TABLE 4.

Randomized trials evaluating oncologic outcomes after postoperative therapy for resected squamous cell carcinoma of the head and neck (N = 24)

First author (country)	Arms	Patients (N)		Median f/u	Results	LOE
		Sites
		Stage	Years accrued
		Definition of risk (if applicable)	Regimen details
Observation vs postoperative RT (PORT)
Kokal (USA) 41	Observation vs PORT	51, OC, Pharynx, Lx Stage III/IV	1981 to 1984 RT was 50 Gy	30.3 mo	Decreased “overall recurrence rate” in PORT arm (55.6% vs 36.5%, P = “NS”)	2 2
Mishra (India) 45	Observation vs PORT	140, OC (all buccal) Stage III/IV	1990 to 1994 RT: cobalt‐60, mean dose of 60 Gy	NR	DFS improved with PORT 38% and 68% (P < .005).	2
PORT timing, dose, and fractionation
Ang (USA) 31	Adjuvant treatment by pathologic risk stratification. Low risk: no PORT Intermediate: PORT High‐risk: PORT vs accelerated PORT	213, OC, OPX, LX, HPX Stage III (48%), Stage IV(38%) ECE in 49% Risk group definition: Low risk: no RF; intermediate risk = 1 RF other than ECE: high‐risk = ECE or ≥2 risk factors. Risk factors: ECE, >1 nodal group, ≥2positive nodes >3 cm node, OC site, microscopic +margin and PNI.	1991 to 1995 Low risk: no PORT Intermediate risk: 57.6 Gy in 32 f over 6.5 wk High risk: 63 Gy in 1.8 Gy/f over 7 wk vs 63 Gy 1.8 Gy/d × 3 wk then 2 fractions per day for last 2 wk (5 wk total)	59 months.	Patients with low or intermediate risks had higher LRC and OS than those with high‐risk features (P = .003 and P = .0001, respectively), despite receiving no PORT or lower dose PORT. For high‐risk patients, there was a trend toward higher LRC and OS when PORT was delivered in 5 rather than 7 wk. Prolonged interval between surgery and PORT in the 7‐week schedule was associated with lower LRC (P = .03) and OS (P = .01).	1
Awwad (Egypt) 33	Accelerated hyperfractionation (AHF) vs conventional fractionation (CF)	56 OPX, OC, LX, HPX, Nodal metastases T3/4, N0‐2 postoperative. 31% “inadequate margin” Fresh tissue labeled with in vitro 3H‐thymidine labeling index (TLI) as marker of fast vs slower growing tumors.	1987 to 1989. AHF: 42 Gy/30 F/11 d (3 F/d, interval 4 h) CF: conventional 50 Gy/25 F/5 wk All with telecobalt. Chemo: none	NR	NSD in 3‐y DFS (39% ± 9% CF vs 54% ± 10% AHF) or OS (36% ± 9% CF vs 54% ± 10% AHF). Higher late complications in CFX arm (87% vs 63%). AHF associated with a significant DFS benefit in faster growing tumors (especially for TLI 10.4% corresponding to T pot of <4.5 d). No benefit to AHF for slower growing tumors.	2
Awwad (Egypt) 34	Accelerated hyperfractionation (AHF) vs conventional fractionation (CF)	70 OC, LX, HPX T2/N1‐2N2 or T3‐4/any N 48% “inadequate margin”	1995 to 1997. AHF: 3 fractions per day at 1.4 Gy/fraction to 46.2 Gy/33 fractions in 12 d. 6 d per week CF: 60 Gy in 30 fx in 6 wk, 5 d a week.	NR	3‐y LRC was significantly better in the accelerated hyperfractionation (88 + 4%) than in the CF (57 + 9%) group, P = .01. NSD in OS Late normal tissue reactions were worse in AFX group (either significant or “trend.”) Overall treatment time (time between surgery and the end of radiotherapy) longer than 10 wk had a significantly unfavorable effect on the LRC for all patients.) (P = .005)	2
Kramer (USA) 42 RTOG 73‐03 10 y update: Tupchong 55	Preoperative RT vs PORT	277 OC, OPX, SGL or HPX Stage III/IV: >85%	1973 to 1979 SGL/HPX: 2 arms randomized to preoperative 50 Gy or postoperative 60 Gy OC/OPX: 3 arms randomized to preoperative 50 Gy or postoperative 60 Gy or definitive RT 65 to 70 Gy w surgery for salvage if residual at 6 wk post RT. RT dose: preoperative RT (50 Gy) or postoperative RT (60 Gy)	10 y	RC was significantly better for PORT patients than for preoperative RT patients (P = .04), but absolute survival was not affected (P = .15). 31% (18/58) of preoperative patients failed locally within 2 y vs 18% (11/60) in surgery + PORT group. After 2 y, distant metastases and second primaries were main failure types, particularly in surgery + PORT group.	1
Peters (USA) 46 Update: Rosenthal 50	Stratified by risk factors and randomized: Lower risk group: 57.6 vs 63 Gy Higher risk group: 63 vs 68.4 Gy, all at 1.8 Gy per fraction.	240 OC, OPX, HPX, LX T3/4:72% Very few early stage pts with risk factors: T1: 5 pts T2: 42 pts (26 T2N+) Risk group based on a point‐system. Patients' primary sites and involved necks were independently assigned to higher‐ or lower‐risk categories based on a cumulative point score representing increasing risk of recurrence.	1983 to 1991. RT: Cobalt. 54 Gy given surgically undisturbed sites of potential disease; 57.6 Gy to pathologically uninvolved parts of surgical bed, including dissected region with negative nodes. Lower risk: 57.6 Gy vs 63 Gy (1.8 Gy/d) Higher risk: 63 Gy vs 68.4 Gy (1.8 Gy/d) Note: lower risk group initially was 52.2 to 54 Gy but due to early recurrences, minimal dose was changed to 57.6 Gy.	>20 y	Patients who received a dose of ≤54 Gy had a higher primary failure rate than those receiving ≥57.6 Gy (P = .02). For patients with ECE, recurrence was higher at 57.6 than 63 Gy or more. The long‐term report clarified that for low‐risk patients 57.6 Gy was sufficient. For high risk patients, doses >63 Gy did not have a SS benefit (they did not receive lower than 63 Gy). Two or more of the following risk factors were associated with an increased risk of recurrence: oral cavity primary, mucosal margins close or positive, nerve invasion, ≥2 positive lymph nodes, largest node >3 cm, treatment delay greater than 6 wk, and ≥ Zubrod performance status 2. Moderate to severe complications of combined treatment occurred in 7.1% of patients; these were more frequent in patients who received >63 Gy.	1
Sanguinetti (Italy) 51	Conventional fractionation (CF) vs accelerated fractionation (AF)	226, OC, OPX, HPX, Lx Stage III: 9.3% Stage IV: 87.6% Patients with at least 1 high‐risk feature: pT4, positive margin, pN >1, perineural/ lymphovascular invasion, ENE, subglottic extension	1994 to 2000 CF: 2 Gy fraction per day (60 Gy in 6 wk) AF: (64 Gy in 5 wk) with a biphasic concomitant boost delivered during the first and last weeks of treatment.	30.6 months.	NSD in 2‐y LRC [80% ± 4% for CF, 78% ± 5% for AF (P = .52)] or 2‐y OS [67% ± 5% for CF, 64% ± 5% for AF (P = .84)]. Trend for improved LRC for patients who had a delay in starting RT (≥6.9 wk) and were treated with AF compared with CF (HR = 0.5, 95% CI 0.2‐1.1).	2
Suwinski (Poland) 54	Conventional fractionation CF) vs accelerated fractionation (AF)	279, OC, OPX: 121 LX: 158 Median time from surgery to RT was 9 wk. Risk group based on MDACC described in Peters et al 46 High‐risk patients: score of ≥3 at primary site and/or neck. In brief, score of 3 for neck would be any ENE, 2 or more involved nodes, grade 3 tumor and a positive node. For primary site score of 3 would be non‐larynx site except T1N0, microscopic positive margin, or a combination of LVI, grade 3 tumor, + <5 mm margin.	2001 to 2004 No chemotherapy RT: 3D‐RT with parallel opposed fields: adjuvant CF: 63 Gy in 35 fractions of 1.8 Gy given 5 d per week AF: same RT but given 7 d a week (postoperative continuous accelerated irradiation: p‐CAIR). 45 to 50 Gy in 25 fractions given to the elective areas (undissected areas and dissected pathologically negative).	48 months.	Actuarial 3‐y LRC was 64% vs 70% for CF and p‐CAIR (P = .32). Subset analysis demonstrated significant improvement of 3‐y LRC in patients with OPX/OC tumors receiving p‐CAIR vs CF (74% vs 53%, P = .02). No improvement in LRC for Lx patients (P = .46). Acute/late toxicity was acceptable, although more patients had confluent mucositis with p‐CAIR (60% vs 33%). Limit: ENE not routinely reported (approximately 30% unknown ENE status), delay in RT start (approximately 50% >9 wk from surgery to RT), lack of systemic radiosensitizer	2
Vandenbrouck (France) 56	Preoperative RT vs PORT	49, HPX Stage III/IV (74%)	1967 to 1969 RT: preoperative was 5500 cGy over 5.5 wk; postoperative was 5500 cGy over 6 wk with interval to start less than 4 wk postoperative.		Trial stopped early due to unexpected high rate of postoperative deaths in patients who received preoperative RT. PORT improved OS (56% vs 20%, P < .01)	2
Addition of concurrent chemotherapy to PORT
Argiris (USA) 32	PORT vs PORT + weekly carboplatin 100 mg/m2	76, OC, OPX, HPX, LX Stage IV 92% All high‐risk High‐risk features: ECE (75%) or + margin (0.5 mm or less), LVI, PNI, ≥3 + LN	1994 to 2002 RT: 59.4 Gy/1.8 Gy/fraction, 50.4 Gy to clinically uninvolved. Carboplatin: 6 cycles	5.3 y	No statistically significant differences in DFS (HR 0.82, P = .60) or OS (HR 0.90, P = .73). The 2‐y DFS (primary endpoint) was 58% (95% CI 39%‐76%) in arm A (radiation alone) vs 71% (95% CI, 56%‐ 88%) in arm B (radiation and carboplatin). Terminated early due to slow accrual.	2
Bachaud (France) 35	PORT vs PORT + weekly cisplatin 50 mg/m2	83, OC OPX, LX, HPX, CUP Stage III/IV All with ECE	1984 to 1988 RT: All Cobalt‐60 Cisplatin: weekly 50 mg/m2 (7‐9 cycles)	NR	Improved OS in chemo‐PORT group (P < .01). The RT group displayed a higher rate of LRF compared to chemotherapy group (41 vs 23%; P = .08). Survival without LRF was better in the chemotherapy group, the difference being close to the level of significance (P = .05).	1
Bandyopadhyay (India) 36	PORT vs PORT + cisplatin 35 to 40 mg/m2 weekly	54, OC All had high‐risk factors defined as: Stage III or IV (n = 43,80%), 2 or more +LN, ECE, PNI or LVI, positive margin (n = 8, 15%), level IV/V involvement.	2006 to 2008 PORT (60 Gy/30 F/6 wk)	47 mo	LRC 51.4% with chemo‐PORT vs 35.6% in PORT (P = .39). 5‐y OS 56.4% in CRT vs 51.3% PORT with significant increase in grade 3‐4 toxicity.	2
Bernier (Europe) 37	PORT vs PORT + cisplatin 100 mg/m2	334, OC, OPX, HPX, LX Stage III/IV ENE 57% High‐risk defined as: pT3 or pT4 and any N‐stage except pT3N0 larynx with negative margins; T1‐2N2‐3; T1‐2N0‐01 with ≥1: ENE, positive margins, PNI, or vascular tumor embolism; or OC/OPX with nodes at level IV or V.	1994 to 2000 RT: 66 Gy over 6 1/2 wk Cisplatin 100 mg/m2 on days 1, 22, and 43	60 mo	PFS higher in the chemo‐PORT vs PORT (HR 0.75; 95% CI, 0.56 to 0.99, P = .04), with 5‐y PFS of 47% and 36%, respectively. The OS higher in chemo‐PORT group p (P = .02 by the log‐rank test; HR for death, 0.70; 95% CI, 0.52 to 0.95). Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41%) than after RT (21%, P = .001).	1
Cooper (USA) 38 Update: Cooper 39	PORT vs PORT + cisplatin 100 mg/m2	459 OC, OPX, HPX, LX High risk defined as ≥1 factor: 2 or more involved nodes, ECE, microscopically involved mucosal margins (n = 73, 18%).	1995 to 2000 PORT was 60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 wk. Cisplatin: 100 mg/m2 q3 wk × 3 cycles	45.9 mo	Improved LRC in chemo‐PORT group than in the PORT‐alone group (HR for local or regional recurrence, 0.61; 95% CI, 0.41 to 0.91; P = .01). OS did not reach statistical significance in initial report and with longer follow‐up (HR for death, 0.84; 95% CI, 0.65 to 1.09; P = .19). The incidence of acute adverse effects of grade 3 or greater was 34% in the RT group and 77% in the combined‐therapy group (P < .001).	1
Noronha (India) 19	PORT + cisplatin 30 mg/m2 weekly vs PORT + cisplatin 100 mg/m2 every 3 wk	N = 300 Stage III/IV OC, OPX, HPX, LX, CUP 90% ENE Adjuvant therapy in 93% (7% were definitive) If adjuvant, patients had ≥1 of: ENE, ≤5 mm margin or positive margin, more than 2 positive lymph nodes, T4 primary	2013 to 2017 RT: 60 Gy for adjuvant to high risk areas (tumor bed and involved nodal area). Cobalt or 2D (conventional simulator)	22 mo	2‐y LRC 58.5% in once a week vs 73.1% in every‐3‐week arm (P = .14). Acute grade 3 or higher 71.6% in once‐a‐week vs 84.6% in once‐every‐3‐wk (P = .006)	1
Racadot (France) 47	PORT vs PORT + carboplatin 50 mg/m2 twice weekly	144, OPX, HPX, LX Patients: Resected node positive with or without ECE.	1994 to 2002 PORT (54‐72 Gy, 30‐40 fractions, 6‐8 wk) ± concomitant Carboplatin (50 mg/m2 administered by IV infusion twice weekly × 6 wk).	106 mo	2‐y rate of LRC was 73% (95% CI: 0.61‐0.84) in the combined treatment group and 68% (95% CI: 0.57‐0.80) in the radiotherapy group (P = .26). OS did not differ significantly between groups (HR, 1.05; 95% CI: 0.69‐1.60; P = .81) Stopped early due to publication of preliminary results of EORTC.	2
Smid 52 (Slovenia) Update: Zakotnik 57	PORT vs PORT + mitomycin C and bleomycin	114, OC, OPX, HPX, LX, NC, PNS Stage III/IV ENE 53% 59% ≥1 high‐risk factor High‐risk factors: ENE, PNI, LVI, microscopic or macroscopic residual disease).	1997 to 2001 Total RT dose (56‐70 Gy).	32.2 mo, Update: 76 mo	At 5‐y in the PORT and postoperative CRT arms, LRC was 65% and 88% (P = .03), DFS 33% and 53% (P = .04), and OS 37% and 55% (P = .09). On planned subgroup analysis, benefit of chemotherapy appeared restricted to those with high‐risk factors.	1
Adjuvant chemotherapy regimens
Harari (USA) 40	PORT + cetuximab + cisplatin 30 mg/m2 vs PORT + cetuximab + docetaxel 15 mg/m2	238, OC, OPX, HPX, LX Stage III/IV All patients had ≥1: Positive margins and/or ENE and/or two or more nodal metastases.	2004 to 2006	4.4 y	Delivery of chemo‐PORT and cetuximab is feasible and tolerated. 2‐y OS was 69% for the cisplatin arm and 79% for the docetaxel arm; 2‐y DFS was 57% and 66%, respectively. Grade 3 to 4 myelosuppression was observed in 28% of patients in the cisplatin arm and 14% in the docetaxel arm; mucositis was observed in 56% and 54%, respectively.	2 2
Head and Neck Contracts Program Study, National Cancer Institute (USA) 53	Induction cisplatin + bleomycin × 1 cycle followed by S + PORT vs induction cisplatin and bleomycin followed by S + PORT and adjuvant monthly cisplatin 80 mg/m2 × 6 mo vs PORT	462 OC, LX, HPX Stage III/IV Stage II pyriform sinus	1978 to 1982 RT: during week 3 or 4 after surgery. 60 Gy in 5 to 5.5 wk for clear margins. 60 Gy for microscopic residual or close margins (<0.5 cm on permanent), positive frozen followed by re‐excision or ENE. 70 Gy to gross residual.	61 mo	While OS and DFS were NS different between 3 groups, adjuvant chemotherapy group had a lower rate of distant relapse (P < .03).	1
Lam (Hong Kong) 43	No postoperative chemotherapy vs Postoperative levamisole and UFT (uracil/tegafur)	65 OC, OPX, HPX, LX Stage III/IV	1993 to 1995 Not clear how chemotherapy sequenced with PORT (majority received PORT)	30 mo	A non‐statistically significant difference in DM (10% chemo vs 32% no chemo, P = .06) and 5‐y DFS (57% with chemo and 39% without).	3
Laramore (USA) 44 Aka INT 0034/RTOG 85‐03)	PORT alone vs 3 cycles of adjuvant cisplatin/5FU followed by PORT	448, OC/OPX/LX: stage III/IV HPX: Stage II High risk if ENE, margins <5 mm or CIS at margins. Low risk: no ENE and margins ≥5 mm	1985 to 1990. PORT dose risk‐stratified based on pathology: low risk: 50 Gy/25 F high risk: additional 10 Gy to high risk region. RT was 1.8‐2.0 Gy/d Chemotherapy: cisplatin 100 mg/m2 on d1and 5‐FU 1 g/m2 24hr infusion d1‐5 q 21 d for 3 cycles	45.7 mo	The 4‐y OS was 44% in the RT arm and 48% in the CT/RT arm (P = n.s.). 4‐y DFS was 38% in the RT arm compared to 46% in the CT/RT arm (P = n.s.). At 4 y the local/regional failure rate was 29% vs 26% for the RT and CT/RT arms, respectively (P = n.s.). The incidence of first failure in the neck nodes was 10% on the RT arm compared to 5% on the CT/RT arm (P = .03 without adjusting for multiple testing) and the overall incidence of distant metastases was 23% on the RT arm compared to 15% on the CT/RT arm (P = .03). “Risk group” status was a significant risk factor for LRC.	1
Rao (India) 48	Observation without PORT vs MTX on postoperative day 3, 10, 17.	135, OC (alveolobuccal) Stage III/IV	1987 to 1989 No patients received RT	Minimum 12 mo. (median NR)	DFS of 71% in the MTX arm vs 45% in the control arm, (P < .01) with improved LC at primary site in MTX arm (P < .01)	2
Rentschler (USA) 49	PORT or PORT and adjuvant MTX.	60 Lx, OC, OPX, HPX, NPX Stage III/IV	1979 to 1983 All received surgery and PORT. 5 taken off due to unresectable disease at surgery. MTX dose‐escalated from 40 mg/m2 and escalated 10 mg/m2 weekly. Given as 4 doses preoperative, 4 doses postoperative pre‐RT and 8 doses post‐RT.	43 mo	Closed due to slow accrual. Median peak MTX dose was 80 mg/m2. No statistically significant difference in actuarial DFS (P = 1.0) or OS (P = .61). Although patients on the MTX arm appeared to have less local and regional recurrences at first recurrence (thus more distant metastases), this did not reach statistical significance (P = .06). There was NSD between the sites of recurrence at death or last follow‐up (P = .38).	3

Abbreviations: Key: 5‐FU, fluorouracil; AF, accelerated fractionation; CF, conventional fractionation; CI, confidence interval; CRT, chemoradiation; CUP, carcinoma of unknown primary site; DFS, disease‐free survival; DSS, disease‐specific survival; DM, distant metastases; EBRT, external beam radiation therapy; ECS, extracapsular spread; ENE, extranodal spread; HNSCC, head and neck squamous cell carcinoma; HPX, hypopharynx; HR, hazard ratio; LOE, level of evidence; LRC, local‐regional control; LX, larynx; LVI, lymphovascular invasion; MTX, methotrexate; NC, nasal cavity; NPX, nasopharynx; NR, not reported; NSD, no significant difference; OC, oral cavity; OPX, oropharynx; OS, overall survival; PNI, perineural invasion; PNS, paranasal sinus; PORT, postoperative radiation therapy; QOL, quality of life; RCT, randomized controlled trial; RFS, recurrence‐free survival; RT, radiation therapy; S, surgery; SCC, squamous cell carcinoma; TORS, transoral robotic surgery.