American Journal of Cancer

, Volume 3, Issue 5, pp 291–298 | Cite as

Oral complications of radiotherapy in head and neck cancer

Strategies for prevention and management
  • Cai Grau
  • Christian N. Andreassen
  • Kenneth Jensen
  • Jacob C. Lindegaard
Therapy in Practice
  • 11 Downloads

Abstract

Radiotherapy in the head and neck region constitutes a major therapeutic challenge. Tumors and elective nodal areas are often in close proximity to radiosensitive normal tissues, a factor which often limits the success of radiotherapy.

Acute radiation-induced adverse effects such as mucositis and skin reactions occur during the course of treatment. They are generally reversible and patients normally recover from these adverse effects within 3 months. Late radiation reactions such as fibrosis and osteoradionecrosis occur more than 3 months after treatment. Such reactions are characterized by their gradual progression. Xerostomia is the single most important factor leading to chronic loss of quality of life in head and neck cancer patients.

Oral complications can be prevented or modified by altered fractionation, by reducing the irradiated volume, or by pharmacologic intervention. Altered fractionation in the form of acceleration or hyperfractionation has improved the therapeutic ratio in several large clinical studies and a recent meta-analysis. Reducing the high-dose volume, and especially avoiding irradiating sensitive structures, is the basis for the increasing use of conformal and intensity-modulated radiotherapy. Such techniques may eventually allow dose escalation in tumor areas leading to increased local tumor control while keeping morbidity at an acceptable level.

Numerous pharmacologic agents have been evaluated for the prevention and management of both acute and late complications. The only agent with documented radioprotective activity is amifostine, which can reduce late xerostomia. However, it is still unclear whether amifostine also protects tumor cells. Pilocarpine may relieve late xerostomia in some patients with remaining functional salivary gland reserve. Apart from this limited Indication, pharmacologic agents against oral complications should not be used outside of clinical trials.

Notes

Acknowledgment

This review was funded by the Danish Cancer Society. The authors have no conflicts of interest that are directly relevant to the content of this review.

References

  1. 1.
    Greene FL, American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging handbook. 6th ed. N w York: Springer, 2002Google Scholar
  2. 2.
    Trotti A. Toxicity in head and neck cancer: a review of trends and issues. Int J Radiat Oncol Biol Phys 2000; 47(1): 1–12PubMedCrossRefGoogle Scholar
  3. 3.
    Kaanders JH, Ang KK. Early reactions as dose-limiting factors in radiotherapy. Semin Radiat Oncol 1994; 4(2): 55–67PubMedCrossRefGoogle Scholar
  4. 4.
    Eisbrach A, Ten Haken RK, Kim HM, 0. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999; 45(3): 577–87CrossRefGoogle Scholar
  5. 5.
    Epstein JB, Emerton S, Kolbinson DA, et al. Quality of life and oral function following radiotherapy for head and neck cancer. Head Neck 1999; 21(1): 1–11PubMedCrossRefGoogle Scholar
  6. 6.
    Jensen AB, Hansen O, Jorgensen K, et al. Influence of late side-effects upon daily life after radiotherapy for laryngeal and pharyngeal cancer. Acta Oncol 1994; 33(5): 487–91PubMedCrossRefGoogle Scholar
  7. 7.
    Friedman RB. Osteoradionecrosis: causes and prevention. Natl Cancer Inst Monogr 1990; 9: 145–9Google Scholar
  8. 8.
    Beumer J, Harrison R, Sanders B, et al. Osteoradionecrosis: predisposing factors and outcomes of therapy. Head Neck Surg 1984;6(4): 819–27PubMedCrossRefGoogle Scholar
  9. 9.
    Thorn JJ, Kallehave F, Westergaard P, et al. The effect of hyperbaric oxygen on irradiated oral tissues: transmucosal oxygen tension measurements. J Oral Maxillofac Surg 1997; 55(10): 1103–7PubMedCrossRefGoogle Scholar
  10. 10.
    David LA, Sandor GK, Evans AW, et al. Hyperbaric oxygen therapy and mandibular osteoradionecrosis: a retrospective study and analysis of treatment outcomes. J Can Dent Assoc 2001; 67(7): 384PubMedGoogle Scholar
  11. 11.
    Marx RE, Johnson RP, Kline SN. Prevention of osteoradionecrosis: a randomized prospective clinical trial of hyperbaric oxygen versus penicillin. J Am Dent Assoc 1985; 111(1): 49–54PubMedGoogle Scholar
  12. 12.
    Jereczek-Fossa BA, Orecchia R. Radiotherapy-induced mandibular bone complications. Cancer Treat Rev 2002; 28(1): 65–74PubMedCrossRefGoogle Scholar
  13. 13.
    Maier A, Gaggl A, Klemen H, et al. Review of severe osteoradionecrosis treated by surgery alone or surgery with postoperative hyperbaric oxygenation. Br J Oral Maxillofac Surg 2000; 38(3): 173–6PubMedCrossRefGoogle Scholar
  14. 14.
    Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27(2): 131–46PubMedCrossRefGoogle Scholar
  15. 15.
    Overgaard J, Hjelm-Hansen M, Johansen LV, et al. Comparison of conventional and split-course radiotherapy as primary treatment in carcinoma of the larynx. Acta Oncol 1988; 27(2): 147–52PubMedCrossRefGoogle Scholar
  16. 16.
    Overgaard J, Alsner J, Eriksen J, et al. Importance of overall treatment time for the response to radiotherapy in patients with squamous cell carcinoma of the head and neck. Rays 2000; 25(3): 313–9PubMedGoogle Scholar
  17. 17.
    Overgaard J, Hansen HS, Specht L, et al., on behalf of the Danish Head and Neck Cancer Study Group. Five compared with six fractions per week of conventional radiotherapy of squamos-cell carcinoma of head and neck: DAHANCA 6 & 7 randomized control trial [published erratum appears in Lancet 2003 Nov 8; 362: 1588]. Lancet 2003; 362: 933–40PubMedCrossRefGoogle Scholar
  18. 18.
    Skladowski K, Maciejewski B, Golen M, et al. Randomized clinical trial on 7-day-continuous accelerated irradiation (CAIR) of head and neck can. Radiother Oncol 2000; 55(2): 101–10PubMedCrossRefGoogle Scholar
  19. 19.
    Jackson SM, Weir LM, Hay JH, et al. A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997; 43(1): 39–46PubMedCrossRefGoogle Scholar
  20. 20.
    Horiot JC, Le Fur R, N’Guyen T, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. Radiother Oncol 1992; 25(4): 231–41PubMedCrossRefGoogle Scholar
  21. 21.
    Fu KK, Pajak TF, Trotti A, et al. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 2000; 48(1): 7–16PubMedCrossRefGoogle Scholar
  22. 22.
    Dische S, Saunders M, Barrett A, et al. A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. Radiother Oncol 1997; 44(2): 123–36PubMedCrossRefGoogle Scholar
  23. 23.
    Horiot JC, Bontemps P, van den Bogaert W, et al. Accelerated fractionation (AF) compared to conventional fractionation (CF) improves loco-regional control in the radiotherapy of advanced head and neck cancers: results of the EORTC 2 2851 randomized trial. Radiother Oncol 1997; 44(2): 111–21PubMedCrossRefGoogle Scholar
  24. 24.
    Bourhis J, Syz N, Overgaard J, et al. Conventional versus modified fractionated radiotherapy: meta-analysis based on Individual data of patients with head and neck squamous cell carcinoma (HNSCC) [abstract]. Radiother Oncol 2002; 64Suppl. 1: 25Google Scholar
  25. 25.
    Grau C, Prakash AJ, Jabeen K, et al. Radiotherapy with or without mitomycin c in the treatment of locally advanced head and neck cancer: results of the IAEA multicentre randomised trial. Radiother Oncol 2003; 67(1): 17–26PubMedCrossRefGoogle Scholar
  26. 26.
    Lee N, Xia P, Quivey JM, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys 2002; 53: 12–22PubMedCrossRefGoogle Scholar
  27. 27.
    Maes A, Weltens C, Flamen P, et al. Preservation of parotid function with uncomplicated conformal radiotherapy. Radiother Oncol 2002; 63(2): 203–11PubMedCrossRefGoogle Scholar
  28. 28.
    Hazuka MB, Martel MK, Marsh L, et al. Preservation of parotid function after external beam irradiation in head and neck cancer patients: a feasibility study using 3-dimensional treatment planning. Int J Radiat Oncol Biol Phys 1993; 27(3): 731–7PubMedCrossRefGoogle Scholar
  29. 29.
    Chao KS. Protection of salivary function by intensity-modulated radiation therapy in patients with head and neck cancer. Semin Radiat Oncol 2002; 12(1 Suppl. 1): 20–5PubMedCrossRefGoogle Scholar
  30. 30.
    Pignon JP, Bourhis J, Domenge C, et al. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 2000; 355(9208): 949–55PubMedGoogle Scholar
  31. 31.
    Adelstein DJ, Saxton JP, Lavertu P, et al. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 1997; 19(7): 567–75PubMedCrossRefGoogle Scholar
  32. 32.
    Wendt TG, Grabenbauer GG, Rodel CM, et al. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 1998; 16(4): 1318–24PubMedGoogle Scholar
  33. 33.
    Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst 1999; 91(24): 2081–6PubMedCrossRefGoogle Scholar
  34. 34.
    Olmi P, Crispino S, Fallai C, et al. Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs accelerated hyperfractionated radiotherapy vs concomitant radiotherapy and chemotherapy: a multicenter randomized trial. Int J Radiat Oncol Biol Phys 2003; 55(1): 78–92PubMedCrossRefGoogle Scholar
  35. 35.
    Brizel DM, Albers ME, Fisher SR, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 1998; 338(25): 1798–804PubMedCrossRefGoogle Scholar
  36. 36.
    Merlano M, Benasso M, Corvo R, et al. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst 1996; 88(9): 583–9PubMedCrossRefGoogle Scholar
  37. 37.
    Denis F, Garaud P, Bardet E, et al. Late toxicity results of the GORTEC 94-01 randomized trial comparing radiotherapy with concomitant radiochemotherapy for advanced-stage oropharynx carcinoma: comparison of LENT/SOMA, RTOG/EORTC, and NCI-CTC scoring systems. Int J Radiat Oncol Biol Phys 2003; 55(1): 93–8PubMedCrossRefGoogle Scholar
  38. 38.
    Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy: results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001; 50(5): 1161–71PubMedCrossRefGoogle Scholar
  39. 39.
    Henk JM. Controlled trials of synchronous chemotherapy with radiotherapy in head and neck cancer: overview of radiation morbidity. Clin Oncol (R Coll Radiol) 1997; 9(5): 308–12CrossRefGoogle Scholar
  40. 40.
    Sutherland SE, Browman GP. Prophylaxis of oral mucositis in irradiated head-and-neck cancer patients: a proposed classification scheme of interventions and meta-analysis of randomized controlled trials. Int J Radiat Oncol Biol Phys 2001; 49(4): 917–30PubMedCrossRefGoogle Scholar
  41. 41.
    Johnson JT, Ferretti GA, Nethery WJ, et al. Oral pilocarpine for post-irradiation xerostomia in patients with head and neck cancer. N Engl J Med 1993; 329(6): 390–5PubMedCrossRefGoogle Scholar
  42. 42.
    Horiot JC, Lipinski F, Schraub S, et al. Post-radiation severe xerostomia relieved by pilocarpine: a prospective French cooperative study. Radiother Oncol 2000; 55(3): 233–9PubMedCrossRefGoogle Scholar
  43. 43.
    Haddad P, Karimi M. A randomized, double-blind, placebo-controlled trial of concomitant pilocarpine with head and neck irradiation for prevention of radiation-induced xerostomia. Radiother Oncol 2002; 64(1): 29–32PubMedCrossRefGoogle Scholar
  44. 44.
    Warde P, O’Sullivan B, Aslanidis J, et al. A phase III placebo-controlled trial of oral pilocarpine in patients undergoing radiotherapy for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002; 54(1): 9–13PubMedCrossRefGoogle Scholar
  45. 45.
    Takahashi I, Nagai T, Miyaishi K, et al. Clinical study of the radioprotective effects of Amifostine (YM-08310, WR-2721) on chronic radiation injury. Int J Radiat Oncol Biol Phys 1986; 12(6): 935–8PubMedCrossRefGoogle Scholar
  46. 46.
    Brizel DM, Wasserman TH, Henke M, et al. Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000; 18(19): 3339–45PubMedGoogle Scholar
  47. 47.
    McDonald S, Meyerowitz C, Smudzin T, et al. Preliminary results of a pilot study using WR-2721 before fractionated irradiation of the head and neck to reduce salivary gland dysfunction. Int J Radiat Oncol Biol Phys 1994; 29(4): 747–54PubMedCrossRefGoogle Scholar
  48. 48.
    Bourhis J, De Cevoisier R, Abdulkarim B, et al. A randomized study of very accelerated radiotherapy with and without amifostine in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2000; 46(5): 1105–8PubMedCrossRefGoogle Scholar
  49. 49.
    Lindegaard JC, Grau C. Has the outlook improved for amifostine as a clinical radioprotector? Radiother Oncol 2000; 57(2): 113–8PubMedCrossRefGoogle Scholar
  50. 50.
    Lindegaard JC. Has the time come for routine use of amifostine in clinical radiotherapy practice? Acta Oncol 2003; 42(1): 2–3PubMedCrossRefGoogle Scholar
  51. 51.
    Herskind C, Bamberg M, Rodemann HP. The role of cytokines in the development of normal-tissue reactions after radiotherapy. Strahlenther Onkol 1998; 174Suppl. 3: 12–5PubMedGoogle Scholar
  52. 52.
    Hill RP, Rodemann HP, Hendry JH, et al. Normal tissue radiobiology: from the laboratory to the clinic. Int J Radiat Oncol Biol Phys 2001; 49(2): 353–65PubMedCrossRefGoogle Scholar
  53. 53.
    Martin M, Lefaix J, Delanian S. TGF-beta 1 and radiation fibrosis: a master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 2000; 47(2): 277–90PubMedCrossRefGoogle Scholar
  54. 54.
    Trotti A. Toxicity antagonists in head and neck cancer. Semin Radiat Oncol 1998; 8(4): 282–91PubMedCrossRefGoogle Scholar
  55. 55.
    Lefaix JL, Delanian S, Vozenin MC, et al. Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study. Int J Radiat Oncol Biol Phys 1999; 43(4): 839–47PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Cai Grau
    • 1
  • Christian N. Andreassen
    • 1
  • Kenneth Jensen
    • 1
  • Jacob C. Lindegaard
    • 1
  1. 1.Department of Oncology and Department of Experimental Clinical OncologyAarhus University HospitalAarhusDenmark

Personalised recommendations