Hyperfractionated Irradiation with or without Concurrent Chemotherapy for Locally Advanced Head and Neck Cancer

Author: Reviewer: Roberto Santiago, MD
Content Contributor: Abramson Cancer Center of the University of Pennsylvania
Last Reviewed: April 11, 2003

Source: The New England Journal of Medicine Vol 338(25): 1798-1804, 1998
Author: Brizel, David M. et al
Affiliation: Departments of Radiation Oncology, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, N.C.


  • Cure of locally advanced carcinoma of the head and neck is uncommon, and most patients die with progressive local disease.
  • Accelerated fractionation and hyperfractionation can improve disease control by about 20%, as compared with conventional radiation, without an increase in long-term toxicity.
  • Several randomized studies have shown improved overall survival or disease-free survival when radiation therapy (RT) was combined with concurrent chemotherapy as compared to sequential chemotherapy plus RT or RT alone.
  • This study tests the hypothesis that hyperfractionated RT plus concurrent chemotherapy followed by additional chemotherapy leads to better locoregional control, relapse-free survival, and overall survival than accelerated hyperfractionation alone.


  • Multicenter randomized study (6/1990-12/1995) of 116 patients with advanced head and neck carcinoma treated either with:
    1. 3-Field, hyperfractionated radiation therapy (RT) alone (4-6 MV photons, 125 cGy twice a day (BID), at least 6 hours apart, to 7500 cGy)
    2. 3-Field, hyperfractionated RT (4-6 MV photons, 125 cGy BID, at least 6 hours apart, to 7000 cGy) plus 5 days of cisplatin plus 5FU (12mg/m2/d plus 600mg/m2/d) during weeks 1 and 6 of irradiation followed by 2 more courses of the two drugs.
  • Eligibile patients had previously untreated squamous-cell carcinoma of the head and neck region stages T3-T4, N0-N3, M0 (T2N0 Base of tongue were eligible) with good renal and hematologic function
  • Primary tumors were classified and stratified as resectable or unresectable as well as low ( < 12 g/dL) or normal hemoglobin.
  • CT or MRI was repeated 4-6 weeks after treatment to assess response.
  • Patients with stage N0-N1 were treated only with RT or RT plus chemotherapy.
  • Patients with N2-N3 were evaluated after RT and elective neck dissection was planned for complete responders.
  • The primary outcome measures were:
    1. Rate of complete response at the primary site
    2. Rate of locoregional control


  • From 142 eligible, 122 were enrolled and 6 were excluded. Thus, only 116 patients were included in the analysis.
  • Characteristics of the Patients:
    1. Just over 50% in both arms had unresectable disease
    2. Approximately 90% in both arms had stage T3-T4 (meanT diameter was > 5 cm in both arms)
    3. Approximately 70% of patients in both arms had involved lymph nodes
    4. 60% in the hyperfractionation arm vs. 44% in the combined-treatment arm had N2-N3 disease
    5. The median follow-up of surviving patients was 41 months
  • Short-term adverse effects:
    • Sepsis (including one fatal case) was more frequent in the combined-treatment arm.
    • The incidence of confluent mucositis was similar in both treatment groups (~75%).
    • The mean time before mucositis resolved was longer in the combined-treatment group (6 vs. 4 weeks).
    • More patients required feeding tubes with the combined-treatment.
    • Severe long-term adverse effects:
    • Osteonecrosis and soft-tissue necrosis were rare in both groups.
  • Response, control and survival:
    • 73% in the hyperfractionation group vs. 88% in the combined-treatment group had a complete response (P=0.52).
    • Of the patients with stage N2-N3 treated with hyperfractionation alone, 68% had a complete clinical response in the neck.
      i. About 2/3 underwent neck dissection. Pathologic review revealed viable tumor in 38% of the specimens.
    • Of the patients with stage N2-N3 treated with combined-treatment, 76% had a complete clinical response in the neck.
      i. About 3/4 underwent neck dissection. Pathologic review revealed viable tumor in 21% of the specimens.
    • The rates of local-regional tumor control at three years were 70% in the combined modality arm and 44% in the RT alone arm (p=0.01).
    • The rates of relapse-free survival at three years were 61% and 41%, respectively (p=0.07).
    • The 3-year overall survival rate was 55% and 34%, respectively (p=0.07).
  • Patterns of Relapse:
    • All recurrences occurred within 18 months of treatment.
    • The primary site was the area most commonly (~?) involved in first recurrences after both treatments.
    • Distant metastases were involved in 18% of first recurrences after hyperfractionation alone vs. 27% after combined therapy, but 83% of the metastases after combined therapy were among patients who refused post-radiation chemotherapy.
    • There were no recurrences in the neck in the patients who underwent elective neck dissection in either treatment group.


  • This study compared maximally intensive RT alone (total dose, 7500 cGy) with a slightly less intense RT program (total dose, 7000 cGy) plus concurrent chemotherapy.
  • Overall survival, relapse-free survival, and locoregional control were all improved by the addition of concurrent chemotherapy to the hyperfractionation program.
  • Moreover, these results were achieved without an increase in severe late toxicity and only a slight increase in acute toxicity in the combined-treatment group.
  • However:
    • The study was statistically underpowered
    • More patients had N2-N3 disease in the hyperfractionation group
    • More patients had hypopharynx tumors in the combined-treatment group
    • More patients had oropharynx tumors in the hyperfractionation group
    • More patients underwent neck dissection in the combined-treatment group
    • Although the rate of acute mucositis was similar between the two groups, the patients in the combined treatment arm received a slightly lower RT dose as well as a mid-course treatment break
  • Interestingly:
    • Not all patients with N2-N3 disease underwent elective neck dissection, which would have resulted in a lower failure rate in the neck.
    • Because there was an association between receiving the adjuvant portion of the chemotherapy and a reduction in distant relapses, relapse-free survival in the combined treatment group might have been higher had all patients in that arm received all planned chemotherapy


  • Despite the improvements in overall survival, relapse-free survival, and locoregional control of disease with the use of hyperfractionated RT and concurrent chemotherapy, approximately half the patients who received this treatment ultimately died of their disease, mostly from uncontrolled locoregional disease
  • Accelerated fractionation and hyperfractionation both use multiple daily dosages of irradiation to overcome tumor repopulation, tumor resistance, and late adverse effects associated with dose escalation. Phase 3 trials have confirmed these strategies provide a local control advantage of approximately 20% when compared with conventional RT
  • Chemotherapy has been combined with RT to take advantage of the radiation sensitizing effects of certain chemotherapeutic agents
  • Recent meta-analyses have concluded that concurrent chemoradiotherapy has an advantage as compared with RT alone and sequential chemoradiotherapy
  • Regimens of concurrent chemoradiotherapy have typically employed once-daily RT with doses ranging from 65 to 70 Gy
  • Many studies report an increased toxicity with combined treatments, notably hematological and mucosal toxicities, which limit the ability to deliver full doses of RT or the chemotherapeutic drugs
  • Severe mucositis is the most important factor limiting the intensity of combined modality therapy for head and neck cancer and is proportional to the aggressiveness (dose and/or number of agents) of the chemotherapy delivered concurrently with RT
  • The optimal drugs, doses and schedules of concurrent chemotherapy and RT for head and neck cancer are not yet known

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