Radical external beam reirradiation of recurrent head and neck cancer

Česká verzia

Authors: M. Švajdová ^1,2; T. Kazda ²; P. Dubinský ^3,4; P. Šlampa ²
Authors place of work: Klinika radiačnej a klinickej onkológie ÚVN Ružomberok, Slovenská republika ¹; Klinika radiační onkologie LF MU a MOÚ Brno, Česká republika ²; Východoslovenský onkologický ústav, a. s., Košice, Slovenská republika ³; Fakulta zdravotníctva, Katolícka univerzita, Ružomberok, Slovenská republika ⁴
Published in the journal: Klin Onkol 2021; 34(2): 103-112
Category: Review
doi: https://doi.org/10.48095/ccko2021103

Summary

Background: Recurrent head and neck carcinomas represent a therapeutic challenge for the surgeons as well as for the treating radiation oncologists. Despite advances in the treatment of newly diagnosed head and neck carcinomas, relapses occur very frequently and contribute significantly to patient mortality. External beam reirradiation is still considered to be a controversial therapeutic intervention. Historically, in the era of 2- and 3-dimensional conformal radiotherapy, its narrow therapeutic ratio has long led to a general concern that the potential benefit could not sufficiently outweigh the high risk associated with the treatment. The unfavorable therapeutic ratio, however, could be positively influenced by the use of modern techniques of intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT), stereotactic body radiation therapy (SBRT) and heavy-ion radiotherapy (protons, carbon ions). Purpose: The purpose of this review is to create a practical tool for clinical decision-making on the type of patient suitable for reirradiation and the exact type of radiotherapy technique with respect to its expected therapeutic effect, toxicity profile and availability throughout the institutions. In the introductory section, selection of patients is defined with an emphasis on factors that significantly affect overall survival and may be particularly useful in shared decision-making approach within multidisciplinary teams. Furthermore, the text deals with the individual types of external beam radiotherapy techniques (IMRT, SBRT, heavy-ion radiotherapy) with a clear summary of therapeutic outcomes and toxicity from published scientific evidence that had a significant impact on clinical practice.

Keywords:

head and neck cancer – recurrence – external beam radiotherapy – reirradiation – toxicity

Zdroje

1. Coatesworth AP, Tsikoudas A, MacLennan K. The cause of death in patients with head and neck squamous cell carcinoma. J Laryngol Otol 2002; 116 (4): 269–271. doi: 10.1258/0022215021910726.

2. Lambrecht M, Dirix P, Van den Bogaert W et al. Incidence of isolated regional recurrence after definitive (chemo) radiotherapy for head and neck squamous cell carcinoma. Radiother Oncol 2009; 93 (3): 498–502. doi: 10.1016/j.radonc.2009.08.038.

3. Baxi SS, Pinheiro LC, Patil SM et al. Causes of death in long-term survivors of head and neck cancer. Cancer 2014; 120 (10): 1507–1513. doi: 10.1002/cncr.28588.

4. Bourhis J, Le Maître A, Baujat B et al. Individual patients‘ data meta-analyses in head and neck cancer. Curr Opin Oncol 2007; 19 (3): 188–194. doi: 10.1097/CCO.0b013e3280f01010.

5. Brockstein B, Haraf DJ, Rademaker AW et al. Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337 patient, multi-institutional experience. Ann Oncol 2004; 15 (8): 1179–1186. doi: 10.1093/annonc/mdh308.

6. Cooper JS, Zhang Q, Pajak TF et al. Long-term follow--up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012; 84 (5): 1198–1205. doi: 10.1016/j.ijrobp.2012.05.008.

7. Lippman S, Hong W. Second malignant tumors in head and neck squamous carcinoma: The overshadowing threat for patients with early-stage disease. Int J Radiat Oncol Biol Phys 1989; 17 (3): 691–694. doi: 10.1016/0360-3016 (89) 90126-0.

8. Chao KS, Ozyigit G, Tran BN et al. Patterns of failure in patients receiving definitive and postoperative IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2003; 55 (2): 312–321. doi: 10.1016/s0360-3016 (02) 03940-8.

9. Leon X, Del Prado Venegas M, Orus C et al. Metachronous second primary tumours in the aerodigestive tract in patients with early stage head and neck squamous cell carcinomas. Eur Arch Otorhinolaryngol 2005; 262 (11): 905–909. doi: 10.1007/s00405-005-0922-5.

10. McDonald MW, Lawson J, Garg MK et al. 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 2011; 80 (5): 1292–1298. doi: 10.1016/j.ijrobp.2011.02.014.

11. Janot F, de Raucourt D, Benhamou E et al. Randomized trial of postoperative reirradiation combined with chemotherapy after salvage surgery compared with salvage surgery alone in head and neck carcinoma. J Clin Oncol 2008; 26 (34): 5518–5523. doi: 10.1200/JCO.2007.15.0102.

12. Ward MC, iaz N, Caudell JJ et al. Refining patient selection for reirradiation of head and neck squamous carcinoma in the IMRT era: a multi-institution cohort study by the MIRI Collaborative. Int J Radiat Oncol Biol Phys 2018; 100 (3): 586–594. doi: 10.1016/j.ijrobp.2017.06.012.

13. Lee N, Chan K, Bekelman JE et al. Salvage re-irradiation for recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2007; 68 (3): 731–740. doi: 10.1016/j.ijrobp.2006.12.055.

14. Vargo JA, Ferris RL, Ohr J et al. A prospective phase 2 trial of reirradiation with stereotactic body radiation therapy plus cetuximab in patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2015; 91 (3): 480–488. doi: 10.1016/j.ijrobp.2014.11.023.

15. Lok BH, Jiang G, Gutiontov S et al. Palliative head and neck radiotherapy with the RTOG 8502 regimen for incurable primary or metastatic cancers. Oral Oncol 2015; 51 (10): 957–962. doi: 10.1016/j.oraloncology.2015.07.011.

16. Ma J, Lok BH, Zong J et al. Proton Radiotherapy for Recurrent or Metastatic Head and Neck Cancers with Palliative Quad Shot. Int J Part Ther 2018; 4 (4): 10–19. doi: 10.14338/IJPT-18-00003.1.

17. Corry J, Peters LJ, Costa ID et al. The ‚QUAD SHOT‘ – a phase II study of palliative radiotherapy for incurable head and neck cancer. Radiother Oncol 2005; 77 (2): 137–142. doi: 10.1016/j.radonc.2005.10.008.

18. Langer CJ, Harris J, Horwitz EM et al. 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 2007; 25 (30): 4800–4805. doi: 10.1200/JCO.2006.07.9194.

19. Spencer SA, Harris J, Wheeler RH et al. Final report of RTOG 9610, a multi-institutional trial of reirradiation and chemotherapy for unresectable recurrent squamous cell carcinoma of the head and neck. Head Neck 2008; 30 (3): 281–288. doi: 10.1002/hed.20697.

20. Dionisi F, Fiorica F, D‘Angelo E et al. Organs at risk‘s tolerance and dose limits for head and neck cancer re-irradiation: a literature review. Oral Oncol 2019; 98: 35–47. doi: 10.1016/j.oraloncology.2019.08.017.

21. Ward MC, Lee NY, Caudell JJ. A competing risk nomogram to predict severe late toxicity after modern reirradiation for squamous carcinoma of the head and neck. Oral Oncol 2019; 90: 80–86. doi: 10.1016/j.oraloncology.2019.01.

22. Goodwin WJ Jr. Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means? Laryngoscope 2000; 110 (3 Pt 2 Suppl 93): 1–18. doi: 10.1097/000 05537-200003001-00001.

23. Chen AM, Phillips TL, Lee NY. Practical considerations in the re-irradiation of recurrent and second primary head-and-neck cancer: who, why, how, and how much? Int J Radiat Oncol Biol Phys 2011; 81 (5): 1211–1219. doi: 10.1016/j.ijrobp.2011.06.1998.

24. Tanvetyanon T, Padhya T, McCaffrey J et al. Prognostic factors for survival after salvage reirradiation of head and neck cancer. J Clin Oncol 2009; 27 (12): 1983–1991. doi: 10.1200/JCO.2008.20.0691.

25. Spencer SA, Harris J, Wheeler RH et al. RTOG 96–10: reirradition with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck. Int J Radiat Oncol Biol Phys 2001; 51 (5): 1299–1304. doi: 10.1016/s0360-3016 (01) 01745-x.

26. Di Martino E, Sellhaus B, Hausmann R et al. Survival in second primary malignancies of patients with head and neck cancer. J Laryngol Otol 2002; 116 (10): 831–838. doi: 10.1258/00222150260293664.

27. Rennemo E, Zätterström U, Boysen M. Impact of second primary tumors on survival in head and neck cancer: an analysis of 2,063 cases. Laryngoscope 2008; 118 (8): 1350–1356. doi: 10.1002/lary.20189.

28. De Crevoisier R, Bourhis J, Domenge C et al. Reirradiation for unresectable head and neck carcinoma: experience at the Gustave-Roussy institute in a series of 169 patients. J Clin Oncol 1998; 16 (11): 3556–3562. doi: 10.1200/JCO.1998.16.11.3556.

29. Chen AM, Farwell GD, Luu Q et al. Prospective trial of high-dose reirradiation using daily image guidance with intensity-modulated radiotherapy for recurrent and second primary head-and-neck cancer. Int J Rad Oncol Biol Phys 2011; 80 (3): 669–676. doi: 10.1016/j.ijrobp.2010.02.023.

30. Parsons JT, Mendenhall WM, Stringer SP et al. Salvage surgery following radiation failure in squamous cell carcinoma of the supraglottic larynx. Int J Radiat Oncol Biol Phys 1995; 32 (3): 605–609. doi: 10.1016/0360-3016 (95) 00527-6.

31. Bachar GY, Goh C, Goldstein DP et al. Long-term outcome analysis after surgical salvage for recurrent tonsil carcinoma following radical radiotherapy. Eur Arch Otorhinolaryngol. 2010; 267 (2): 295–301. doi: 10.1007/s00405-009-1070-0.

32. Milano MT, Vokes EE, Salama JK et al. Twice-daily reirradiation for recurrent and second primary head-and-neck cancer with gemcitabine, paclitaxel, and 5-fluorouracil chemotherapy. Int J Radiat Oncol Biol Phys 2005; 61 (4): 1096–1106. doi: 10.1016/j.ijrobp.2004.08.029.

33. Langendijk JA, Bourhis J. Reirradiation in squamous cell head and neck cancer: recent developments and future directions. Curr Opin Oncol 2007; 19 (3): 202–209. doi: 10.1097/CCO.0b013e3280f00ff8.

34. Salama JK, Vokes EE. Concurrent chemotherapy and re-irradiation for locoregionally recurrent head and neck cancer. Semin Oncol 2008; 35 (3): 251–261. doi: 10.1053/j.seminoncol.2008.03.010.

35. Zafereo ME, Hanasono MM, Rosenthal DI et al. The role of salvage surgery in patients with recurrent squamous cell carcinoma of the oropharynx. Cancer 2009; 115 (24): 5723–5733. doi: 10.1002/cncr.24595.

36. De Crevoisier R, Domenge C, Wibault P et al. Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma. Cancer 2001; 91 (11): 2071–2076. doi: 10.1002/1097-0142 (20010601) 91: 11<2071:: aid-cncr1234>3.0.co; 2-z.

37. Kasperts N, Slotman BJ, Leemans CR et al. Results of postoperative reirradiation for recurrent or second primary head and neck carcinoma. Cancer 2006; 106 (7): 1536–1547. doi: 10.1002/cncr.21768.

38. Merlotti A, Mazzola R, Alterio D et al. What is the role of postoperative re-irradiation in recurrent and second primary squamous cell cancer of head and neck? A literature review according to PICO criteria. Crit Rev Oncol Hematol 2017; 111: 20–30. doi: 10.1016/j.critrevonc.2017.01.008.

39. Chen YJ, Kuo JV, Ramsinghani NS et al. Intensity modulated radiotherapy for previously irradiated recurrent head and neck cancer. Med Dosim 2002; 27 (2): 171–176. doi: 10.1016/s0958-3947 (02) 00100-0.

40. Salama JK, Vokes EE, Chmura SJ et al. Long-term outcome of concurrent chemotherapy and reirradiation for recurrent and second primary head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2006; 64 (2): 382–391. doi: 10.1016/j.ijrobp.2005.07.005.

41. Caudell JJ, Ward MC, Riaz N et al. Volume, dose, and fractionation considerations for IMRT-based reirradiation in head and neck cancer: a multi-institution analysis. Int J Radiat Oncol Biol Phys 2018; 100 (3): 606–617. doi: 10.1016/j.ijrobp.2017.11.036.

42. Mabanta SR, Mendenhall WM, Stringer SP et al. Salvage treatment for neck recurrence after irradiation alone for head and neck squamous cell carcinoma with clinically positive neck nodes. Head Neck 1999; 21 (7): 591–594. doi: 10.1002/ (sici) 10970347 (199910) 21: 7<591:: aid-hed1>3.0.co; 2-y.

43. Maddalo M, Bonomo P, Belgioia L et al. Re-irradiation with curative intent in patients with squamous cell carcinoma of the head and neck: a national survey of usual practice on behalf of the Italian Association of Radiation Oncology (AIRO). Eur Arch Otolaryngol 2018; 275 (2): 561–567. doi: 10.1007/s00405-017-4853-8.

44. Popovtzer A, Gluck I, Chepeha DB et al. The pattern of failure after reirradiation of recurrent squamous cell head and neck cancer: implications for defining the targets. Int J Radiat Oncol Biol Phys 2009; 74 (5): 1342–1347. doi: 10.1016/j.ijrobp.2008.10.042.

45. Biagioli MC, Harvey M, Roman E et al. Intensity-modulated radiotherapy with concurrent chemotherapy for previously irradiated, recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2007; 69 (4): 1067–1073. doi: 10.1016/j.ijrobp.2007.04.057.

46. Dawson LA, Myers LL, Bradford CR et al. Conformal re-irradiation of recurrent and new primary head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001; 50 (2): 377–385. doi: 10.1016/s0360-3016 (01) 01456-0.

47. Grimard L, Esche B, Lamothe A et al. Interstitial low--dose-rate brachytherapy in the treatment of recurrent head and neck malignancies. Head Neck 2006; 28 (10): 888–895. doi: 10.1002/hed.20422.

48. Langendijk JA, Kasperts N, Leemans CR et al. A phase II study of primary reirradiation in squamous cell carcinoma of head and neck. Radiother Oncol 2006; 78 (3): 306–312. doi: 10.1016/j.radonc.2006.02.003.

49. Goldstein DP, Karnell LH, Yao M et al. Outcomes following reirradiation of patients with head and neck cancer. Head Neck 2008; 30 (6): 765–770. doi: 10.1002/hed.20786.

50. Creak AL, Harrington K, Nutting C. Treatment of recurrent head and neck cancer: Re-irradiation or chemotherapy? Clin Oncol (R Coll Radiol) 2005; 17 (3): 138–147. doi: 10.1016/j.clon.2004.10.008.

51. Wong SJ, Machtay M, Li Y. Locally recurrent, previously irradiated head and neck cancer: concurrent re-irradiation and chemotherapy, or chemotherapy alone? J Clin Oncol 2006; 24 (17): 2653–2658. doi: 10.1200/JCO.2005.05.3850.

52. Sulman EP, Schwartz DL, Le TT et al. IMRT reirradiation of head and neck cancer-disease control and morbidity outcomes. Int J Radiat Oncol Biol Phys 2009; 73 (2): 399–409. doi: 10.1016/j.ijrobp.2008.04.021.

53. Curtis KK, Ross HJ, Garrett AL et al. Outcomes of patients with loco-regionally recurrent or new primary squamous cell carcinomas of the head and neck treated with curative intent reirradiation at Mayo Clinic. Radiat Oncol 2016; 11: 55. doi: 10.1186/s13014-016-0630-x.

54. Takiar V, Garden AS, Ma D et al. Reirradiation of head and neck cancers with intensity modulated radiation therapy: outcomes and analyses. Int J Radiat Oncol Biol Phys 2016; 95 (4): 1117–1131. doi: 10.1016/j.ijrobp.2016.03.015.

55. McDonald MW, Moore MG, Johnstone PA. Risk of carotid blowout after reirradiation of the head and neck: a systematic review. Int J Radiat Oncol Biol Phys 2012; 82 (3): 1083-1089. doi: 10.1016/j.ijrobp.2010.08.029.

56. Baliga S, Kabarriti R, Ohri N et al. Stereotactic body radiotherapy for recurrent head and neck cancer: A critical review. Head Neck 2017; 39 (3): 595–601. doi: 10.1002/hed.24633.

57. Timmerman RD, Herman J, Cho LC. Emergence of stereotactic body radiation therapy and its impact on current and future clinical practice. J Clin Oncol 2014; 32 (26): 2847–2854. doi: 10.1200/JCO.2014.55.4675.

58. Lee Y, Auh SL, Wang Y et al. Therapeutic effects of ablative radiation on local tumor require CD8+ T cells: changing strategies for cancer treatment. Blood 2009; 114 (3): 589–595. doi: 10.1182/blood-2009-02-206870.

59. SBRT +/- pembrolizumab in patients with local-regionally recurrent or second primary head and neck carcinoma (KEYSTROKE). [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT03546582.

60. Voynov G, Heron DE, Burton S et al. Frameless stereotactic radiosurgery for recurrent head and neck carcinoma. Technol Cancer Res Treat 2006; 5 (5): 529–535. doi: 10.1177/153303460600500510.

61. Roh KW, Jang JS, Kim MS et al. Fractionated stereotactic radiotherapy as reirradiation for locally recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2009; 74 (5): 1348–1355. doi: 10.1016/j.ijrobp.2008.10.013.

62. Siddiqui F, Patel M, Khan M et al. Stereotactic body radiation therapy for primary, recurrent, and metastatic tumors in the head-and-neck region. Int J Radiat Oncol Biol Phys 2009; 74 (4): 1047–1053. doi: 10.1016/j.ijrobp.2008.09.022.

63. Rwigema JC, Heron DE, Ferris RL et al. Fractionated stereotactic body radiation therapy in the treatment of previously-irradiated recurrent head and neck carcinoma: updated report of the University of Pittsburgh experience. Am J Clin Oncol 2010; 33 (3): 286–293. doi: 10.1097/COC.0b013e3181aacba5.

64. Unger KR, Lominska CE, Deeken JF et al. Fractionated stereotactic radiosurgery for reirradiation of head-and-neck cancer. Int J Radiat Oncol Biol Phys 2010; 77 (5): 1411–1419. doi: 10.1016/j.ijrobp.2009.06.070.

65. Kodani N, Yamazaki H, Tsubokura T et al. Stereotactic body radiation therapy for head and neck tumor: disease control and morbidity outcomes. J Radiat Res 2011; 52 (1): 24–31. doi: 10.1269/jrr.10086.

66. Ozyigit G, Cengiz M, Yazici G et al. A retrospective comparison of robotic stereotactic body radiotherapy and three-dimensional conformal radiotherapy for the reirradiation of locally recurrent nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2011; 81 (4): 263–268. doi: 10.1016/j.ijrobp.2011.02.054.

67. Vargo JA, Ward MC, Caudell JJ et al. A Multi-institutional comparison of SBRT and IMRT for definitive reirradiation of recurrent or second primary head and neck cancer. Int J Radiat Oncol Biol Phys 2018; 100 (3): 595–605. doi: 10.1016/j.ijrobp.2017.04.017.

68. Vargo JA, Ferris RL, Ohr J et al. A prospective phase 2 trial of reirradiation with stereotactic body radiation therapy plus cetuximab in patients with previously irradiated recurrent squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2015; 91 (3): 480–488. doi: 10.1016/j.ijrobp.2014.11.023.

69. Beitler JJ, Zhang Q, Fu KK et al. Final results of local-regional control and late toxicity of RTOG 9003: a randomized trial of altered fractionation radiation for locally advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2014; 89 (1): 13–20. doi: 10.1016/j.ijrobp.2013.12.027.

70. Brown JM, Carlson DJ, Brenner DJ et al. The tumor radiobiology of SRS and SBRT: are more than the 5 R’s involved? Int J Radiat Oncol Biol Phys 2014; 88 (2): 254–262. doi: 10.1016/j.ijrobp.2013.07.022.

71. Cengiz M, Ozyigit G, Yazici G et al. Salvage reirradiaton with stereotactic body radiotherapy for locally recurrent head-and-neck tumors. Int J Radiat Oncol Biol Phys 2011; 81 (1): 104–109. doi: 10.1016/j.ijrobp.2010.04.027.

72. Yazici G, Sanli TY, Cengiz M et al. A simple strategy to decrease fatal carotid blowout syndrome after stereotactic body reirradiation for recurrent head and neck cancers. Radiat Oncol 2013; 8: 242. doi: 10.1186/1748-717X-8-242.

73. Bates MC, Shamsham FM. Endovascular management of impending carotid rupture in a patient with advanced head and neck cancer. J Endovasc Ther 2003; 10 (1): 54–57. doi: 10.1177/152660280301000112.

74. Chmura SJ, Milano MT, Haraf DJ. Reirradiation of recurrent head and neck cancers with curative intent. Semin Oncol 2004; 31 (6): 816–821. doi: 10.1053/j.seminoncol.2004.09.003.

75. Ling DC, Vargo JA, Ferris RL et al. Risk of severe toxicity according to site of recurrence in patients treated with stereotactic body radiation therapy for recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 2016; 95 (3): 973–980. doi: 10.1016/j.ijrobp.2016.02.049.

76. Heron DE, Ferris RL, Karamouzis M et al. Stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: results of a phase I dose-escalation trial. Int J Radiat Oncol Biol Phys 2009; 75 (5): 1493–1500. doi: 10.1016/j.ijrobp.2008.12.075.

77. Vargo JA, Moiseenko V, Grimm J et al. Head and neck tumor control probability: radiation dose-volume effects in stereotactic body radiation therapy for locally recurrent previously-irradiated head and neck cancer: report of the AAPM Working Group. Int J Radiat Oncol Biol Phys 2018; S0360–3016 (18) 30107-X. doi: 10.1016/j.ijrobp.2018.01.044. Online ahead of print.

78. Deantonio L, Beldi D, Gambaro G et al. FDG-PET/CT imaging for staging and radiotherapy treatment planning of head and neck carcinoma. Radiat Oncol 2008; 3: 29. doi: 10.1186/1748-717X-3-29.

79. Moule RN, Kayani I, Moinuddin SA et al. The potential advantages of (18) FDG PET/CT-based target volume delineation in radiotherapy planning of head and neck cancer. Radiother Oncol 2010; 97 (2): 189–193. doi: 10.1016/j.radonc.2010.04.025.

80. Wang K, Heron DE, Clump DA et al. Target delineation in stereotactic body radiation therapy for recurrent head and neck cancer: A retrospective analysis of the impact of margins and automated PET-CT segmentation. Radiother Oncol 2013; 106 (1): 90–95. doi: 10.1016/j.radonc.2012.11.008.

81. Heron DE, Rwigema JC, Gibson MK et al. Concurrent cetuximab with stereotactic body radiotherapy for recurrent squamous cell carcinoma of the head and neck: a single institution matched case-control study. Am J Clin Oncol 2011; 34 (2): 165–172. doi: 10.1097/COC.0b013e3181dbb73e.

82. Comet B, Kramar A, Faivre–Pierret M et al. Salvage stereotactic reirradiation with or without cetuximab for locally recurrent head-and-neck cancer: a feasibility study. Int J Radiat Oncol Biol Phys 2012; 84 (1): 203–209. doi: 10.1016/j.ijrobp.2011.11.054.

83. Lartigau EF, Tresch E, Thariat J et al. Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer. Radiother Oncol 2013; 109 (2): 281–285. doi: 10.1016/j.radonc.2013.08.012.

84. Stereotactic body radiation therapy (SBRT) with cetuximab +/– docetaxel followed by adjuvant cetuximab +/– docetaxel in recurrent, previously-irradiated squamous cell carcinoma of the head and neck (SCCHN). [online]. Available from: https: //clinicaltrials.gov/ct2/show/NCT02057107.

85. Svajdova M, Dubinsky P, Kazda T. Radical external beam reirradiation in the treatment of recurrent head and neck cancer: critical review. Head Neck 2021; 43 (1): 354-366. doi: 10.1002/hed.26485.

86. Paganetti H. Significance and implementation of RBE variations in proton beam therapy. Technol Cancer Res Treat 2003; 2 (5): 413–426. doi: 10.1177/153303 460300200506.

87. Weyrather WK, Debus J. Particle beams for cancer therapy. Clin Oncol 2003; 15 (1): S23–S28. doi: 10.1053/clon. 2002.0185.

88. Asaithamby A, Hu B, Chen DJ. Unrepaired clustered DNA lesions induce chromosome breakage in human cells. Proc Natl Acad Sci USA 2011; 108 (20): 8293–8298. doi: 10.1073/pnas.1016045108.

89. Eekers DBP, Roelofs E, Jelen U et al. Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial. Radiother Oncol 2016; 121 (3): 387–394. doi: 10.1016/j.radonc.2016.08.020.

90. Cheng Q, Roelofs E, Ramaekers B et al. EP-1480: development and validation of a proton decision support system comparing dose, toxicity and cost-effectiveness. Radiother Oncol 2016; 118 (2): 281–285. doi: 10.1016/j.radonc.2015.12.029.

91. McDonald MW, Zolali-Meybodi O, Lehnert SJ et al. Reirradiation of recurrent and second primary head and neck cancer with proton therapy. Int J Radiat Oncol Biol Phys 2016; 96 (4): 808–819. doi: 10.1016/j.ijrobp.2016.07.037.

92. Phan J, Sio TT, Nguyen TP et al. Reirradiation of head and neck cancers with proton therapy: outcomes and analyses. Int J Radiat Oncol Biol Phys 2016; 96 (1): 30–41. doi: 10.1016/j.ijrobp.2016.03.053.

93. Romesser PB, Cahlon O, Scher ED et al. Proton beam reirradiation for recurrent head and neck cancer: multi-institutional report on feasibility and early outcomes. Int J Radiat Oncol Biol Phys 2016; 95 (1): 386–395. doi: 10.1016/j.ijrobp.2016.02.036.

94. Verma V, Rwigema JM, Malyapa RS et al. Systematic assessment of clinical outcomes and toxicities of proton radiotherapy for reirradiation. Radiother Oncol 2017; 125 (1): 21–30. doi: 10.1016/j.radonc.2017.08.005.

95. Gao J, Hu J, Guan X et al. Salvage carbon-ion radiation therapy for locoregionally recurrent head and neck malignancies. Scientific Reports 2019; 9 (1): 4259. doi: 10.1038/s41598-019-39241-y.

96. Hayashi K, Koto M, Ikawa H et al. Feasibility of Re-irradiation using carbon ions for recurrent head and neck malignancies after carbon-ion radiotherapy. Radiother Oncol 2019; 136: 148–153. doi: 10.1016/j.radonc.2019.04.007.

97. Held T, Windisch P, Akbaba S et al. Carbon ion reirradiation for recurrent head and neck cancer: a single-institutional experience. Int J Radiat Oncol Biol Phys 2019; 105 (4): 803–811. doi: 10.1016/j.ijrobp.2019.07.021.

98. Xu AJ, Luo L, Leeman JE et al. Beyond reirradiation: Efficacy and safety of three or more courses of radiation for head and neck malignancies. Clin Transl Radiat Oncol 2020; 23: 30–34. doi: 10.1016/j.ctro.2020.04.009.