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. Author manuscript; available in PMC: 2024 Mar 1.
Published in final edited form as: CA Cancer J Clin. 2022 Oct 28;73(2):164–197. doi: 10.3322/caac.21758

Table 3.

Surgical Deintensification Trials: TORS to Deintensify Adjuvant Therapy

Study Treatment Arms Outcomes Toxicities
ECOG-ACRIN E3311 45 TORS+ND → risk-adapted adj therapy: 2 yr PFS OBS: 96.9% [90%CI 91.9–100] VS. Grade ≥3 toxicity:
(Phase II)       50Gy: 94.9% [90%CI 91.3–98.6] VS. OBS 17%
Resected HPV+ OPC. LR (T1–2N0–1, ≥ 3mm margin, no ECE/PNI/LVI) → OBS (n=38)       60Gy: 96.0% [90%CI 92.8–99.3] VS. 50Gy: 15%
AJCC7 T1–2N1–2b with RFs: IR → SOC PORT 60Gy (n=108) vs. Reduced PORT 50Gy (n=100)       60–66Gy CRT: 90.7% [90%CI 86.2–95.4] 60Gy: 24%
IR: close margin <3 mm, PNI, LVI, LN>3 cm, HR → SOC adj CRT 60–66Gy + LD cis 40 mg/m2 wkly (n=113) 2 yr OS OBS: 100% VS. 60–66Gy CRT: 61%
 2–4 LNs, or ≤1 mm ECE       50Gy: 99.0% [90%CI 9.3–100] VS.
HR: +margin, ECE >1mm, ≥ 5 LNs Median FU = 35 months       60Gy: 98.1% [90%CI 95.9–100] VS. PROs did not differ between 50Gy and 60Gy PORT.
      60–66Gy CRT: 96.3% [90%CI 93.3–99.3]
Mayo MC1273 58–59 All had surgery + ND with margin neg resection. 95% TORS. 2 yr PFS: 91.1% overall, 97.2% IR, 86.0% HR 1 patient required a peg.
(Phase II) DART + wkly doce for all. 2 yr LRC: 96.2% overall, 100.0% IR, 93.0% HR 0% grade 3 or worse toxicity 2 yrs after treatment.
p16+ OPC resected with neg margins AND ≥1 RF: IR (n=37) → 30Gy (1.5Gy BID) 2 yr OS: 98.7% overall, 100.0% IR, 97.7% HR
IR: ≥T3, ≥N2, PNI, LVI HR (n=43) → 36Gy (1.5Gy BID/1.8Gy BID SIB) 2 yr DMFS: 94.9%
HR: ECE
AJCC7 Stage III/IV, ≤10 PYSH. Median FU = 35.7 months 21% of HR ECE pts recurred (5 of 9 distant)
DART-HPV/MC1675 61–62 IR: 2 yr PFS: 86.5% DART vs. 95.1% SOC Grade ≥3 toxicity at 3 months (p=0.058):
(Phase III) DART 30Gy + wkly doce (n=53) 2 yr LRRFS: 95.5% DART vs. 97.9% SOC 1.6% DART vs. 7.1% SOC
p16+ OPC resectable by TORS. VS. 2 yr OS: 96.1% DART vs. 97.0% SOC
Neg margins (≤2 excisions to clear a margin edge) SOC 60Gy + LD cis 40 mg/m2 wkly (n=26) If pN2 and +ECE: Pegs (p<0.0001):
AND at least one risk factor: - 2 yr LRC 77.0% DART vs. 100% SOC 1.6% DART vs. 27.4% SOC
IR: ≥T3, ≥N2, PNI, LVI HR: - 2 yr DMFS 59.4% DART vs. 100% SOC
HR: ECE DART 36Gy + wkly doce (n=77) - 2 yr PFS 42.9% DART vs. 100% SOC
AJCC7 Stage III/IV, ≤10 PYSH. VS. If pN0–1 and +ECE:
SOC 60Gy + LD cis 40 mg/m2 wkly (n=38) - 2 yr LRC 95.8% DART vs. 100% SOC
- 2 yr DMFS 96.4% DART vs. 95.8% SOC
- 2 yr PFS 89.6% DART vs. 95.8% SOC
MC1273/MC1675 pooled analysis, 2 yr PFS:
ECE+: 85.2% [78.6%−92.5%]
ECE+/pN1: 92.5% [86.9%−98.5%]
ECE+/pN2: 54.5% [36.4%−81.7%]
No ECE: 97.7% [94.6%−100.0%]
No ECE/pN0–1: 97.5% [94.7%−100.0%]
No ECE/pN2: 100.0%
SIRS Sinai Robotic Surgery Trial/ NCT02072148 TORS, and then based on pathology (n=200): Ongoing, not reported Ongoing, not reported
(Parallel Assignment) - LR (>1 mm margin for tonsil, >3 mm margin for tongue, no LVI,
p16+ and HR HPV subtype (16/18/33/35,etc) OPC. no PNI, <3 +LNs, no ECE, no matted/level IV/level V LNs): OBS
AJCC7 T1–2N0–2b. - IR: 50Gy Reduced PORT
IR: <1 mm margin tonsil, <1 mm margin tongue, - HR: 50Gy Reduced PORT + LD cis 40 mg/m2 wkly
 LVI, PNI, <3 LNs, ≤1 mm ECE - HR incomplete resection (+margins, >1 mm ECE, matted LNs):
HR: ≥3 +LNs, >1 mm ECE, contralateral or 56Gy Reduced PORT + LD cis 40 mg/m2 wkly
 supraclavicular LNs
Univ of Pittsburgh/NCT03715946 Reduced PORT (45 or 50Gy) Ongoing, not reported Ongoing, not reported
(Phase II) + immunotherapy (concurrent+adj nivolumab)
p16+ OPC resected by TORS.
T0–3 with at least 1 IR factor.
<10PYSH: >N2b (>5 LNs), >1 mm ECE, +margin
>10PYSH: N2, > 1 mm ECE, +margin
Minimalist Trial(MINT)/ NCT03621696 LR (neg margin, no T4, no N3): 42Gy Reduced PORT Ongoing, not reported Ongoing, not reported
(Phase II) IR (+margin or ECE): 42Gy Reduced PORT + HD cis x1c
p16+ or HPV+ OPC, resectable by TORS. HR (T4 or N3): SOC 60Gy adj PORT + HD cis x3c
AJCC8 I-III.
PATHOS / NCT02215265 TORS → risk-adapted adj therapy: Ongoing, not reported Ongoing, not reported
(Phase III)
p16+ and HPV+ OPC. T3, N2a or N2b, +PNI, +LVI, 1–5 mm margin:
AJCC7 T1–3 N0–2B. SOC 60Gy PORT vs. 50Gy Reduced PORT
+ECE or +margin: SOC 60Gy PORT ± cis (HD or LD)
No risk factors: OBS
AVOID 63 Omission of PORT to resected primary site (n=60). 2 yr PFS: 92.1% [80.2–97.0] No pegs during RT.
(Phase II) SOC 60–66Gy PORT to at-risk neck. 2 yr LRC: 97.9% [86.1–99.7]
HPV+ OPC resected by TORS, Chemo for ECE. 2 yr RRFS: 97.9% [86.3–99.7] - 2 pegs (3.3%) due to surgery for recurrence
pT1–2N1–3, neg margin (≥2 mm), no PNI, no LVI. - LD cis 40 mg/m2 wkly (n=9); HD cis (n=2); cetux (n=2) 2 yr DMFS: 96.2% [85.5–99.0] with soft tissue necrosis, both at 3 months after RT.
Median FU= 2.4 years Only 1 of 60 pts recurred at the omitted primary site Both pegs subsequently removed.
ADEPT / NCT01687413 Omission of adjuvant chemo in +ECE patients: Trial terminated due to poor accrual Trial terminated due to slow accrual
(Phase III) SOC PORT (60Gy) VS. CRT (60Gy + LD cis 40 mg/m2 wkly)
p16+ OPC.
AJCC7 T1–4a N1–3.
TORS + ND with neg margin and must have +ECE.
ADAPT/ NCT03875716 Omission of adjuvant chemo in +ECE or +margin patients: Ongoing, not reported Ongoing, not reported
(Phase II) LR (pT0–2N0–1, neg margin, no ECE, ≤2 LNs in Level II/III, ≥15 LNs
p16+ or HPV+ OPC, resectable by TORS. dissected): OBS
AJCC8 cT0–2N0–1, ≤20PYSH. IR: 46Gy Reduced PORT
IR: >2 LNs, <15 LNs dissected, +Level IB/IV/V LN, HR: 60Gy SOC PORT, but no SOC chemo
≤1 mm ECE, close margins, or +contralateral LN.
HR: >1 mm ECE or microscopic +margin.

adj=adjuvant, AJCC7=American Joint Committee on Cancer 7th Edition, AJCC8=American Joint Committee on Cancer 8th Edition, BID=bidaily, c=cycle, chemo=chemotherapy, CI=confidence interval, cis=cisplatin, CRT=chemoradiation therapy, DART=de-escalated adjuvant radiation therapy, def=definitive, DMFS=distant metastasis free survival. doce=docetaxel, ECE=extracapsular extension, FU=follow-up, Gy=gray, HD=high-dose, HPV=human papillomavirus, HR=high-risk, IMRT=intensity-modulated radiation therapy, IR=intermediate-risk, LD=low-dose, LN=lymph node, LR=low-risk, LRC=locoregional control, LRRFS=locoregional relapse free survival, LVI=lymophovascular invasion, NAC=neoadjuvant chemotherapy, ND=neck dissection, neg=negative, OBS=observation, OPC= oropharyngeal cancer, OS=overall survival, +=positive, peg=percutaneous endoscopic gastrostomy, PNI=perineural invasion, PORT=postoperative radiation therapy, PFS=progression-free survival, PORT=postoperative radiation therapy, PRO=patient-reported outcome, PYSH=pack-year smoking history, RF=risk factor, RRFS=regional relapse free survival, RT=radiation therapy, SIB=simultaneous integrated boost, SOC=standard of care, TORS=transoral robotic surgery, wkly=weekly, wks=weeks, yr=year.