. 2022 Jul 18;44(11):2579–2599. doi: 10.1002/hed.27142

TABLE 3.

Detailed study outcomes of randomized and non‐randomized studies (n = 28)

Study	Interval from treatment to intervention ^c	Comparison	Intervention type	Outcomes	Measures	Results	Conclusions
Randomized trials (n = 13)
Alamoudi 2018 ¹²	30 ± 12 months	Intervention versus observation	Submental liposuction	Appearance/Lymphedema	MBOE ^a DAS‐59 (Derriford Appearance Scale)	SS improvement in both scales	Submental liposuction vs. no intervention associated with improvement in patient‐reported appearance
Bhatia 2017 ¹³	1‐61 months	Intervention versus placebo	13 Cis‐retinoic acid	Prevention of second primary cancer	Number of secondary primary tumors (SPT) & time to diagnosis of SPT ^a OS	N‐SS difference in SPT or time to SPT	13‐CRA did not reduce SPT in underpowered trial
Cramer 2021 ¹⁴	Intervention group: median 9 years (IQR 6–13 years) CXR: median 10 years (IQR 6–17 years)	Low‐dose CT (LDCT) versus chest‐x‐ray (CXR)	Lung cancer screening	Incidence of second primary lung cancer	Incidence of second primary lung cancer (SPLC) ^a Incidence of a second primary HNC, combined SPHNC or SPLC, OS, incidence of abnormal imaging findings	N‐SS difference in SPLC identified on LDCT compared to CXR SS‐higher incidence of SPLC in HNC survivors compared to other	Post hoc analysis of a RCT did not show SS difference in SPLC in LDCT in HNC subgroup; SS higher SPLC in HNC survivors
Guglielmo 2020 ¹⁵	≥12 months	Intervention versus placebo	Ginseng	Fatigue	BFI ^a	No SS difference in BFI from baseline to post‐intervention	Ginseng did not reduce patient‐reported fatigue
Jansen 2020 ¹⁶	78%: 6 months–5 years 22%: <6 months	Intervention versus self‐care education program alone	Guided self‐help exercise program and self‐care education program	Swallow/communication	SWAL‐QOL ^a SHI (speech handicap index) Shoulder problems (SDQ) PAM EORTC QLQ‐C30 EORTC QLQ‐H&N35	SS improvement in SWAL‐QOL in intervention group N‐SS improvement in other domains Time since cancer treatment moderated effectiveness of intervention on speech problems	Guided self‐help exercise program improvement patient‐reported swallowing function
Kaae 2020 ¹⁷	75%: 6–24 months 25%: 36–60 months	Intervention versus CAU	Chewing gum	Dry mouth	EORTC QLQ‐H&N35 “dry mouth” question ^a GRIX UWS and SWS sialometry	SS reduction improvement in primary endpoint N‐SS difference in other measures	Chewing gum associated with improvement with dry mouth question on EORTC‐QLQ‐HN35
McNeely 2015 ¹⁸	44%: ≥18 months 42%: <9 months 15%: 9–17 months	Intervention versus CAU, option to crossover	Progressive resistance exercise training	Shoulder dysfunction	SPADI ^a Upper extremity strength Shoulder ROM FACT‐An NDII	SS improvement in all measures	Progressive resistance exercise training reduced patient‐reported shoulder pain and disability and improved muscle strength/endurance
Millgard 2020 ¹⁹	Follow‐up extended to 2 years	Intervention versus CAU	Voice rehabilitation	Voice quality	CPPS ^a GRBAS sale	N‐SS differences in measures	Voice rehab may have positive effects but N‐SS correlation found between CPPS and perceptual parameters of GRBAS
Pereira 2020 ²⁰	2–6 years	Intervention versus placebo	Pilocarpine spray	Dry mouth	SWSF ^a XI OHIP‐14	N‐SS difference in measures	Topical pilocarpine spray did no lead to SS difference in measures of xerostomia
Schutte 2021 ²¹	46%: >12 months 37%: >7 months 18%: 7–12 months	Intervention versus CAU	Stepped care program targeting psychological distress	Sexual interest/enjoyment	Sexuality symptom subscale of EORTC QLQ‐H&N35 ^a	N‐SS improvement	SC targeting psychological distress did not reduce problems with sexuality. Interventions specifically targeting sexuality are recommended
Tang 2011 ²²	Mean 4.6 years for intervention versus 4.8 years for control	Intervention versus CAU	Rehabilitation exercise therapy	Trismus and dysphagia	Water swallow test ^b LENT/SOMA IID	SS‐improvement in all measures	Swallow and trismus therapy improved swallow function and reduced severity of trismus
Vadcharavivad 2013 ²³	≥1 year	Intervention versus commercially available saliva substitute	In‐hospital prepared saliva substitute	Dry mouth	XeQoLS ^a	SS inferior score in intervention group	Commercially available saliva substitute was better than the hospital‐prepared formulation
Wu 2019 ²⁴	≥1 year	Intervention versus sham	Endoscopic dilation	Dysphagia	SSQ score + satisfactory global assessment by swallow therapist ^a SAE Dysphagia relapse	SS improvement in all measures, no SAEs	Dilation improves swallowing function
Non‐randomized prospective studies (N = 15)
Al‐Bazie 2016 ²⁵	12–33 months	None	Perioperative antibiotics (oral amoxicillin) and antibacterial mouthwash	Prevention of osteoradionecrosis after dental extractions	No. extracted teeth ^b Osteoradionecrosis (no further definition)	232 extractions (average 2.6 teeth/patient) and no ORN	No patients using the antibiotic protocol had ORN after extractions
Chan 2004 ²⁶	Intervention: mean 15.47 years (SD 5.3 years) Control: 13.80 years (7.45)	Matched control group	Alpha‐tocopherol	Cognitive function for temporal lobe necrosis	Cantonese MMSE ^b Category Fluency Test Hong Kong List Learning Test (HKLLT) Visual Reproduction subtest of the Wechsler Memory Scale‐III (WMS‐III VR) Cognitive Flexibility Test Self‐evaluation questionnaire	SS improvement in MSSE, and verbal and visual memory, and executive function N‐SS difference between groups in attention, language, or self‐reported improvement	Alpha‐tocopherol may improve cognitive function
Chen 2020 ²⁷	Mean 33 months	None	Endoscopic surveillance	Metachronous esophageal squamous cell carcinoma	Biospy‐proven dysplasia or squamous cell carcinoma	Metachronous esophageal squamous cell neoplasms ESCN) developed in 11.4% patients (17 low‐grade dysplasia, 3 squamous cell carcinoma. Median time to ESCN was 33 ± 22.9 months	Endoscopic surveillance can detect ESCN
DeLeeuw 2013 ²⁸	Intervention extended to 12 months post‐treatment	CAU group recruited in preceding year	Nurse‐led additional follow‐up consults	Psychosocial adjustment and HRQOL	PAIS‐SR ^b EORTC QLQ‐C30 and QLQ‐H&N35	N‐SS difference between groups	Nurse‐led consultations had a positive but not SS effect on HRQOL
Dholam 2011 ²⁹	≥1 year	No	Implant‐retained dental prosthesis into reconstructed maxillae and mandibles	HRQOL, and speech	EORTC QLQ‐H&N 35 and EORTC QLQ‐C30 ^b Dr. Speech Software	N‐SS improvement in pre‐intervention versus post‐intervention assessment, even if numerically improved	QOL parameters did not markedly change after implant retained prosthesis reconstruction even if individual parameters numerically improved
Fong 2014 ³¹	Mean 12.5 years in intervention group versus 8.4 years in control group	Self‐selected volunteers who did CAU	Qigong training	HRQOL, physical	EORTC QLQ‐H&N, QLQ‐C30 ^b Blood flow velocity Arterial resistance by Doppler ultrasound Functional aerobic capacity measured by walking distance and self‐report of fatigue Palmar skin temperature measurement	NS‐SS difference between intervention and control group for EORTC QLQ measures SS higher diastolic blood flow, lower arterial blood flow resistance, and higher palmar skin temperature, and functional aerobic capacity	Tai Chi Qigong program may improve arterial hemodynamics and functional aerobic capacity
Fong 2014 ³⁰		Self‐selected volunteers who did CAU	Qigong training	HRQOL, physical
Kraaijenga 2017 ³²	≥88%: ≥2 years	None	Swallowing exercise program	Dysphagia	Feasibility and compliance ^a SWAL‐QOL EQ‐5D Interincisal opening FOIS VFS parameters PAS IOPI Dynamometer for jaw muscle strength	High compliance (97%) and completion rate (88%) SS‐not reported, but descriptive statistics for numeric improvements in strength in various muscles	Feasibility and compliance for a swallowing exercise program can be high with some objective and subjective effects of muscle strength and swallow function despite most being at least 2 years post‐treatment
Liu 2021 ³³	Mean 8.81 years (SD 4.66) in high plaque (HP) group and 9.56 years (SD 3.67) in low plaque (LP) group	At enrolment, 2 groups created: high‐plaque group versus low‐plaque group	Carotid duplex ultrasound (CDU)	Carotid artery stenosis (CAS) progression	>50% stenosis on B‐mode CDU with compatible hemodynamic pattern in any ICA or CCA on a follow‐up CDU study ^b	HP group had a SS higher frequency of CAS progression and N‐SS increased future ischemic stroke	Patients with total plaque sore of ≥7 on CDU are susceptible to CAS progression and should have close monitoring
Manne 2020 ³⁴	1–3 years	None	Web‐based tool: “Empowered Survivor”	Feasibility, preliminary impact on health/QOL outcomes	22‐item scale composed for the study to represent confidence in managing different aspects of self‐care ^a 10‐item scale used previously by study group for assessing preparedness for oral and oropharyngeal survivorship EORTC QLQ‐HN35 Study‐specific measure for performance and thoroughness of oral self‐exam, maintenance of exercise, and action/coping planning, activation, and information needs Supportive Care Needs Survey	82% pts viewed intervention Descriptive statistics showed increased self‐efficacy, preparedness for survivorship, HRQOL, rates of oral self‐exam, and other secondary endpoints	The web‐based survivorship empowerment tool showed a beneficial impact on multiple domains
Martin‐Harris 2015 ³⁵	>1 year	None	Respiratory‐swallow training	Dysphagia related QOL, spirometry	Respiratory‐swallow phase pattern ^b MBSImP PAS MDADI	SS improvement in optimal phase swallowing patterning, and component scores of MBSimP including laryngeal vestibular closure, tongue base retraction, and pharyngeal residue SS improvement in PAS and MDADI	Improvements in respiratory‐swallowing coordination can be trained in patients with chronic dysphagia with favorable effects on airway protection and bolus clearance
Montalvo 2020 ³⁶	Mean 6.2 years (range 0.7–14.8)	None	Therabite	Trismus	MIO ^b Gothenburg Trismus Questionnaire (GTQ) EORTC QLQ C30 and EORTC QLQ‐H&N35	SS improvement in MIO and individual domains in the other questionnaires	Structured exercise with the jaw‐mobilizing device was beneficial for patients with trismus
Mozzati 2014 ³⁷	Mean 4.1 ± 2.5 years	Same patient, contralateral extraction sockets with CAU	Plasma rich growth factors	Healing post‐extraction	Healing index (HI), residual socket volume (RSV), postoperative complications ^b	Intervention showed SS‐better RSV and HI and no postoperative complications (bone exposure)	Plasma rich in growth factors accelerated mucosal healing and avoided post‐extraction bone exposure
Nativ‐Zelter 2021 ³⁸	Mean 11.5 years, (SD 7.6)	No	Autologous muscle‐derived cell therapy	Safety (phase I trial with efficacy measurements), dysphagia	IOPI ^a PAS Pharyngeal constriction ratio Pharyngo‐esophageal segment (PES) opening Pharyngeal transit time Pharyngeal peak pressure EAT‐10 VHI‐10	No SAEs SS increase in tongue pressure. N‐SS change in other metrics	Injection with autologous muscle‐derived cell therapy was feasible and safe and was accompanied by increase in tongue strength
Pauli 2016 ³⁹	Includes 2‐year f/u The 10‐week Intervention was 3–6 months post‐treatment	Control group receiving CAU (no structured trismus‐focused program	Therabite®	Trismus	MIO ^a Gothenburg Trismus Questionnaire (GTQ) EORTC QLQ C30 and EORTC QLQ‐H&N35	SS higher MIO and GTQ at 2‐year follow‐up in intervention group. Individual domains in other questionnaires had SS differences	There is a positive persistent effect of jaw opening exercises on trismus and patient reported outcomes
Sterba 2019 ⁴⁰	9 patients: >12 months 6 patients: 6–12 months 11 patients: 0–6 months	No	SNAP (Survivorship Needs Assessment Planning Tool)	Feasibility and short‐term change in psychosocial outcomes	PROMIS (depression) ^a Cancer Survivors/Partners Unmet Needs instruments PLANS Dyadic coping inventory Zarit Burden Inventory FOCUS—2 single items Other study‐specific surveys	SS improvement in scores for depression, unmet needs, and survivorship knowledge in survivors and caregivers NS‐SS change in symptom distress and management	The SNAP tool is feasible and able to address dyads' needs; the tool merits further testing in a clinical trial

Abbreviations: BFI, brief fatigue inventory; CAU, care as usual; CPPS, smoothed cepstral peak prominence; EAT‐10, Eating Assessment Tool; EORTC‐QLQ, European Organization for Research and Treatment of Cancer generic and HNC‐specific health‐related quality of life measures; EQ‐5D, European Quality of Life 5 Dimensional Questionnaire; FACT‐An scale, Functional Assessment of Cancer Therapy‐Anemia scale; FOCUS, National Cancer Institute Follow‐up Care Use and Health Outcomes of Cancer Survivors; FOIS, functional oral intake scale; GRBAS, Grade, Roughness, Breathiness, Asthenia and Strain scale; GRIX, Groningen Radiation‐Induced Xerostomia questionnaire; HNC, head and neck cancer; HRQOL, health‐related quality of life; IID, interincisal distance; IOPI, Iowa Oral Performance Instrument; LENT/SOMA, Late Effects Normal Tissue/Subjective, Objective, Management, Analytic scales; MBOE, Modified blepharoplasty Outcomes Evaluation; MBSImP, Modified Barium Swallow Impairment Profile; MDADI, MD Anderson Dysphagia Inventory; MIO, maximal interincisal opening; MMSE, Mini‐Mental Status Examination; NDII, neck dissection impairment index; No., number; NOS, not otherwise specified; N‐SS, non‐statistically significant; OHIP‐14, Oral Health Impact Profile; PAIS‐SR, Psycho‐social Adjustment to Illness Scale‐Self Report; PAM, patient activation measure; PAS, penetration aspiration scale; PLANS, Preparing for Life As a New Survivor; PROMIS, Patient‐Reported Outcomes Measure Information System; ROM, range of motion; SAE, serious adverse event; SDQ, shoulder disability questionnaire; SHI, speech handicap index; SPADI, shoulder pain and disability index; SS, statistically significant; SSQ, Sydney Swallow Questionnaire; SWAL‐QOL, swallowing quality of life questionnaire; SWSF, stimulated whole saliva flow; UWS, unstimulated whole saliva; VFS, video fluoroscopy; VHI, Voice Handicap Index; XeQoLS, Xerostomia Quality of Life Scale; XI, Xerostomia Inventory.

^{^a}

Primary endpoint.

^{^b}

Primary endpoint not specifically stated in methods.

^{^c}

Time from treatment to intervention is given, time from diagnosis is given if specific time from treatment not given.