Drug combination (n)	Chemotherapy regimen	RT employed	Survival data and comments
Cisplatin and 5-FU
Brizel et al. (1998)[72] (56)a	Cisplatin 12 mg/m2 daily on weeks 1 and 6; 5-FU 600 mg/m2 CI days 1–5 on weeks 1 and 6	70 Gy (hyperfractionation)	55% 3-year OS. Trend towards improved survival; improved locoregional control
Taylor et al. (1997)[74] (219)a	Cisplatin 60 mg/m2 every 2 weeks; 5-FU 800 mg/m2 CI days 1–5	70 Gy on days 1–5 (once-daily fractionation) week on/week off	60% 3-year OS
Adelstein et al. (2006)[36] (219)	Cisplatin 20 mg/m2/day CI days 1–4 during weeks 1 and 4; 5-FU 1,000 mg/m2 CI days 1–4 during weeks 1 and 4	70 Gy (once-daily or hyperfractionation)	65.7% 5-year OS
Cisplatin and paclitaxel
RTOG 97-03 Garden et al. (2004)[27] (60)	Cisplatin 20 mg/m2 weekly; paclitaxel 30 mg/m2 weekly	70 Gy (once-daily fractionation)	67% 2-year OS. Improved survival in comparison with cisplatin and 5-FU. Equivalent survival in comparison with FHX platform
Carboplatin and paclitaxel
Carter et al. (2003)[77] (52)	Carboplatin AUC = 1 weekly; paclitaxel 40 mg/m2 weekly	69.6 Gy (hyperfractionation)	63% 2-year OS. Preliminary results, but several previous trials
FHX
RTOG 97-03 Garden et al. (2004)[27] (64)	5-FU 800 mg/m2 CI days 1–5 every 2 weeks; hydroxyurea 1 g twice daily on days 0–5 every 2 weeks	70 Gy on days 1–5 (once-daily fractionation) week on/week off	69% 2-year OS. Improved survival in comparison with cisplatin/5-FU. Equivalent survival in comparison with cisplatin/paclitaxel
TFHX
Vokes et al. (2003)[43] (69)	Paclitaxel 100 mg/m2 every 2 weeks; 5-FU; 600 mg/m2 CI days 1–5 every 2 weeks; hydroxyurea 500 mg twice daily on days 0–5 every 2 weeks	70 Gy on days 1–5 (hyperfractionation) week on/week off	77% 2-year OS and 70% 3-year OS. Combined with induction chemotherapy
Cisplatin and cetuximab
Pfister et al. (2006)[85] (22)	Cisplatin 100 mg/m2 during weeks 1 and 4; cetuximab 400 mg/m2 during week 1, then 250 mg/m2 weekly	70 Gy (concomitant RT boost)	76% 3-year OS. Trial ended early because of two deaths and adverse effects. Two randomized trials with this regimen are ongoing (RTOG and the University of Chicago, Chicago, IL)
IFHX
Cohen et al. (2005)[42] (69)	Gefitinib 250 mg daily; 5-FU 600 mg/m2 CI on days 1–5 every 2 weeks; hydroxyurea 500 mg twice daily on days 0–5 every 2 weeks	70–72 Gy on days 1–5 (hyperfractionation) week on/week off	89% 2-year OS. Combined with induction chemotherapy