CT has been used in conjunction with RT in an attempt to increase locoregional control and survival of advanced squamous cell carcinoma (SCC) of HN. CT has been combined with RT according to one of the following modalities: —adjuvant or neoadjuvant CT, which implies the sequential administration of CT and RT; —concomitantor alternating CT and RT, which results in a close temporal integration of the two modalities. While the results of the sequential use of CT and RT at best reflects the sum of the efficacies of the single modalities used, the integration of CT and RT has an impact on the biologic mechanisms by which each modality determines its cytotoxic effect with a possibly synergistic outcome. Inhibition of DNA-repair has been demonstrated in “in vitro” models after radiation exposition, adding cytotoxic drugs. This phenomenon may result in the conversion of “potentially lethal damage” or “sublethal DNA damage” to lethal damage increasing cell killing rate. Moreover, cyclospecific and phase specific drugs are effective on “S phase” of cyclating tumor cells, which are, generally, less sensitive to RT. Finally Split RT has been reported to be less effective than continous RT due to the repopulation occurring during the rests between courses. Filling-up these pauses with chemotherapy, gives the chance to administer drugs to a quickly proliferating tumor, with positive implications for cure. Simultaneous CT and RT using single agent 5-Fluorouracil (5-FU) i. v. bolus, Bleomycin (B), Mitomycin C or Cisplatin (CDDP) have been evaluated in phase II trials and in randomized trials against RT alone with controversial results, being the positive ones mainly observed when 5-FU was employed. Multiagent CT combined with simultaneous RT has been evaluated in many phase II trials using 5-FU continuous infusion (c.i.) with CDDP with or without Leucovorin and/or Hydroxiyurea; these combinations yield a large proportion of complete responses at the cost of substantial mucosal toxicity. Randomized trials against RT alone have not yet been reported. Alternating CT and RT utilizing Vinblastine, B, Methotrexate, 5-FU i. v. bolus or (c. i.) and CDDP has been evaluated in both phase II and III studies. The data suggest that alternating CT and RT promotes optimal tolerance of the host. Moreover alternating CT and RT correlates with significant better survival when compared to neoadjuvant CT followed by RT or to RT alone. These data definitively require further investigations. CT has been used in conjunction with RT in an attempt to increase locoregional control and survival of advanced squamous cell carcinoma (SCC) of HN. CT has been combined with RT according to one of the following modalities: —adjuvant or neoadjuvant CT, which implies the sequential administration of CT and RT; —concomitantor alternating CT and RT, which results in a close temporal integration of the two modalities. While the results of the sequential use of CT and RT at best reflects the sum of the efficacies of the single modalities used, the integration of CT and RT has an impact on the biologic mechanisms by which each modality determines its cytotoxic effect with a possibly synergistic outcome. Inhibition of DNA-repair has been demonstrated in “in vitro” models after radiation exposition, adding cytotoxic drugs. This phenomenon may result in the conversion of “potentially lethal damage” or “sublethal DNA damage” to lethal damage increasing cell killing rate. Moreover, cyclospecific and phase specific drugs are effective on “S phase” of cyclating tumor cells, which are, generally, less sensitive to RT. Finally Split RT has been reported to be less effective than continous RT due to the repopulation occurring during the rests between courses. Filling-up these pauses with chemotherapy, gives the chance to administer drugs to a quickly proliferating tumor, with positive implications for cure. Simultaneous CT and RT using single agent 5-Fluorouracil (5-FU) i. v. bolus, Bleomycin (B), Mitomycin C or Cisplatin (CDDP) have been evaluated in phase II trials and in randomized trials against RT alone with controversial results, being the positive ones mainly observed when 5-FU was employed. Multiagent CT combined with simultaneous RT has been evaluated in many phase II trials using 5-FU continuous infusion (c.i.) with CDDP with or without Leucovorin and/or Hydroxiyurea; these combinations yield a large proportion of complete responses at the cost of substantial mucosal toxicity. Randomized trials against RT alone have not yet been reported. Alternating CT and RT utilizing Vinblastine, B, Methotrexate, 5-FU i. v. bolus or (c. i.) and CDDP has been evaluated in both phase II and III studies. The data suggest that alternating CT and RT promotes optimal tolerance of the host. Moreover alternating CT and RT correlates with significant better survival when compared to neoadjuvant CT followed by RT or to RT alone. These data definitively require further investigations.