Reirradiation of head and neck cancer: literature review

«Radiation and Risk», 2023, vol. 32, No. 1, pp.72-92

DOI: 10.21870/0131-3878-2023-32-1-72-92


Smyk D.I. – Junior Researcher. Contacts: 4 Korolyov str., Obninsk, Kaluga region, Russia, 249035. Tel.: (484) 393-17-36; e-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. .
Gulidov I.A. – Head of Dep., MD, Prof.
Gordon K.B. – Senior Researcher. A. Tsyb MRRC.
A. Tsyb MRRC, Obninsk


Locoregional recurrences occurring in every second patient with locally advanced head and neck tumors are the main cause of treatment failures. The primary treatment modality for patients with the relapsed disease is surgery. However, the resection of head and neck cancer recurrences is effective for one-third of patients only because of the complex spatial anatomical localization of the relapses and the wide spread of the tumor. In most cases the use of different combinations of chemotherapy and immunotherapy can increase life expectancy by up to one year. In order to extend the lifespan of patients for a longer period researchers add to look for new, more effective treatments. Reirradiation improves local control of the tumor, however due to the use of large irradiated of the targets and high radiation doses delivered in the primary irradiation does not leave a tolerance reserve for surrounding healthy tissues, it is a cause of higher incidence of complications. That is why reirradiation has been used quite rarely. However, in recent years radiotherapy has made a big step in technical development and new radiotherapy techniques have appeared. The advanced treatment allows to reduce the radiation dose delivering to healthy tissues and the risk of late radiation-induced complications development. The review presents analysis published research on the effectiveness of head and neck tumors reirradiation with various radiotherapy techniques available in Russian and foreign scientific literature, as well as physico-dosimetric comparison of the methods and parametrization of reirradiation.

Key words
reirradiation, relapse, head and neck cancer, proton therapy, radiation therapy, nasopharynx tumors, oropharynx tumors, paranasal sinuses tumors, squamous cell carcinoma, complications of radiation therapy.


1. Malignant neoplasms in Russia in 2019 (morbidity and mortality). Eds.: A.D. Kaprin, V.V. Starinskiy, A.O. Shakhzadova. Moscow, Р. Hertsen MORI, 2020. 252 p. (In Russian).

2. Global Burden of Disease Cancer Collaboration; Fitzmaurice C., Allen C., Barber R.M. et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 32 cancer groups, 1990 to 2015: a systematic analysis for the Global Burden of Disease Study. JAMA Oncol., 2017, vol. 3, no. 4, pp. 524-548.

3. Blanchard P., Baujat B., Holostenco V., Bourredjem A., Baey C., Bourhis J., Pignon J.-P.; MACH-CH Collaborative group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumor site. Radiother. Oncol., 2011, vol. 100, no. 1, pp. 33-40.

4. Denaro N., Merlano M.C., Russi E.G. Follow-up in head and neck cancer: do more does it mean do better? A systematic review and our proposal based on our experience. Clin. Exp. Otorhinolaryngol., 2016, vol. 9, no. 4, pp. 287-297.

5. Chang J.-H., Wu C.-C., Yuan K.S.-P., Wu A.T.H., Wu S.-Y. Locoregionally recurrent head and neck squa-mous cell carcinoma: incidence, survival, prognostic factors, and treatment outcomes. Oncotarget, 2017, vol. 8, no. 33, pp. 55600-55612.

6. Bossi P., Alfieri S., Strojan P., Takes R.P., López F., Mäkitie A., Saba N.F., Rodrigo J.P., Bradford C., Suarez C., Zafereo M., Forastiere A.A., Vermorken J.B., Quer M., Sanabria A., Simo R., de Bree R., Rinaldo A., Ferlito A. Prognostic and predictive factors in recurrent and/or metastatic head and neck squa-mous cell carcinoma: a review of the literature. Crit. Rev. Oncol. Hematol., 2019, vol. 137, pp. 84-91.

7. Mollnar S., Pondorfer P., Kasparek A.K., Reinisch S., Moik F., Stotz M., Halm M., Szkandera J., Terbuch A., Eisner F., Gerger A., Kapp K.S., Partl R., Vasicek S., Weiland T., Pichler M., Stöger H., Thurnher D., Posch F. Decrease in treatment intensity predicts worse outcome in patients with locally advanced head and neck squamous cell carcinoma undergoing radiochemotherapy. Clin. Transl. Oncol., 2021, vol. 23, no. 3, pp. 543-553.

8. Gevorkov A.R., Boyko A.V., Bolotina L.V., Shashkov S.V., Abuzarova G.R., Sarmanayeva R.R. Results of the implementation of an individual therapy program for accompanying patients with head and neck tumors undergoing chemoradiotherapy. Opukholi golovy i shei – Head and Neck Tumors, 2020, vol. 10, no. 4, pp. 60-73. (In Russian).

9. León X., García J., López M., Rodriguez C., Gutierrez A., Quer M. Risk of onset of second neoplasms and successive neoplasms in patients with a head and neck index tumor. Acta Otorrinolaringol. Esp. (Engl. Ed.), 2020, vol. 71, no. 1, pp. 9-15.

10. Pfister D.G., Spencer S., Adelstein D., Adkins D., Brizel D., Burtness B. Head and neck cancers. Version 3.2021. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). NCCN, 2021. Available at: (Accessed 22.01.2022).

11. Malignant neoplasms of the oral cavity. Clinical recommendations of the Association of oncologists of Russia. Moscow, 2020, pp. 39-40. Available at: (Accessed 12.02.2020). (In Russian).

12. Maruo T., Zenda S., Shinozaki T., Tomioka T., Okano W., Sakuraba M., Tahara M., Hayashi R. Comparison of salvage surgery for recurrent or residual head and neck squamous cell carcinoma. Jpn. J. Clin. Oncol., 2020, vol. 50, no. 3, pp. 288-295.

13. Salama J.K., Vokes E.E., Chmura S.J., Milano M.T., Kao J., Stenson K.M., Witt M.E., Haraf D.J. 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, vol. 64, no. 2, pp. 382-391.

14. Karabajakian A., Toussaint P., Neidhardt E.M., Paulus V., Saintigny P., Fayette J. Chemotherapy for recurrent/metastatic head and neck cancers. Anticancer Drugs, 2017, vol. 28, no. 4, pp. 357-361.

15. Vermorken J.B., Peyrade F., Krauss J., Mesía R., Remenar E., Gauler T.C., Keilholz U., Delord J.P., Schafhausen P., Erfán J., Brümmendorf T.H., Iglesias L., Bethe U., Hicking C., Clement P.M. Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann. Oncol., 2014, vol. 25, no. 3, pp. 682-688.

16. Burtness B., Harrington K.J., Greil R., Soulières D., Tahara M., de Castro G. Jr., Psyrri A., Basté N., Neupane P., Bratland Å., Fuereder T., Hughes B.G.M., Mesía R., Ngamphaiboon N., Rordorf T., Wan Ishak W.Z., Hong R.L., González Mendoza R., Roy A., Zhang Y., Gumuscu B., Cheng J.D., Jin F., Rischin D.; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chem-otherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet, 2019, vol. 394, no. 10212, pp. 1915-1928.

17. Ferris R.L., Licitra L., Fayette J., Even C., Blumenschein G. Jr., Harrington K.J., Guigay J., Vokes E.E., Saba N.F., Haddad R., Ramkumar S., Russell J., Brossart P., Tahara M., Colevas A.D., Concha-Bena-vente F., Lynch M., Li L., Gillison M.L. Nivolumab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: efficacy and safety in CheckMate 141 by prior cetuximab use. Clin. Cancer Res., 2019, vol. 25, no. 17, pp. 5221-5230.

18. National Cancer Registration Analysis Service and Cancer Research UK: Chemotherapy, Radiotherapy and Tumor Resections in England: 2013-2014. London, NCRAS, 2017.

19. Kaprin A.D., Mardynskiy Yu.S. Therapeutic radiology: national guidelines. Moscow, G·EOTAR-Media, 2018. 704 p. (In Russian).

20. Puthawala A., Nisar Syed A.M., Gamie S., Chen Y.J., Londrc A., Nixon V. Interstitial low-dose-rate brachy-therapy as a salvage treatment for recurrent head-and-neck cancers: long-term results. Int. J. Radiat. Oncol. Biol. Phys., 2001, vol. 51, no. 2, pp. 354-362.

21. Breen W., Kelly J., Park H.S., Son Y., Sasaki C., Wilson L., Decker R., Husain Z.A. Permanent interstitial brachytherapy for previously irradiated head and neck cancer. Cureus, 2018, vol. 10, no. 4, pp. e2517.

22. Song C.W., Kim M.S., Cho L.C., Dusenbery K., Sperduto P.W. Radiobiological basis of SBRT and SRS. Int. J. Clin. Oncol., 2014, vol. 19, no. 4, pp. 570-578.

23. Lee J., Kim W.C., Yoon W.S., Koom W.S., Rim C.H. Reirradiation using stereotactic body radiotherapy in the management of recurrent or second primary head and neck cancer: a meta-analysis and systematic review. Oral Oncol., 2020, vol. 107, pp. 104757.

24. Mikhaylov A.V., Vorob’yev N.A., Sokurenko V.P., Smirnova E.V., Martynova N.I., Gutsalo Y.V. Experi-ence of repeated stereotactic irradiation in the mode of hypofractionation in recurrent head and neck cancer. RMZh – Russian Medical Journal, 2017, vol. 16, pp. 1190-1194. (In Russian).

25. Ling D.C., Vargo J.A., Ferris R.L., Ohr J., Clump D.A., Yau W.W., Duvvuri U., Kim S., Johnson J.T., Bauman J.E., Branstetter B.F., Heron D.E. 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, vol. 95, no. 3, pp. 973-980.

26. Cengiz M., Özyiğit G., Yazici G., Doğan A., Yildiz F., Zorlu F., Gürkaynak M., Gullu I.H., Hosal S., Akyol F. Salvage reirradiaton with stereotactic body radiotherapy for locally recurrent head-and-neck tumors. Int. J. Radiat. Oncol. Biol. Phys., 2011, vol. 81, no. 1, pp. 104-109.

27. Yamazaki H., Ogita M., Kodani N., Nakamura S., Inoue H., Himei K., Kotsuma T., Yoshida K., Yoshioka Y., Yamashita K., Udono H. Frequency, outcome and prognostic factors of carotid blowout syndrome after hypofractionated reirradiation of head and neck cancer using CyberKnife: a multi-institutional study. Radiother. Oncol., 2013, vol. 107, no. 3, pp. 305-309.

28. Yamazaki H., Ogita M., Himei K., Nakamura S., Kotsuma T., Yoshida K., Yoshioka Y. Carotid blowout syndrome in pharyngeal cancer patients treated by hypofractionated stereotactic re-irradiation using Cyber-Knife: a multi-institutional matched-cohort analysis. Radiother. Oncol., 2015, vol. 115, no. 1, pp. 67-71.

29. Vargo J.A., Ferris R.L., Ohr J., Clump D.A., Davis K.S., Duvvuri U., Kim S., Johnson J.T., Bauman J.E., Gibson M.K., Branstetter B.F., Heron D.E. 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, vol. 91, no. 3, pp. 480-488.

30. Kharofa J., Choong N., Wang D., Firat S., Schultz C., Sadasiwan C., Wong S. Continuous-course reirra-diation with concurrent carboplatin and paclitaxel for locally recurrent, nonmetastatic squamous cell carcinoma of the head-and-neck. Int. J. Radiat. Oncol. Biol. Phys., 2012, vol. 83, no. 2, pp. 690-695.

31. Bakiu E., Telhaj E., Kozma E., Ruçi F., Malkaj P. Comparison of 3D CRT and IMRT treatment plans. Acta Inform. Med., 2013, vol. 21, no. 3, pp. 211-212.

32. Gordon K.B., Gulidov I.A., Rozhnov V.A., Podlesnykh N.I., Buksha A.Yu., Lepilina O.G. Repeated conformal radiotherapy for recurrent head and neck tumours. Onkologiya. Zhurnal im. P.A. Gertsena – P.A. Herzen Journal of Oncology, 2016, vol. 5, no. 2, pp. 54-57. (In Russian).

33. Rozhnov V.A., Andreyev V.G., Gordon K.B., Gulidov I.A., Akki E.D. Modern methods of treatment of re-current inoperable squamous cell carcinoma of the larynx (Literature review). Sibirskiy onkologicheskiy zhurnal – Siberian Journal of Oncology, 2016, vol. 15, no. 2, pp. 90-100. (In Russian).

34. Spencer S.A., Harris J., Wheeler R.H., Machtay M., Schultz C., Spanos W., Rotman M., Meredith R., Ang K.-K. 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, vol. 30, no. 3, pp. 281-288.

35. Langer C.J., Harris J., Horwitz E.M., Nicolaou N., Kies M., Curran W., Wong S., Ang K. Phase II study of low-dose paclitaxel and cisplatin in combination with split-course concomitant twice-daily reirradiation in re-current squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Protocol 9911. J. Clin. Oncol., 2007, vol. 25, no. 30, pp. 4800-4805.

36. Sokurenko V.P., Mikhaylov A.V., Vorob’yev N.A., Andreyev G.I. Possibilities of repeated radiation therapy in patients with recurrent squamous cell carcinoma of the head and neck. Luchevaya diagnostika i terapiya – Radiation Diagnostic and Therapy, 2017, vol. 1, pp. 82-87. (In Russian).

37. Qiu S., Lin S., Tham I.W., Pan J., Lu J., Lu J.J. Intensity-modulated radiation therapy in the salvage of locally recurrent nasopharyngeal carcinoma. Int. J. Radiat. Oncol. Biol. Phys., 2012, vol. 83, no. 2, pp. 676-683.

38. Kong L., Wang L., Shen C., Hu C., Wang L., Lu J.J. Salvage Intensity-Modulated Radiation Therapy (IMRT) for locally recurrent nasopharyngeal cancer after definitive IMRT: a novel scenario of the modern era. Sci. Rep., 2016, vol. 6, pp. 32883.

39. Mazal A., Vera Sanchez J.A., Sanchez-Parcerisa D., Udias J.M., España S., Sanchez-Tembleque V., Fraile L.M., Bragado P., Gutierrez-Uzquiza A., Gordillo N., Garcia G., Castro Novais J., Perez Moreno J.M., Mayorga Ortiz L., Ilundain Idoate A., Cremades Sendino M., Ares C., Miralbell R., Schreuder N. Biological and mechanical synergies to deal with proton therapy pitfalls: minibeams, FLASH, arcs, and gantryless rooms. Front. Oncol., 2021, vol. 10, pp. 613669.

40. Lansonneur P., Mammar H., Nauraye C., Patriarca A., Hierso E., Dendale R., Prezado Y., De Marzi L. First proton minibeam radiation therapy treatment plan evaluation. Sci. Rep., 2020, vol. 10, no. 1, pp. 7025.

41. Weber D.C., Langendijk J.A., Grau C., Thariat J. Proton therapy and the European Particle Therapy Network: the past, present and future. Cancer Radiother., 2020, vol. 24, no. 6-7, pp. 687-690.

42. Yuan T.Z., Zhan Z.J., Qian C.N. New frontiers in proton therapy: applications in cancers. Cancer Commun. (Lond.), 2019, vol. 39, no. 1, pp. 61.

43. Gulidov I.A., Gordon K.B., Gogolin D.V., Mardynskiy Yu.S., Lepilina O.G., Neledov D.V., Galkin V.N., Kaprin A.D. Repeated irradiation of intracranial tumors with an active scanning proton beam. Sibirskiy onko-logicheskiy zhurnal – Siberian Journal of Oncology, 2017, vol. 16, no. 5, pp. 63-70. (In Russian).

44. Eekers D.B.P., Roelofs E., Jelen U., Kirk M., Granzier M., Ammazzalorso F., Ahn P.H., Janssens G.O., Hoebers F.J.P., Friedmann T., Solberg T., Walsh S., Troost E.G.C., Kaanders J.H., Lambin P. Benefit of particle therapy in re-irradiation of head and neck patients. Results of a multicentric in silico ROCOCO trial. Radiother. Oncol., 2016, vol. 121, no. 3, pp. 387-394.

45. Kandula S., Zhu X., Garden A.S., Gillin M., Rosenthal D.I., Ang K.K., Mohan R., Amin M.V., Garcia J.A., Wu R., Sahoo N., Frank S.J. Spot-scanning beam proton therapy vs intensity-modulated radiation therapy for ipsilateral head and neck malignancies: a treatment planning comparison. Med Dosim., 2013, vol. 38, no. 4, pp. 390-394.

46. Koroulakis A., Molitoris J., Kaiser A., Hanna N., Bafford A., Jiang Y., Bentzen S., Regine W.F. Reirradi-ation for rectal cancer using pencil beam scanning proton therapy: a single institutional experience. Adv. Radiat. Oncol., 2020, vol. 6, no. 1, pp. 100595.

47. Medvedeva K.E., Gulidov I.A., Mardynskiy Yu.S., Gogolin D.V., Gordon K.B., Semenov A.V., Lepilina O.G., Kaprin A.D., Kostin A.A., Ivanov S.A. Possibilities of proton therapy in reirradiation of recurrent glio-mas. Meditsinskaya radiologiya i radiatsionnaya bezopasnost’ – Medical Radiobiology and Radiation Safety, 2019, vol. 64, no. 2, pp. 70-74. (In Russian).

48. Gordon K., Gulidov I., Semenov A., Golovanova O., Koryakin S., Makeenkova T., Ivanov S., Kaprin A. Proton re-irradiation of unresectable recurrent head and neck cancers. Rep. Pract. Oncol. Radiother., 2021, vol. 26, no. 2, pp. 203-210.

49. Phan J., Sio T.T., Nguyen T.P., Takiar V., Gunn G.B., Garden A.S., Rosenthal D.I., Fuller C.D., Morrison W.H., Beadle B., Ma D., Zafereo M.E., Hutcheson K.A., Kupferman M.E., William W.N.Jr., Frank S.J. Reirradiation of head and neck cancers with proton therapy: outcomes and analyses. Int. J. Radiat. Oncol. Biol. Phys., 2016, vol. 96, no. 1, pp. 30-41.

50. Romesser P.B., Cahlon O., Scher E.D., Hug E.B., Sine K., DeSelm C., Fox J.L., Mah D., Garg M.K., Han-Chih Chang J., Lee N.Y. Proton beam reirradiation for recurrent head and neck cancer: multi-institutional report on feasibility and early outcomes. Int. J. Radiat. Oncol. Biol. Phys., 2016, vol. 95, no. 1, pp. 386-395.

51. McDonald M.W., Zolali-Meybodi O., Lehnert S.J., Estabrook N.C., Liu Y., Cohen-Gadol A.A., Moore M.G. Reirradiation of recurrent and second primary head and neck cancer with proton therapy. Int. J. Radiat. Oncol. Biol. Phys., 2016, vol. 96, no. 4, pp. 808-819.

52. Shuja M., Routman D.M., Foote R.L., Garces Y., Neben-Wittich M.A., Patel S.H., McGee L.A., Harmsen W.S., Ma D.J. Clinical outcomes after re-irradiation in recurrent head and neck cancers treated with intensity modulated proton and photon therapies. Int. J. Radiat. Oncol. Biol. Phys., 2019, vol. 105, no. 1, pp. 382-383.

53. Margalit D.N., Wong S.J. Reirradiation for head and neck cancer: the who and the how. Int. J. Radiat. Oncol. Biol. Phys., 2018, vol. 100, no. 3, pp. 618-620.

54. Kim Y.S. Reirradiation of head and neck cancer in the era of intensity-modulated radiotherapy: patient selec-tion, practical aspects, and current evidence. Radiat. Oncol. J., 2017, vol. 35, no. 1, pp. 1-15.

55. Caudell J.J., Ward M.C., Riaz N., Zakem S.J., Awan M.J., Dunlap N.E., Isrow D., Hassanzadeh C., Vargo J.A., Heron D.E., Marcrom S., Boggs D.H., Reddy C.A, Dault J., Bonner J.A., Higgins K.A., Beitler J.J., Koyfman S.A., Machtay M., Yao M., Trotti A.M., Siddiqui F., Lee N.Y.; Multi-Institution Reirradiation (MIRI) Collaborative. 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, vol. 100, no. 3, pp. 606-617.

56. Wang K., Heron D.E., Clump D.A., Flickinger J.C., Kubicek G.J., Rwigema J.C., Ferris R.L., Ohr J.P., Quinn A.E., Ozhasoglu C., Branstetter B.F. 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, vol. 106, no. 1, pp. 90-95.

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