KM, Gragoudas ES, Adams JA, Collier JM, Munzenrider JE (2006) Conservation treatment of the eye: conformal proton reirradiation for recurrent uveal melanoma. Int J Radiat Oncol Biol Phys 64(4):1018–1022CrossRefPubMedGoogle Scholar
  32. Marucci L, Ancukiewicz M, Lane AM, Collier JM, Gragoudas ES, Munzenrider JE (2011) Uveal melanoma recurrence after fractionated proton beam therapy: comparison of survival in patients treated with reirradiation or with enucleation. Int J Radiat Oncol Biol Phys 79(3):842–846CrossRefPubMedGoogle Scholar
  33. Massimino M, Gandola L, Spreafico F, Biassoni V, Luksch R, Collini P, Solero CN, Simonetti F, Pignoli E, Cefalo G, Poggi G, Modena P, Mariani L, Potepan P, Podda M, Casanova M, Pecori E, Acerno S, Ferrari A, Terenziani M, Meazza C, Polastri D, Ravagnani F, Fossati-Bellani F (2009) No salvage using high-dose chemotherapy plus/minus reirradiation for relapsing previously irradiated medulloblastoma. Int J Radiat Oncol Biol Phys 73(5):1358–1363CrossRefPubMedGoogle Scholar
  34. McAvoy SA, Ciura KT, Rineer JM, Allen PK, Liao Z, Chang JY, Palmer MB, Cox JD, Komaki R, Gomez DR (2013) Feasibility of proton beam therapy for reirradiation of locoregionally recurrent non-small cell lung cancer. Radiother Oncol 109(1):38–44CrossRefPubMedGoogle Scholar
  35. McAvoy S, Ciura K, Wei C, Rineer J, Liao Z, Chang JY, Palmer MB, Cox JD, Komaki R, Gomez DR (2014) Definitive reirradiation for locoregionally recurrent non-small cell lung cancer with proton beam therapy or intensity modulated radiation therapy: predictors of high-grade toxicity and survival outcomes. Int J Radiat Oncol Biol Phys 90(4):819–827CrossRefPubMedGoogle Scholar
  36. McDonald MW, Lawson J, Garg MK, Quon H, Ridge JA, Saba N, Salama JK, Smith RV, Yeung AR, Yom SS, Beitler JJ, Expert Panel on Radiation O-H, Neck C (2011) ACR appropriateness criteria retreatment of recurrent head and neck cancer after prior definitive radiation expert panel on radiation oncology-head and neck cancer. Int J Radiat Oncol Biol Phys 80(5):1292–1298CrossRefPubMedGoogle Scholar
  37. McDonald MW, Linton OR, Shah MV (2013a) Proton therapy for reirradiation of progressive or recurrent chordoma. Int J Radiat Oncol Biol Phys 87(5):1107–1114CrossRefPubMedGoogle Scholar
  38. McDonald MW, Wolanski MR, Simmons JW, Buchsbaum JC (2013b) Technique for sparing previously irradiated critical normal structures in salvage proton craniospinal irradiation. Radiat Oncol 8:14CrossRefPubMedPubMedCentralGoogle Scholar
  39. McDonald MW, Linton OR, Moore MG, Ting JY, Cohen-Gadol AA, Shah MV (2016a) Influence of residual tumor volume and radiation dose coverage in outcomes for clival chordoma. Int J Radiat Oncol Biol Phys 95(1):304–311Google Scholar
  40. McDonald MW, Zolali-Meybodi O, Lehnert SJ, Cohen-Gadol AA, Moore MG (2016b) Reirradiation of recurrent and second primary head and neck cancer with proton therapy. Int J Radiat Oncol Biol Phys 94(4):930–931Google Scholar
  41. Merchant TE, Boop FA, Kun LE, Sanford RA (2008) A retrospective study of surgery and reirradiation for recurrent ependymoma. Int J Radiat Oncol Biol Phys 71(1):87–97CrossRefPubMedGoogle Scholar
  42. Mokutani Y, Yamamoto H, Uemura M, Haraguchi N, Takahashi H, Nishimura J, Hata T, Takemasa I, Mizushima T, Doki Y, Mori M (2015) Effect of particle beam radiotherapy on locally recurrent rectal cancer: three case reports. Mol Clin Oncol 3(4):765–769CrossRefPubMedPubMedCentralGoogle Scholar
  43. Moriya Y (2006) Treatment strategy for locally recurrent rectal cancer. Jpn J Clin Oncol 36(3):127–131CrossRefPubMedGoogle Scholar
  44. Paganetti H (2012) Proton therapy physics, Series in medical physics and biomedical engineering. CRC Press, Boca RatonGoogle Scholar
  45. Romesser PB, Cahlon O, Scher ED, Hug EB, Sine K, DeSelm C, Fox JL, Mah D, Garg MK, Chang JH, Lee NY (2016) Proton beam re-irradiation for recurrent head and neck cancer: multi-institutional report on feasibility and early outcomes. Int J Radiat Oncol Biol Phys 95(1):386–395CrossRefPubMedPubMedCentralGoogle Scholar
  46. Sharma V, Mahantshetty U, Dinshaw KA, Deshpande R, Sharma S (2002) Palliation of advanced/recurrent esophageal carcinoma with high-dose-rate brachytherapy. Int J Radiat Oncol Biol Phys 52(2):310–315CrossRefPubMedGoogle Scholar
  47. Sikuade MJ, Salvi S, Rundle PA, Errington DG, Kacperek A, Rennie IG (2015) Outcomes of treatment with stereotactic radiosurgery or proton beam therapy for choroidal melanoma. Eye (Lond) 29(9):1194–1198CrossRefGoogle Scholar
  48. Simone CB 2nd, Kramer K, O’Meara WP, Bekelman JE, Belard A, McDonough J, O’Connell J (2012) Predicted rates of secondary malignancies from proton versus photon radiation therapy for stage I seminoma. Int J Radiat Oncol Biol Phys 82(1):242–249CrossRefPubMedGoogle Scholar
  49. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466Google Scholar
  50. Stupp R, Brada M, van den Bent MJ, Tonn JC, Pentheroudakis G, Group EGW (2014) High-grade glioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(Suppl 3):iii93–101Google Scholar
  51. Suit H, Goldberg S, Niemierko A, Trofimov A, Adams J, Paganetti H, Chen GT, Bortfeld T, Rosenthal S, Loeffler J, Delaney T (2003) Proton beams to replace photon beams in radical dose treatments. Acta Oncol 42(8):800–808CrossRefPubMedGoogle Scholar
  52. van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van de Velde CJ (2011) Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol 12(6):575–582Google Scholar
  53. Verburg JM, Seco J (2013) Dosimetric accuracy of proton therapy for chordoma patients with titanium implants. Med Phys 40(7):071727CrossRefPubMedPubMedCentralGoogle Scholar
  54. Wallis CJ, Mahar AL, Choo R, Herschorn S, Kodama RT, Shah PS, Danjoux C, Narod SA, Nam RK (2016) Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ 352:i851CrossRefPubMedPubMedCentralGoogle Scholar
  55. Wang Z, Nabhan M, Schild SE, Stafford SL, Petersen IA, Foote RL, Murad MH (2013) Charged particle radiation therapy for uveal melanoma: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys 86(1):18–26CrossRefPubMedGoogle Scholar
  56. Wei RL, Nguyen ST, Yang JN, Wolff J, Mahajan A (2012) Salvage craniospinal irradiation with an intensity modulated radiotherapy technique for patients with disseminated neuraxis disease. Pract Radiat Oncol 2(4):e69–e75CrossRefPubMedGoogle Scholar
  57. Zhang R, Howell RM, Giebeler A, Taddei PJ, Mahajan A, Newhauser WD (2013) Comparison of risk of radiogenic second cancer following photon and proton craniospinal irradiation for a pediatric medulloblastoma patient. Phys Med Biol 58(4):807–823CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Radiation OncologyWinship Cancer Institute of Emory UniversityAtlantaUSA
  2. 2.Department of Radiation OncologyThe Cancer Center at Columbus Regional HealthColumbusUSA

Personalised recommendations