Table 6.
Radiation Deintensification Trials: Induction Chemotherapy to Select Patients from Radiation Dose Reduction
| Study | Treatment Arms | Outcomes | Toxicities |
|---|---|---|---|
| ECOG 1308 86 | IND cis/pacl/cetux (n=80). | 2 yr PFS : 81% [69–89] 54Gy, 67% [38–85] SOC | Acute ≥ Grade 3 toxicity: |
| (Phase II) | 2 yr OS : 93% [83–97] 54Gy, 87% [56–96] SOC | - Mucositis : 30% 54Gy, 47% SOC | |
| p16+ and/or HPV+ OPC. | Response to IND (n=51) → Reduced dose def CRT 54Gy + cetux | - Dysphagia : 15% 54Gy, 29% SOC | |
| AJCC7 III, IVA, IVB. | 2 yr PFS, 54Gy in T1–3,N1-N2b,<10 PYSH: 96% [76–99] | At 12 months: | |
| T4 included, N3 allowed but none enrolled. Smokers permitted. | No response to IND (n=15) → SOC CRT 69.3Gy | Primary site clinical CR to IND (n=51) | - Difficulty swallowing solids: 40% 54Gy, 89% SOC |
| Median FU = 35.4 months | CR/PR/SD (n=62) | - Impaired nutrition: 10% 54Gy, 44% SOC | |
| University of CA CCRO-022 87 | IND carbo/pacl (n=45). | 2 yr PFS: 92% [77–97] | Acute ≥ Grade 3 toxicities in 39%: |
| (Phase II) | 2 yr LRC: 95% [80–99] | 9% mucositis, 9% dysphagia | |
| p16+ OPC. | CR/PR (n=24) → Reduced dose def CRT (54Gy + pacl) | 2 yr OS: 98% [85–100] | 3 pegs before and 3 pegs during RT |
| AJCC7 Stage III or IV. T4 and N3 enrolled. | <PR/no response (n=20) → Reduced dose def CRT (60Gy + pacl) | ||
| Smokers permitted. | Median FU = 2.5 years | 3 of 4 failures in 60Gy with minimal response to IND | |
| OPTIMA 78–79 | IND carbo/nab-pacl→ | 2 yr PFS: 95% overall, 95% LR, 94% HR | Acute ≥ Grade 3 mucositis: |
| (Phase II) | - LR ≥50% response (n=30): | 2 yr LRC: 98% overall, 100% LR, 97% HR | 30% 50Gy RT, 63% 45Gy CRT, 91% 75Gy CRT |
| p16+ OPC. AJCC7 | Reduced dose def RT 50Gy | 2 yr DMFS: 100% overall, 100% LR, 100% HR | |
| T1–4 N2–3 and T3–4 N0–3. Smokers permitted. | - LR 30–50% response, HR ≥50% response (n=45): | 2 yr OS: 98% overall, 100% LR, 97% HR | Peg tubes: 3% RT50, 33% CRT45, 80% CRT75 |
| LR (n=44): ≤T3, ≤N2B, and ≤10 PYSH | Reduced dose def CRT 45Gy BID + pacl/5FU/HU | ||
| HR (n=46): T4, ≥N2C, or >10 PYSH) | BID on days 1–5, 15–19, 29–33 (over 6 wks) | 3 recurrences within 2 yrs: 2 in 45Gy CRT, 1 in 50Gy RT | |
| - All others 75Gy BID + pacl/5FU/HU (n=15) | |||
| Note: prophylactic LN RT was limited to only | BID on days 1–5,15–19,29–33,43–47,57–61 (over 10 wks) | ||
| the first echelon of uninvolved LNs | Median FU = 4.2 years | ||
| OPTIMA II 73–74 | IND carbo/nab-pacl/nivolumab x3c → RECIST response: | 2yr PFS 90.4%[79.3–95.7]: | Peg tubes: |
| (Phase II) | De-escalated treatment administered in 84.9%. | 50Gy RT: 96.3% | 50Gy RT 7.1% |
| p16+ and HPV+ OPC. | LR with ≥50% reduction: | 45–50Gy CRT: 85.8% | 45–50Gy CRT 44.1% |
| LR: | - TORS+selective ND (n=9) | 70–75Gy CRT: 100% | 70–75Gy CRT 75.0% |
| T1-T2 non-bulky tonsil or well-lateralized BOT ≤3 cm, | - Reduced dose def RT 50Gy(n=28): did not qualify for/refused TORS | ||
| non-bulky N2A-2B with ≤2 non-lower neck LNs measuring ≤5 cm. | 2yr OS 93.3%[82.4–97.5]: | Grade 4 toxicity: | |
| HR: | LR <50% but ≥30% reduction, HR with ≥50% reduction: | 50Gy RT: 96.0% | 50Gy RT 7.1% |
| T4, N2C-3, >20 PYSH, or non-HPV16 subtype. | - Reduced dose def CRT (n=34): 50Gy+HD cis x2c or 45Gy+THFXx3c | 45–50Gy CRT: 91.9% | 45–50Gy CRT 8.8% |
| 70–75Gy CRT: 100% | 70–75Gy CRT 10.0% | ||
| LR <30% reduction, HR <50% reduction: | |||
| - SOC def CRT (n=10): 70Gy+HD cis x3c or 75Gy+TFHX x5c | −3 local failures, 0 distant failures | 1 patient died during IND. | |
| Adjuvant nivolumab x6 months in all. | - among 9 TORS patients, 66.7% had pCR. | ||
| Median FU = 23.1 months | |||
| Quarterback 88–89 | IND doce/cis/5FU x3c (n=20). | Initial results: | After enrolling first 4/12 patients in 56Gy arm, due to |
| (Phase III) | If response → randomized 1:2 to | 2 yr PFS (p=0·85): 87·5% SOC vs. 83·3% 56Gy | higher than expected mucositis and 2 pegs, protocol |
| p16+ and HPV+ OPC. HPV subtype assessed. | SOC def CRT 70Gy (n=8) or Reduced dosed def CRT 56Gy (n=12) | - 1 LRF in SOC, 2 LRF in 56Gy | was amended. Remaining 8/12 paties in 56Gy arm |
| AJCC7 Stage III/IV. | CRT=RT+carbo | - PFS hazard ratio: 1·46 [0·13–16·12] | received carbo only. |
| T4 and N3 enrolled. | Including phase 2b update (n= 32 patients 56Gy): | - 6 pegs in total: 4 (33%) 56Gy, 2 (25%) 70Gy | |
| T1N1 permitted, none enrolled. | Phase 2b update, IND doce/cis/5FU x3c and responders (n=20): | - 2yr PFS: 84.4% [66.5–93.2] | - no therapy-related mortality |
| Smokers permitted. | Reduced dose def CRT 56Gy + carbo | - 2yr LRC: 87.4% [69.8–95.1] | - Phase 2b trial toxicity to be reported |
| - 3yr LRC 85% was considered non-inferior to SOC CRT | - 2yr OS: 90.6% [73.7–96.9] | ||
| - 3yr PFS 80% was considered acceptable | 72% had poor risk factors (ECE, T4, N2c, Non-HPV16) | ||
| - All 5 recurrences occurred within 1 yr | |||
| Median FU = 50 months | - All 5 recurrences had ≥1 poor risk factors |
5FU=5-fluorouracil, AFRT= altered fractionation radiation therapy, AJCC7=American Joint Committee on Cancer 7th Edition, AJCC8=American Joint Committee on Cancer 8th Edition, BID=bidaily, c=cycle, carbo=carboplatin, cetux=cetuximab, chemo=chemotherapy, cis=cisplatin, CR=complete response, CRT=chemoradiation therapy, def=definitive, DM=distant metastasis, DMFS=distant-metastasis free survival, doce=docetaxel, FU=follow-up, Gy=gray, HD=high-dose, HPV=human papillomavirus, HR=high-risk, HU=hydroxyurea, IMPT=intensity-modulated proton therapy, IMRT=intensity-modulated radiation therapy, IND=induction, LD=low-dose, LN=lymph node, LR= low-risk, LRC=locoregional control, LRF= locoregional failure, ND=neck dissection, OPC= oropharyngeal cancer, OS=overall survival, pacl=paclitaxel, pCR=pathological complete response, peg=percutaneous endoscopic gastrostomy, PFS=progression-free survival, PR=partial response, PYSH=pack-year smoking history, RT=radiation therapy, SD=stable disease, SOC=standard of care, THFX=paclitaxel,5FU,HU, TORS=transoral robotic surgery, wk=week, wkly=weekly, yr=year.