title: Time-dose relationship for local tumor control following alternate week concomitant radiation and chemotherapy of advanced head and neck cancer.
abstract: OBJECTIVE
  To analyze the time-dose relationship for local control of disease in patients with advanced head and neck neoplasms enrolled in two sequential Phase I dose escalation studies in which concomitant chemotherapy and radiotherapy were delivered on an alternate week schedule (i.e., 1 week of concomitant therapy alternated with 1 week of rest).
  
  
  METHODS
  From 1986-1988, 65 patients were enrolled in two Phase I clinical trials. In trial one, 5-fluorouracil and hydroxyurea were administered concomitantly with radiation on an alternate week schedule (39 pts). In trial two, cisplatin was added to 5-fluorouracil and hydroxyurea (26 pts). Fifty-seven patients were evaluable for local control, including 26 patients who had failed prior local therapy and were retreated (group A), and 31 patients who had received no prior local therapy (group B). The median dose of RT and the median duration of therapy were 59.7 Gy and 12 weeks for group A, and 70.2 Gy and 14 weeks for group B, respectively. The biological effective dose of radiation therapy (RT) was calculated using the equation based on the linear quadratic model as proposed by J. Fowler. Univariate and multivariate logistic regression analyses were performed to evaluate prognostic factors for local control.
  
  
  RESULTS
  Six of 26 patients in group A and 30 of 31 patients in group B had local control of disease. The 2-year Kaplan-Meier local failure rates were 84% for group A and 4% for group B, respectively. Despite the doubling of treatment duration compared to conventional daily radiotherapy and the low biological equivalent dose calculated (median biological equivalent dose for patients with local control of disease were 50.3 Gy and 48.8 Gy in groups A and B, respectively), local control was achieved in 5/17 patients in group A and 30/31 patients in group B who received RT dose of 59.4 Gy or higher. In multivariate logistic regression analysis, the only significant predictor for local control of disease was RT dose (p = 0.004). Treatment duration, chemotherapy dose intensities, age, and performance status were not significant variables. Decreasing the RT dose by 10 Gy would increase the rate of local failure by 24%.
  
  
  CONCLUSIONS
  Our data suggest that prolongation of treatment duration to twice the normal duration of conventional once-a-day radiotherapy does not result in loss of local control when aggressive cell-cycle specific chemotherapy is given concomitantly with radiotherapy. The usual time-dose relationship based on RT alone does not appear to be applicable when concomitant chemotherapy is added. The clinical significance of biological equivalent dose calculation based on radiotherapy alone is unclear when chemotherapy is given with radiation.
authors.affiliation: Department of Radiation and Cellular Oncology, University of Chicago, IL 60637.
authors.forename: W W
authors.initials: WW
authors.lastname: Wong
authors.forename: R
authors.initials: R
authors.lastname: Mick
authors.forename: D J
authors.initials: DJ
authors.lastname: Haraf
authors.forename: R R
authors.initials: RR
authors.lastname: Weichselbaum
authors.forename: E E
authors.initials: EE
authors.lastname: Vokes
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011879:Radiotherapy Dosage; D012044:Regression Analysis; D013997:Time Factors
chemical_list: D002945:Cisplatin; D005472:Fluorouracil; D006918:Hydroxyurea