Is there an optimum overall time for head and neck radiotherapy? A review, with new modelling.

AIMS To test by modelling whether a non-standard fractionated schedule giving optimum log cell kill could be expected, between short (accelerated) and longer multiple fraction/day schedules. MATERIALS AND METHODS Linear quadratic modelling was carried out for many schedules, with biologically effective doses converted to normalised total doses (NTDs; in 2 Gy fractions). Late complication and acute mucosal NTDs were calculated as constraint doses for each schedule, and the highest tumour NTDs and log cell kill values within both constraints were calculated. This modelling is robust and agrees with conclusions in a very recent meta-analysis (Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. www.thelancet.com. Published online August 17, 2006). RESULTS The six schedules that gave the highest tumour log cell kill deliver a narrow range of 11.1-11.2 log10 cell kill in the present parameters. Other regularly used schedules give closer to 10 log10. Using one fraction/day fails to achieve the highest therapeutic ratios. Suggestions are made for escalating certain UK schedules. Fractionated radiotherapy results in a nearly constant tumour cell kill if the acute mucosal NTD is held constant. However, a small (3%) gain in tumour cell kill occurs from 3 weeks to 73 fractions of 1.15 Gy in 7 weeks. That is how fractionation works, within both acute and late constraints. Short accelerated schedules enable fewer late complications, but do not do as well for the minority of head and neck tumours that repopulate slowly. CONCLUSIONS Schedules of 4-6 weeks overall time could be chosen to give at least 11 log10 cell kill, which are safe. Most tumours would require two fractions/day, until routine monitoring of repopulation rates becomes feasible to select individual tumours. There is no 'optimum schedule', but each chosen schedule can be balanced against its own risk of excessive acute or late complications, as shown in these examples.

[1]  P M Harari,et al.  Dose intensification in curative head and neck cancer radiotherapy--linear quadratic analysis and preliminary assessment of clinical results. , 1993, International journal of radiation oncology, biology, physics.

[2]  J. M. Taylor,et al.  The hazard of accelerated tumor clonogen repopulation during radiotherapy. , 1988, Acta oncologica.

[3]  S M Bentzen,et al.  Repair halftimes estimated from observations of treatment-related morbidity after CHART or conventional radiotherapy in head and neck cancer. , 1999, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[4]  Jay S. Cooper,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 , 1999 .

[5]  E. Zubizarreta,et al.  Accelerated hyperfractionated irradiation for advanced head and neck cancer: Effect of shortening the median treatment duration by 13 days , 2001, Head & neck.

[6]  J. Fowler.  The linear-quadratic formula and progress in fractionated radiotherapy. , 1989, The British journal of radiology.

[7]  C. Leemans,et al.  The importance of immunohistochemical expression of EGFr in squamous cell carcinoma of the oral cavity treated with surgery and postoperative radiotherapy. , 2006, International journal of radiation oncology, biology, physics.

[8]  J. Collier,et al.  A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated X-ray treatments. , 1991, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[9]  J H Hendry,et al.  Time factors in larynx tumor radiotherapy: lag times and intertumor heterogeneity in clinical datasets from four centers. , 1999, International journal of radiation oncology, biology, physics.

[10]  J. Fowler.  Repair between Dose Fractions: A Simpler Method of Analyzing and Reporting Apparently Biexponential Repair1 , 2002, Radiation research.

[11]  L. Peters,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 , 2001 .

[12]  S Schraub,et al.  Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: final analysis of a randomized trial of the EORTC cooperative group of radiotherapy. , 1992, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[13]  Søren M Bentzen,et al.  Theragnostic imaging for radiation oncology: dose-painting by numbers. , 2005, The Lancet. Oncology.

[14]  C. C. Wang,et al.  Local control of oropharyngeal carcinoma after two accelerated hyperfractionation radiation therapy schemes. , 1988, International journal of radiation oncology, biology, physics.

[15]  J. Kaanders,et al.  ARCON: experience in 215 patients with advanced head-and-neck cancer. , 2001, International journal of radiation oncology, biology, physics.

[16]  S. Dische,et al.  From CHART to CHARTWEL in non-small cell lung cancer: clinical radiobiological modelling of the expected change in outcome. , 2002, Clinical oncology (Royal College of Radiologists (Great Britain)).

[17]  K. Ang,et al.  Altered fractionation: limited by mucosal reactions? , 1999, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[18]  George Starkschall,et al.  Late rectal toxicity: dose-volume effects of conformal radiotherapy for prostate cancer. , 2002, International journal of radiation oncology, biology, physics.

[19]  S. Bentzen.  Towards evidence based radiation oncology: improving the design, analysis, and reporting of clinical outcome studies in radiotherapy. , 1998, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[20]  Srinivasan Vijayakumar,et al.  Technical Basis of Radiation Therapy , 2006 .

[21]  J. Fowler,et al.  Loss of biological effect in prolonged fraction delivery. , 2004, International journal of radiation oncology, biology, physics.

[22]  Dose-volume analysis of predictors for chronic rectal toxicity following treatment of prostate cancer with high-dose conformal radiotherapy , 2003 .

[23]  Tolerance to accelerated fractionation in the head and neck region. , 1994, Acta oncologica.

[24]  Brian O'Sullivan,et al.  Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis , 2006, The Lancet.

[25]  P. Wust,et al.  Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  W. Dörr,et al.  Radiation-induced changes in cellularity and proliferation in human oral mucosa. , 2002, International journal of radiation oncology, biology, physics.

[27]  J. Pignon,et al.  Altered fractionated radiotherapy in the management of head and neck carcinomas: advantages and limitations , 2004, Current opinion in oncology.

[28]  J. Fowler,et al.  Acute radiation reactions in oral and pharyngeal mucosa: tolerable levels in altered fractionation schedules. , 2003, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[29]  M. Parmar,et al.  A randomised multicentre trial of CHART versus conventional radiotherapy in head and neck cancer. , 1997, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[30]  Cai Grau,et al.  Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial , 2003, The Lancet.

[31]  T. Kron,et al.  Extinction of the weakest. , 2001, International journal of radiation oncology, biology, physics.

[32]  J. Fowler,et al.  The radiobiology of prostate cancer including new aspects of fractionated radiotherapy , 2005, Acta oncologica.

[33]  Randomized clinical trial on 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer - report on 3-year tumour control and normal tissue toxicity. , 2000 .

[34]  K. Ang,et al.  Clinical radiation doses for spinal cord: the 1998 international questionnaire. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[35]  A. Niemierko.  Reporting and analyzing dose distributions: a concept of equivalent uniform dose. , 1997, Medical physics.

[36]  M. Lindstrom,et al.  Loss of local control with prolongation in radiotherapy. , 1992, International journal of radiation oncology, biology, physics.

[37]  A. Ruifrok,et al.  Repair capacity and kinetics for human mucosa and epithelial tumors in the head and neck: clinical data on the effect of changing the time interval between multiple fractions per day in radiotherapy. , 1996, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[38]  J. Hendry,et al.  The effect of increasing the treatment time beyond three weeks on the control of T2 and T3 laryngeal cancer using radiotherapy. , 1992, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[39]  D. Brenner.  Accelerated repopulation during radiotherapy: Quantitative evidence for delayed onset , 1993 .

[40]  Jacques Bernier,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. , 1997, Radiotherapy and Oncology.

[41]  G. Barendsen,et al.  Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. , 1982, International journal of radiation oncology, biology, physics.