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

Abstract Purpose: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. Methods and Materials: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. Results: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control ( p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival ( p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. Conclusions: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

[1]  N. Mantel.  Evaluation of survival data and two new rank order statistics arising in its consideration. , 1966, Cancer chemotherapy reports.

[2]  P. Rubin,et al.  Late effects of hyperfractionated radiotherapy for advanced head and neck cancer: long-term follow-up results of RTOG 83-13. , 1995, International journal of radiation oncology, biology, physics.

[3]  M. Martel,et al.  Comprehensive irradiation of head and neck cancer using conformal multisegmental fields: assessment of target coverage and noninvolved tissue sparing. , 1998, International journal of radiation oncology, biology, physics.

[4]  D. Brizel.  Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma. , 1998, Seminars in radiation oncology.

[5]  S. Spencer,et al.  Monoclonal antibodies as potentiators of radiotherapy and chemotherapy in the management of head and neck cancer. , 1999, Current opinion in oncology.

[6]  Satyandra K. Gupta,et al.  Twice a day versus once a day radiation therapy in head and neck cancer , 1989 .

[7]  T. Pajak,et al.  Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC) , 1995, International journal of radiation oncology, biology, physics.

[8]  W. Curran,et al.  Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. , 1995, International journal of radiation oncology, biology, physics.

[9]  D. Bristol.  Designing clinical trials for two-sided multiple comparisons with a control. , 1989, Controlled clinical trials.

[10]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .

[11]  M Zelen,et al.  The randomization and stratification of patients to clinical trials. , 1974, Journal of chronic diseases.

[12]  D. Wazer,et al.  Concomitant boost technique using accelerated superfractionated radiation therapy for advanced squamous cell carcinoma of the head and neck , 1992, Cancer.

[13]  R. Gray.  A Class of $K$-Sample Tests for Comparing the Cumulative Incidence of a Competing Risk , 1988 .

[14]  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.

[15]  H. Suit,et al.  Twice-a-day radiation therapy for supraglottic carcinoma. , 1986, International journal of radiation oncology, biology, physics.

[16]  R K Ten Haken,et al.  Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. , 1999, International journal of radiation oncology, biology, physics.

[17]  K. Fu.  Combined-modality therapy for head and neck cancer. , 1997, Oncology.

[18]  K. Ang,et al.  Randomized phase I/II trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: results of RTOG 88-09. , 1995, International journal of radiation oncology, biology, physics.

[19]  R Mohan,et al.  The potential for sparing of parotids and escalation of biologically effective dose with intensity-modulated radiation treatments of head and neck cancers: a treatment design study. , 2000, International journal of radiation oncology, biology, physics.

[20]  H. Awwad,et al.  Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and neck cancer: influence of tumour proliferation. , 1992, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[21]  H. Withers.  Biologic basis for altered fractionation schemes , 1985, Cancer.

[22]  M. I. Saunders,et al.  Randomised multicentre trials of CHART vs conventional radiotherapy in head and neck and non-small-cell lung cancer: an interim report. CHART Steering Committee. , 1996, British Journal of Cancer.

[23]  C. Dunnett.  A Multiple Comparison Procedure for Comparing Several Treatments with a Control , 1955 .

[24]  B. Maciejewski,et al.  Randomized clinical trial on accelerated 7 days per week fractionation in radiotherapy for head and neck cancer. Preliminary report on acute toxicity. , 1996, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[25]  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.

[26]  P. Rubin,et al.  Dose-response for local control with hyperfractionated radiation therapy in advanced carcinomas of the upper aerodigestive tracts: preliminary report of radiation therapy oncology group protocol 83-13. , 1990, International journal of radiation oncology, biology, physics.

[27]  L. Souhami,et al.  Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma. , 1991, International journal of radiation oncology, biology, physics.

[28]  H. Suit,et al.  Twice‐a‐day radiation therapy for cancer of the head and neck , 1985, Cancer.

[29]  J. Kaanders,et al.  Accelerated fractionation radiotherapy for laryngeal cancer, acute, and late toxicity. , 1992, International journal of radiation oncology, biology, physics.

[30]  L. Bastholt,et al.  106 Conventional radiotherapy as primary treatment of squamous cell carcinoma of the head and neck. A randomized multicenter study of 5 versus 6 fractions per week-report from the Dahanca 7 trial , 1997 .

[31]  P. Rubin,et al.  ASTRO plenary: interfraction interval is a major determinant of late effects, with hyperfractionated radiation therapy of carcinomas of upper respiratory and digestive tracts: results from Radiation Therapy Oncology Group protocol 8313. , 1991, International journal of radiation oncology, biology, physics.

[32]  K. Ang,et al.  Altered fractionation trials in head and neck cancer. , 1998, Seminars in radiation oncology.

[33]  Chao Wang.  Accelerated hyperfractionation radiation therapy for carcinoma of the nasopharynx. Techniques and results , 1989 .

[34]  C. C. Wang,et al.  Role of accelerated fractionated irradiation for supraglottic carcinoma: assessment of results. , 1997, The cancer journal from Scientific American.

[35]  G. Calais,et al.  Randomized Trial of Radiation Therapy Versus Concomitant Chemotherapy and Radiation Therapy for Advanced-Stage Oropharynx Carcinoma. , 1999, Journal of the National Cancer Institute.

[36]  T. Wendt,et al.  Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  J. Torner,et al.  Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. , 1990, International journal of radiation oncology, biology, physics.

[38]  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.

[39]  A. Trotti.  Toxicity antagonists in cancer therapy , 1997, Current opinion in oncology.

[40]  L. Weir,et al.  A randomised trial of accelerated versus conventional radiotherapy in head and neck cancer. , 1997, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[41]  J. Kalbfleisch,et al.  The Statistical Analysis of Failure Time Data , 1980 .

[42]  T. Pajak,et al.  Hyperfractionated photon radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx, and sinuses, using radiation therapy as the only planned modality: (preliminary report) by the Radiation Therapy Oncology Group (RTOG). , 1987, International journal of radiation oncology, biology, physics.