Optimized Hypofractionation Can Markedly Improve Tumor Control and Decrease Late Effects for Head and Neck Cancer

Published:February 15, 2019DOI:


      Treatment of fast-growing, human papillomavirus–negative, head and neck cancers (HNCs) remains challenging from the perspectives of both tumor control and late sequelae. In this study, we use systematic radiobiological optimization to identify fractionation schemes that markedly improve the radiotherapeutic effectiveness balance between tumor control probability (TCP) and late normal tissue complication probability (LNTCP), as compared with standard fractionation.

      Methods and Materials

      We track the development after each treatment fraction of both tumor control and late sequelae. Toward the end of the treatment, accelerated repopulation of fast-growing HNC tumors means that further fractions minimally improve TCP but result in major LNTCP increases, providing the potential for optimization of the TCP-LNTCP balance. We used a recent improved model of accelerated repopulation, calibrated with extensive HNC clinical trials data, to identify optimally effective treatment regimens that both increase TCP and significantly decrease LNTCP. For comparison, we also used standard repopulation models.


      An optimized hypofractionated schedule of 18 × 3.0 Gy is predicted to substantially increase TCP, particularly for late-stage HNC tumors (eg, ∼35% to 49% for late-stage tumors) while decreasing high-grade LNTCP (eg, ∼13% to <2%), as compared with a standard 35 × 2.0 Gy protocol. In addition, the treatment time is reduced from 47 to 24 days. Twice-daily treatments of 1.8 Gy per fraction provide still better outcomes. The hypofractionation predictions are robust, being almost independent of the details of the repopulation model.


      Hypofractionation or its close variant, accelerated hyperfractionation, efficiently overcomes tumor repopulation in fast-growing tumors and can be optimized toward the end of treatment when repopulation causes the TCP to increase only very slowly while LNTCP increases rapidly. Radiobiological modeling suggests that optimized 3.0 Gy per fraction hypofractionation (or 1.8 Gy per fraction, 2 fractions per weekday, accelerated hyperfractionation) is considerably more effective for HNC tumor control and for reduction of late effects than standard 2.0-Gy fractionation.
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        • Ang K.K.
        • Harris J.
        • Wheeler R.
        • et al.
        Human papillomavirus and survival of patients with oropharyngeal cancer.
        N Engl J Med. 2010; 363: 24-35
        • Young D.
        • Xiao C.C.
        • Murphy B.
        • et al.
        Increase in head and neck cancer in younger patients due to human papillomavirus (HPV).
        Oral Oncol. 2015; 51: 727-730
        • Daraei P.
        • Moore C.E.
        Racial disparity among the head and neck cancer population.
        J Cancer Educ. 2015; 30: 546-551
        • Shuryak I.
        • Hall E.J.
        • Brenner D.J.
        Dose dependence of accelerated repopulation in head and neck cancer: Supporting evidence and clinical implications.
        Radiother Oncol. 2018; 127: 20-26
        • Horiot J.C.
        • 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: 231-241
        • Horiot J.C.
        • 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 22851 randomized trial.
        Radiother Oncol. 1997; 44: 111-121
        • Beitler J.J.
        • Zhang Q.
        • Fu K.K.
        • 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. 2014; 89: 13-20
        • Lacas B.
        • Bourhis J.
        • Overgaard J.
        • et al.
        Role of radiotherapy fractionation in head and neck cancers (MARCH): An updated meta-analysis.
        Lancet Oncol. 2017; 18: 1221-1237
        • Withers H.R.
        • Taylor J.M.
        • Maciejewski B.
        The hazard of accelerated tumor clonogen repopulation during radiotherapy.
        Acta Oncol. 1988; 27: 131-146
        • Holthusen H.
        Erfahrungen uber die Vertraglichkeitsgrenze Fur Rontgenstrahlen and deren Nutzanwendung zur Verhutung von Schaden.
        Strahlen-Therapie. 1936; 57: 254-269
        • Brenner D.J.
        • Hall E.J.
        • Huang Y.
        • Sachs R.K.
        Optimizing the time course of brachytherapy and other accelerated radiotherapeutic protocols.
        Int J Radiat Oncol Biol Phys. 1994; 29: 893-901
        • Poulsen M.G.
        • Denham J.W.
        • Peters L.J.
        • et al.
        A randomised trial of accelerated and conventional radiotherapy for stage III and IV squamous carcinoma of the head and neck: A Trans-Tasman Radiation Oncology Group Study.
        Radiother Oncol. 2001; 60: 113-122
        • Skladowski K.
        • Maciejewski B.
        • Golen M.
        • et al.
        Continuous accelerated 7-days-a-week radiotherapy for head-and-neck cancer: Long-term results of phase III clinical trial.
        Int J Radiat Oncol Biol Phys. 2006; 66: 706-713
        • Skladowski K.
        • Hutnik M.
        • Wygoda A.
        • et al.
        Radiation-free weekend rescued! Continuous accelerated irradiation of 7-days per week is equal to accelerated fractionation with concomitant boost of 7 fractions in 5-days per week: Report on phase 3 clinical trial in head-and-neck cancer patients.
        Int J Radiat Oncol Biol Phys. 2013; 85: 741-746
        • Wang C.C.
        • Blitzer P.H.
        • Suit H.D.
        Twice-a-day radiation therapy for cancer of the head and neck.
        Cancer. 1985; 55: 2100-2104
        • Yamazaki H.
        • Nishiyama K.
        • Tanaka E.
        • et al.
        Radiotherapy for early glottic carcinoma (T1N0M0): Results of prospective randomized study of radiation fraction size and overall treatment time.
        Int J Radiat Oncol Biol Phys. 2006; 64: 77-82
        • Leclerc M.
        • Maingon P.
        • Hamoir M.
        • et al.
        A dose escalation study with intensity modulated radiation therapy (IMRT) in T2N0, T2N1, T3N0 squamous cell carcinomas (SCC) of the oropharynx, larynx and hypopharynx using a simultaneous integrated boost (SIB) approach.
        Radiother Oncol. 2013; 106: 333-340
        • Bourhis J.
        • Lapeyre M.
        • Tortochaux J.
        • et al.
        Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: A GORTEC trial.
        J Clin Oncol. 2006; 24: 2873-2878
        • 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: 123-136
        • Fu K.K.
        • Pajak T.F.
        • 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: 7-16
        • Hansen O.
        • Overgaard J.
        • Hansen H.S.
        • et al.
        Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: Dependency on tumor differentiation.
        Radiother Oncol. 1997; 43: 47-51
        • Hliniak A.
        • Gwiazdowska B.
        • Szutkowski Z.
        • et al.
        A multicentre randomized/controlled trial of a conventional versus modestly accelerated radiotherapy in the laryngeal cancer: Influence of a 1 week shortening overall time.
        Radiother Oncol. 2002; 62: 1-10
        • Jackson S.M.
        • Weir L.M.
        • Hay J.H.
        • et al.
        A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer.
        Radiother Oncol. 1997; 43: 39-46
        • Overgaard J.
        • Hansen H.S.
        • Specht L.
        • et al.
        Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial.
        Lancet. 2003; 362: 933-940
        • Pinto L.H.
        • Canary P.C.
        • Araújo C.M.
        • et al.
        Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma.
        Int J Radiat Oncol Biol Phys. 1991; 21: 557-562
        • Ang K.K.
        • Thames H.D.
        • van der Kogel A.J.
        • et al.
        Is the rate of repair of radiation-induced sublethal damage in rat spinal cord dependent on the size of dose per fraction?.
        Int J Radiat Oncol Biol Phys. 1987; 13: 557-562
        • Turesson I.
        • Thames H.D.
        Repair capacity and kinetics of human skin during fractionated radiotherapy: Erythema, desquamation, and telangiectasia after 3 and 5 year's follow-up.
        Radiother Oncol. 1989; 15: 169-188
        • Fowler J.F.
        Biological factors influencing optimum fractionation in radiation therapy.
        Acta Oncol. 2001; 40: 712-717
        • Unkelbach J.
        • Craft D.
        • Salari E.
        • et al.
        The dependence of optimal fractionation schemes on the spatial dose distribution.
        Phys Med Biol. 2013; 58: 159-167
        • Unkelbach J.
        • Craft D.
        • Hong T.
        • et al.
        Exploiting tumor shrinkage through temporal optimization of radiotherapy.
        Phys Med Biol. 2014; 59: 3059-3079
        • Sugano Y.
        • Mizuta M.
        • Takao S.
        • et al.
        Optimization of the fractionated irradiation scheme considering physical doses to tumor and organ at risk based on dose-volume histograms.
        Med Phys. 2015; 42: 6203-6210
        • Mizuta M.
        • Takao S.
        • Date H.
        • et al.
        A mathematical study to select fractionation regimen based on physical dose distribution and the linear-quadratic model.
        Int J Radiat Oncol Biol Phys. 2012; 84: 829-833
        • Laursen M.
        • Specht L.
        • Kristensen C.A.
        • et al.
        An extended hypofractionated palliative radiotherapy regimen for head and neck carcinomas.
        Front Oncol. 2018; 8: 206
        • Pandey K.C.
        • Revannasiddaiah S.
        • Pant N.K.
        • et al.
        Palliative radiotherapy in locally advanced head and neck cancer after failure of induction chemotherapy: Comparison of two fractionation schemes.
        Indian J Palliat Care. 2013; 19: 139-145
        • Timmerman R.D.
        An overview of hypofractionation and introduction to this issue of seminars in radiation oncology.
        Semin Radiat Oncol. 2008; 18: 215-222
        • Farrell M.J.
        • Yahya J.B.
        • Degnin C.
        • et al.
        Radiation dose and fractionation for limited-stage small-cell lung cancer: Survey of US radiation oncologists on practice patterns.
        Clin Lung Cancer. 2019; 20: 13-19
        • Suzuki R.
        • Wei X.
        • Allen P.K.
        • et al.
        Twice-daily thoracic radiotherapy for limited-stage small-cell lung cancer does not increase the incidence of acute severe esophagitis.
        Clin Lung Cancer. 2018; 19: e885-e891
        • Roach M.C.
        • Bradley J.D.
        • Robinson C.G.
        Optimizing radiation dose and fractionation for the definitive treatment of locally advanced non-small cell lung cancer.
        J Thorac Dis. 2018; 10: S2465-S2473
        • Cagney D.N.
        • Thirion P.G.
        • Dunne M.T.
        • et al.
        A phase II toxicity end point trial (ICORG 99-09) of accelerated dose-escalated hypofractionated radiation in non-small cell lung cancer.
        Clin Oncol (R Coll Radiol). 2018; 30: 30-38
        • Jeong J.
        • Oh J.H.
        • Sonke J.-J.
        • et al.
        Modeling the cellular response of lung cancer to radiation therapy for a broad range of fractionation schedules.
        Clin Cancer Res. 2017; 23: 5469-5479
        • Fang P.
        • Swanick C.W.
        • Pezzi T.A.
        • et al.
        Outcomes and toxicity following high-dose radiation therapy in 15 fractions for non-small cell lung cancer.
        Pract Radiat Oncol. 2017; 7: 433-441
        • de Dios N.R.
        • Sanz X.
        • Foro P.
        • et al.
        Accelerated hypofractionated radiation therapy (AHRT) for non-small-cell lung cancer: Can we leave standard fractionation?.
        Clin Transl Oncol. 2017; 19: 440-447

      Linked Article

      • In Regard to Shuryak et al
        International Journal of Radiation Oncology • Biology • PhysicsVol. 105Issue 1
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          I read with interest the article “Optimized Hypofractionation Can Markedly Improve Tumor Control and Decrease Late Effects for Head and Neck Cancer” by Shuryak et al.1 Although limited to human papillomavirus–negative, radiation therapy–only cases, I believe there is still benefit in further studying this dose-fractionation scheme. Furthermore, the article is provocative enough to suggest an “optimal” dose-fractionation regime that can extend beyond head and neck (HN) cancer.
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