TABLE 3.

Modulation of radiotherapy or chemoradiotherapy dose according to response to induction chemotherapy (ICT).

Study name, ID	AJCC, HPV, smoking	Design and primary endpoint	Adverse events	Survival data
ECOG 1308 Marur et al. (2017) NCT01084083 N = 80	7th AJCC: T3T4N0, T1N1-T4N3 8th AJCC: I, II, III HPV testing: p16 IHC or HPV ISH Smoking: 39% pts >10py	Design: ICT: 3 cycles of cisplatin, paclitaxel, and cetuximab; then cCR: RT 54Gy + cetuximab; no cCR: 69.3 Gy + cetuximab. Response monitoring: clinical. Primary endpoint: 2-year PFS (powered to expect 85% in patients with cCR after induction and 54 Gy)	54 vs. 69.3 Gy: 1 year swallowing dysfunction: (40 vs. 89%, p = 0.011); 1 year impaired nutrition (10 vs. 44%, p = 0.025); 18/80 (22.5%) patients with ICT protocol deviation	cCR group treated with 54 Gy, (n = 51): 2 years PFS 80%, 2 years OS 94% No cCR with 69 Gy (n = 15): 2 years PFS 67%, 2 years OS 87% p16IHC+and HPVISH+: 2 years PFS HR = 0.83, OS HR = 0.93 p16IHC + but HPVISH-2 years PFS = 0.57, OS 0.87
CCRO-022 Chen et al. (2017) NCT01716195 NCT02048020 N = 45	7th AJCC: III-IV 8th AJCC: I-II-III HPV testing: p16 IHC Smoking: 24.4% > 10py	Design: 2 cycles of ICT paclitaxel–carboplatin; then, responders: RT 54 Gy + weekly paclitaxel. Non-responders: RT 60 Gy + weekly paclitaxel. Response: clinical radiography. Primary endpoint: 2-year PFS (72 vs. 86% as thresholds for inefficacy vs. efficacy of trial α = 0.09)	FACT- H&N During ICT: 39% grade III adverse events including 39% leukopenia. During CRT: grade III dysphagia (20%) 2 years grade III + mucosal–esophageal toxicity: no difference in 54 vs. 60 Gy (p = 0.47)	2 years PFS: 92% 2 years OS: 98% 2 years LR: 95% 2 years DM: 98%
OPTIMA NCT02258659 N = 62	7th AJCC: T1T4-N2N3 T3T4-anyN 8th AJCC: I-II-III stratified into: low risk n = 28, ≤T3 and ≤N2b and ≤10py High Risk n = 34, T4 or ≥ N2c or >10py HPV testing: p16-IHC or HPVDNA PCR or HPVRNA ISH Smoking: 35% > 10py	Design: ICT with nab-paclitaxel + carboplatin; then, low risk + >50% pCR after ICT: 50 Gy RT low risk + 30–50% pCR OR high risk + >50% pCR: CRT 45 Gy (THFX). All others: CRT 75 Gy (THFX) Response monitoring: pathologic response. Primary endpoint: 2-year PFS to detect non-inferiority to historical control (85%)	Toxicities (CTCAE) for RT50 < CRT45 < CRT75; acute grade III + mucositis (30, 63, 91%, p = 0.004); acute grade III + dermatitis (0, 20, 55%, p < 0.00001); PEG-tube requirement (0, 31,82%, p < 0.001)	Non-inferiority demonstrated: 2 years overall PFS: 94.5% 2 years PFS: 100% in low risk, 92% for high risk 2 years OS: 100% low risk, 97% in high risk 2 years LC: 100% low risk, 97% in high risk 2 years DM: 100% low risk, 100% high risk
Quarterback trial NCT01706939 (n = 23) Misiukiewicz et al. (2019)	7th AJCC: T3T4-N0 T1N1-T4N3 OPSCC, Nasopharynx or CUP 8th AJCC: I-II-III HPV testing: p16-IHC and HPVDNA PCR Smoking: <20 py	Design: ICT TPF followed by complete or partial remission randomized to - RT 56 Gy + weekly carboplatin - RT 70 Gy + weekly carboplatin. None responders: RT70 Gy + weekly carboplatin. Primary endpoint: 3-year non-inferior PFS, LC	Trial ended early	56 vs. 70 Gy 3 years PFS 83.3 vs. 87.5% 3 years OS: 83.3 vs. 87.5%. Non-inferiority could not be determined