Table 2.

Study design and independent variables considered for data stratification and findings. Legend to Table 2: ACE-27 = Adult Comorbidity Evaluation 27 score; ADM = acellular dermal matrix; BAMM = buccinator myomucosal flap; BOT = base of tongue; CRT = chemoradiotherapy; CT = chemotherapy; DCIA = deep circumflex iliac artery flap; FFF = free fibula flap; FOM = floor of the mouth; G8 = Geriatric 8 screening tool; HADS = Hospital Anxiety and Depression Scale; HNC = head and neck cancer; KFI = Kaplan–Feinstein index; MRND = modified radical neck dissection; ND = neck dissection; NOS = not otherwise specified; OC = oral cavity; OCC = oral cavity cancer; OP = oropharynx; OOP = oral cavity and oropharynx; OOPC = oral/oropharyngeal cancer; ORFFF = osteofasciocutaneous radial forearm free flap; OSCC = oral squamous cell carcinoma; PMMC = pectoralis major myocutaneous flap; RFFF = radial forearm free flap; RT = radiotherapy; SCAIF = supraclavicular artery island flap; SCC = squamous cell carcinoma; SND = selective neck dissection; STSG = split thickness skin graft.

Article	Study Design	Country	Sample	Cohorts Definition	Independent Variables Considered (EORTC Questionnaires as Dependent Variable)	Findings
Airoldi, 2011 [22]	Cross-sectional study	Italy	38	OSCC undergoing RFFF and adjuvant RT	Other: dysphagia severity (grouping algorithm not clearly stated); psychological status (HADS)	Dysphagia severity: severe dysphagia group showed significantly worse global health status/QoL, fatigue, physical and social functioning, sexuality, social eating, and contacts Psychological status: depression showed positive correlation with poor head- and neck-specific functional domains (data not available)
Beck-Broichsitter, 2017 [24]	Cross-sectional study	Germany	50	OC undergoing surgery as primary treatment	Disease/treatment: T stage (Tis-2 vs. T3/4); mandibular involvement (no resection vs. marginal/segmental resection); reconstruction (local flaps NOS vs. distant flaps, including together PMMC, FFF, RFFF)	Reconstruction: local flaps group showed significantly better swallowing No statistical significance of other independent variables
Becker, 2012 [23]	Cross-sectional study	Germany	50	OC	Disease/treatment: site; T stage (Tis-2 vs. T3/4); mandibular involvement (no resection vs. marginal vs. segmental resection); reconstruction (not clearly reported)	Mandibular involvement: no resection showed significantly better results for all scales with the exception of cognitive functioning; marginal resection (compared to segmental resection) showed significantly better results for role functioning and financial difficulties T stage: early-stage group showed significantly better results in all scales; Reconstruction: “more invasive techniques” and combined reconstructions showed significantly worse results for role, emotional and social functioning, financial difficulties, pain, swallowing, speech problems, trouble with social eating, trouble with social contact No statistical significance of other independent variables
Borggreven, 2007 [25]	Prospective cohort study	The Netherlands	45	OOPC undergoing RFFF	Time (baseline vs. 6 months vs. 1 year) Sociodemographic: age; gender; marital status; comorbidity Disease/treatment: site (oral cavity vs. oropharynx); stage (T2 vs. T3-4); metachronous lesions/recurrence	Time: -Improvement at 6 months, preserved at 1 year for emotional functioning, insomnia, general and H&N pain, constipation -Late improvement observed only at 1 year for role functioning -Deterioration at 6 months, recovered to baseline levels at 1 year for physical function, social contacts, dental status -Deterioration at 6 months, partially recovered at 1 year for financial status, swallowing, social eating, dry mouth -Deterioration at 6 months, preserved at 1 year for senses, mouth opening, sticky saliva, coughing -Late deterioration observed only at 1 year for feeling ill -No statistical significance of other independent variables evaluated by linear regression
Bozec, 2009 [26]	Prospective Cohort study	France	50	OOPC undergoing RFFF without flap failure	Time (baseline vs. 6 months vs. 1 year) Sociodemographic: age; gender; comorbidity (KFI < 2 vs. ≥ 2) Disease/treatment: site (oral cavity vs. oropharynx); stage (AJCC2002 II vs. III/IV); RT	Time: significant progressive worsening of mouth opening from baseline to 6 and 1 year after treatment The statistical analysis on all sociodemographic and disease- and treatment-specific variables was performed on 6-month follow-up questionnaires and not considered for critical appraisal.
Bozec, 2020 [27]	Multicenter cross-sectional study	France	21	OOPC undergoing free flaps in elderly patients	Sociodemographic: age (<80 years vs. >80years); gender; educational level (< vs. ≥high school diploma); marital status/family (living at home alone vs. not); alcohol consumption (yes vs. no); tobacco consumption (yes vs. no) Disease/treatment: site (oral cavity vs. oropharynx); T stage (4 vs. <4); N stage (0 vs. >0); adjuvant RT Other: HADS (<15 vs. >15); Geriatric 8 health status scores (G8 < 15 vs. >15); number of patients concerns inventory (PCI)	HADS > 15 and G8 <15: significantly associated with poorer scores in global QoL score, functioning scales, general symptoms, H&N symptoms. The authors also administered the EORTC QLQ-ELD14 questionnaire, reporting significantly poorer results in patients older than 80 years, living alone, and with HADS > 15 in motility, as well as significantly poorer results in patients with HADS > 15 in joint stiffness, worries about the future, worries about others, burden of illness, maintaining purpose. Oropharyngeal cancers, G8 < 15 and HADS ≥ 15 were significantly associated with lower scores in the Dysphagia Outcome and Severity Scale (DOSS). HADS ≥ 15 has been significantly associated with a higher number of PCI. No statistical significance of other independent variables
Canis, 2016 [28]	Retrospective cohort study	Germany	48	Lateral tongue pT3 SCC primarily treated by surgical excision, neck dissection followed by CRT	Disease/treatment: reconstruction (RFFF vs. primary closure)	Reconstruction: RFFF group showed significant better speech, swallowing, and social eating
Crombie, 2014 [10]	Cross-sectional study	Australia	40	OC	Treatment by CRT alone vs. surgery alone/surgery with adjuvant RT/surgery with adjuvant CT	No statistically significant differences between compared groups
Davudov, 2019 [29]	Cross-sectional study	Iran	16	OCC undergoing mandible segmental resection	Disease/treatment: reconstruction (no reconstruction vs. free flap vs. plate)	Reconstruction: no reconstruction showed significantly worse outcomes in speech problems, dry mouth, and feeling ill
Dzioba, 2017 [30]	Prospective cohort study	Canada	120	Cancer of the anterior two-thirds of the tongue, treated by surgical excision and reconstruction alone or by a combination of surgery + RT or surgery + CRT	Time (baseline vs. 1 month vs. 6 months vs. 1 year) substratified by treatment protocol (surgery only vs. surgery + RT vs. surgery + CRT) only for some EORTC items	Surgery + RT group: -baseline vs. 1 year: significantly worse dry mouth at 1-year assessment Surgery + CRT group: -baseline vs. 1 year: significantly worse dry mouth at 1-year assessment -baseline vs. NOS: significantly worse results for eating, mouth opening, swallowing
Ferri, 2020 [31]	Multicenter retrospective cohort study	Italy	70	OSCC (T1-2, N0) involving the tongue and FOM undergoing transoral partial pelviglossectomy/BAMM flap or pull-through partial pelviglossectomy/free flap	Other: treatment protocol (transoral partial pelviglossectomy followed by BAMM flap vs. pull-through partial pelviglossectomy followed by free flap)	Significantly better results in transoral/BAMM flap group for average H&N35 questionnaire. The authors did not provide item-specific data, except for swallowing, which had significantly better result in the transoral/BAMM group
Girod, 2009 [32]	Prospective cohort study	USA	122	OC	Disease/treatment: reconstruction (ADM vs. STSG) substratified by RT (not specified if pre- or post-treatment); major complications (graft failure vs. regular healing)	Reconstruction: ADM group showed significantly better social eating Reconstruction stratified by RT: ADM/RT scored significantly better results in swallowing scale compared to STSG/RT No statistical significance of other independent variables
Huang, 2010 [33]	Cross-sectional study	Taiwan	41	HNC free from disease at least 2 y after combined treatment with curative intent	Sociodemographic: gender; age (32–48 years vs. 49–56 years vs. 57–83 years); marital status; educational level (≤6 years vs. 6–12 years vs. >12 years); family income (annual: <0.6 million NTD vs. 0.6–1.2 million NTD vs. ≥1.2 million NTD); comorbidity (Charlson Comorbidity Index [CCI]: 0 vs. ≥1) Disease/treatment: site (oral cavity vs. oropharynx vs. hypopharynx/larynx); stage (AJCC: II vs. III vs. IV); Other: treatment protocol (surgery + RT vs. surgery + RT + CT vs. RT + CT); RT dose (<63 Gy vs. ≥63 Gy); RT technique (2DRT vs. 3DCRT vs. IMRT); length of follow-up (2.2–3.5 years vs. 3.5–4.7 years vs. 4.7–13.2 years)	The study applied an interesting statistical model to compare several independent variables simultaneously in a double-step general linear model multivariate analysis of variance (GML-MANOVA). Annual family income: patients with ≥1.2 million NTD annual income showed significantly better results for physical functioning, role functioning, social functioning, financial problems, swallowing, speech, social eating, and social contact Site: -oral cancer patients showed significantly better results for physical functioning, cognitive functioning, fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, pain, sense, speech, coughing, and feeling ill -hypopharyngeal/laryngeal cancer patients showed the worst results for mouth opening and coughing (statistically significant) -oropharyngeal cancer patients showed the worst results for dry mouth and sticky saliva (statistically significant) RT technique: patients treated by 3DCRT and IMRT showed significantly better results for swallowing, problems with teeth, mouth opening, dry mouth, and sticky saliva No statistically significant differences were found analyzing other independent variables (age, gender, educational level, marital status, comorbidity, cancer stage, RT dose, treatment protocol, length of follow-up)
Infante-Cossio, 2009 [34]	Prospective cohort study	Spain	67	OOPC	Time (baseline, 1 year, 3 years) Disease/treatment: site (oral cavity vs. oropharynx); adjuvant CRT Other: AJCC stage (I/II vs. III/IV)	Time: the study demonstrated three different evolution patterns among questionnaires items: (I) Improvement at the first and third year for emotional functioning, general pain, and specific H&N pain; (II) Worsening at the first year and improvement at the third year for global QoL, physical, role and social functioning, financial problems, sensory problems, social eating, social relationships, sexuality, mouth opening, and use of painkillers; (III) Worsening at the first and third year: cognitive functioning, fatigue, constipation, diarrhea, swallowing, speech, dry mouth, sticky saliva, cough, feeling ill, and weight loss. Site: oropharyngeal cancer showed worse results in overall QoL, functioning role, tiredness, nausea/emesis, appetite loss, pain, use of painkillers, dyspnea, social relationships Stage: III/IV stage cancers showed significantly worse state of health and QoL, pain, tiredness, loss of appetite, swallowing function, speech, social contacts, eating in public, mouth opening, cough, weight loss, use of pain killers Adjuvant CRT: patients undergoing adjuvant CRT showed significantly worse overall QoL, swallowing function, pain, dry mouth, sticky saliva, mouth opening, sensory disorders, speech, social eating
Kessler, 2004 [35]	Prospective cohort study	Germany	55	Primary OC undergoing nCRT + surgical excision or primary surgical excision + adjuvant RT	Time (baseline vs. 3 month vs. 1 year) substratified by treatment protocols (nCRT + surgery vs. surgery+RT)	nCRT + surgery group: -Baseline vs. 1 year: significantly worse results for global health status, physical function, role function, emotional function, social function, fatigue, nausea and vomiting, pain, dyspnea, insomnia, financial difficulties, swallowing, senses, speech, eating, social contact, teeth, mouth opening, dry mouth, sticky saliva, coughing, feeling ill, feeding tube Surgery + RT group: -Baseline vs. 1 year: significantly worse results for global health status, physical function, role function, emotional function, social function, fatigue, nausea and vomiting, pain, dyspnea, insomnia, financial difficulties, swallowing, senses, speech, eating, social contact, teeth, mouth opening, dry mouth, sticky saliva, coughing, feeling ill, feeding tube, weight gain
Khandelwal, 2017 [9]	Cross-sectional study	India	34	OC undergoing free flaps	Time (1–2 years vs. 3–5 years) Sociodemographic: age (<45 years vs. >45 years); gender Disease/treatment: site (anterior floor of the mouth/sublingual sulcus vs. retromolar region/tonsillar fossa/tongue); T stage (T2 vs. T3 vs. T4) Other: use of feeding tubes	T stage: progressively better results have been found for smaller tumors for global health status/QoL, functional scales, symptom scale, H and NSS (NOS). Feeding tubes: significantly worse results in patients using feeding tubes for functional status and H and N scales (NOS) No statistical significance of other independent variables
Klug, 2002 [36]	Retrospective cohort study	Austria	110	OC undergoing multimodal treatment (preoperative CRT followed by surgery and free flaps)	Disease/treatment: site (anterior vs. posterior); T stage (T2 vs. T4), mandibular involvement (segmental vs. marginal resection); neck dissection (SND vs. MRND (NOS)/bilateral ND)	No statistically significant differences between compared groups
Kovács, 2015 [37]	Cross-sectional study	Germany	100	OOPC undergoing various combinations of multimodality treatment	Sociodemographic: gender Disease/treatment: site (FOM vs. tongue vs. oropharynx vs. retromolar trigone vs. oral cheek vs. mandibular crest vs. lip vs. maxilla); neck dissection laterality (no vs. unilateral vs. bilateral) and type (super selective I-IIa vs. MRND-III); reconstruction (no vs. local flaps NOS vs. distant flaps NOS vs. free flaps NOS); adjuvant RT; adjuvant CRT; adjuvant CT. Other: time since treatment; comparison with EORTC group	Time since treatment: patients evaluated at the 4-years follow-up demonstrated statistically significant worse results for social eating and nutritional support compared to the 1-year follow-up evaluation. Gender: men showed significantly worse results for financial difficulties and cognitive and social functioning Site: cancers of the FOM showed significantly worse social contact compared to tongue; oropharyngeal cancers showed significantly worse results for feeding tubes and sticky saliva compared to tongue and retromolar trigone Reconstruction: -Distant flaps vs. free flaps: worse swallowing than free flaps in the former -Distant flaps vs. no reconstruction: worse swallowing, feeding tubes, social eating, and contact in the former -Distant flaps vs. local flaps: worse results for feeding tubes and social contact in the former -Free flaps vs. no reconstruction: worse need of feeding and social contact tube in the former -Free flaps vs. local flaps: worse results for social contact in the former Neck dissection: -Laterality: both unilateral and bilateral showed significantly worse results for mouth opening than no neck dissection group -Type: compared to super selective I-IIa and no neck dissection groups, MRNDIII showed significantly worse results for swallowing, speech, social eating and contact, sexuality, mouth opening, dry mouth, sticky saliva, feeding tubes, and weight loss Adjuvant therapy: -Adjuvant RT vs. no adjuvant therapy: the former showed significantly worse results for emotional and social functioning, appetite loss, swallowing, senses, speech, social eating and contact, sexuality, mouth opening, dry mouth, sticky saliva, pain, feeding tubes -Adjuvant CT vs. all other: the former showed significantly better results for sticky saliva -Adjuvant CRT showed the same results of adjuvant RT Comparison with the reference group: -Worse in studied sample: global health status, cognitive and social functioning, fatigue, social eating, dental status, mouth opening, dry mouth, and sticky saliva -Better in studied sample: H&N pain, need for pain killers, cough, need for nutritional support, weight loss and gain
Lin, 2020 [38]	Case control study	Taiwan	13	Cancer of the lower lip undergoing surgical resection and reconstruction with RFFF or barrel-shaped RFFF	Disease/treatment: reconstruction (RFFF vs. barrel-shaped RFFF)	Reconstruction: patients undergone barrel-shaped RFFF reconstruction scored better results for swallowing, speech, social eating, social contact and dry mouth
Mair, 2017 [39]	Prospective cohort study	India	38	T4 cancers of the buccal mucosa undergoing surgery (ablation, neck dissection and reconstruction with PMMC) as first-line treatment	Time (baseline vs. 3 months vs. 6 months vs. 9 months vs. 1 year) on the disease-free sub cohort and sub stratified by adjuvant therapy Disease/treatment: adjuvant therapy (RT vs. CRT)	Baseline differences between disease-free patients and those who developed a relapse: significantly worse results in the latter group for global QOL, dyspnea, appetite loss and weight loss Adjuvant therapy: no differences at 1-year evaluation between groups
Moubayed, 2014 [40]	Cross-sectional study and systematic review of literature	Canada	37	OSCC undergoing segmental resection of the mandible and free flaps	Disease/treatment: reconstruction (FFF vs. ORFFF vs. Scapular flap)	No statistically significant differences between compared groups
Nordgren, 2008 [41]	Multicenter prospective cohort study	Sweden/Norway	37	OC	Time (baseline vs. 3 months vs. 6 months vs. 1 year vs. 5 years) in entire cohort and substratified by treatment protocol and survival Other: treatment protocol (surgery alone vs. RT alone vs. combined); survival (5-year survivors vs. 5-year non-survivors and 5-year survivors vs. died after the first year)	Time (baseline vs. 5 years) entire cohort: significant improvement in emotional functioning, significant deterioration in physical and role functioning, dyspnea, problems with senses, teeth, mouth opening, dry mouth, and sticky saliva Time (1 year vs. 5 years) entire cohort: significant deterioration in role functioning, sticky saliva, and mouth opening Time (baseline vs. 5 years) surgery alone: stability of all items Time (baseline vs. 5 years) RT alone: significant improvement of sleep disturbance, H&N pain, social eating and mouth opening; deterioration in physical and role functioning, dyspnea, senses, and dry mouth. Time (baseline vs. 5 years) combined group: significant improvement for emotional functioning and sleep problems; deterioration for role functioning, senses, mouth opening, dry mouth, and sticky saliva. 5-year survivors vs. 5-year non-survivors (compared at baseline): survivors showed significantly better results at baseline for physical, cognitive, and social functioning; fatigue; pain; dyspnea; sleep disturbance; appetite loss; H&N pain; senses; speech; social eating and contacts; dental status; mouth opening; sticky saliva; and dry mouth 5-year survivors vs. died after the first year (compared at baseline): survivors showed significantly better results for physical, cognitive, and social functioning; fatigue; pain; dyspnea; sleep disturbance; appetite loss; H&N pain; senses; speech; social eating; dental status; mouth opening; dry mouth; sticky saliva 5-year survivors vs. died after the first year (compared at 1 year): survivors showed significantly better results for physical and role functioning, fatigue, nausea/vomiting, appetite loss, constipation, diarrhea, swallowing, social eating, sexuality, mouth opening.
Oates, 2008 [42]	Prospective cohort study	Australia	47	HNC	Time (baseline vs. 3 months vs. 6 months vs. 1 year) substratified by site and treatment protocol Disease/treatment: site (oral cavity vs. oropharynx vs. larynx vs. nasopharynx vs. parotid vs. occult primary vs. paranasal sinus) Other: treatment protocol (surgery vs. RT only) substratified by site	Patients undergoing RT only over time: -oral cavity: significant improvement in emotional functioning over time -oropharynx: significant deterioration of dry mouth over time -larynx: significant improvement in emotional, cognitive, and social functioning
Oskam, 2013 [43]	Prospective cohort study	The Netherlands	129	OOPC	Time (baseline vs. 6 months vs. 1 year vs. ≥8 years) Sociodemographic: age (NOS); gender; marital status Disease/treatment: tumor site (OC vs. OP); stage (NOS) Other: long-term survival	Time: the mixed-effects model showed significant deterioration from baseline to long-term evaluation for dry mouth, sticky saliva, speech, coughing, senses, swallowing, and social functioning. Long-term survival: non-survivors showed significantly worse baseline global health status/QoL, general pain, appetite loss, swallowing, dental status, and feeling ill No statistical significance of other independent variables
Peisker, 2016 [44]	Cross-sectional study	Germany	22	OSCC undergoing free flaps	None	Authors performed a bivariate intraquestionnaire analysis to correlate impact of symptom scales on global health status/QoL scale
Petruson, 2005 [45]	Prospective cohort study	Sweden	225	Primary OOPC (mobile tongue vs. OPC) undergoing brachytherapy	Time (baseline vs. 3 months vs. 1 year vs. 3 years) substratified by site (mobile tongue vs. OPC), brachytherapy quality indices dose, dose rate, and tumor target volume	Mobile tongue group: -baseline vs. 1 year post-treatment: significantly worse dry mouth -baseline vs. 3 years post-treatment: significantly worse dry mouth -brachytherapy dose rate: significant association NOS between brachytherapy dose rate and swallowing solid food at NOS timepoint
Pierre, 2014 [46]	Prospective cohort study	France	117	OOPC undergoing free flaps without flap failure and disease free	Sociodemographic: age (>70 years vs. <70 years); gender; comorbidity (KFI ≥2 vs. <2); Disease/treatment: site (oral cavity vs. oropharynx) and OOP subsites (mobile tongue vs. FOM vs. cheek vs. hard palate vs. BOT vs. pharyngeal wall vs. soft palate vs. posterior pharyngeal wall); T stage (T2 vs. T3 vs. T4); mandibular involvement (no vs. segmental resection); reconstruction (FFF/scapular vs. RFFF/ALT); adjuvant RT; neoadjuvant RT; N stage (N ≥ 1 vs. N0)	T stage: T3–4 stage group showed significantly worse results in mean QoL global score, mean C30 symptom domains score and mean H&N35 module score Subsite: BOT showed a significantly worse result in mean H&N35 module score Adjuvant RT: significantly worse results in mean H&N35 module score Neoadjuvant RT: significantly worse results in mean H&N35 module score No statistical significance of other independent variables
Schoen, 2008 [47]	Prospective cohort study	The Netherlands	41	OOPC in edentulous undergoing surgical excision and implant retained prosthesis rehabilitation	Time (baseline vs. 6 weeks vs. 1 year) substratified by adjuvant RT Disease/treatment: adjuvant RT	Adjuvant RT: patients undergoing adjuvant radiotherapy showed significantly worse results for H&N pain, swallowing, speech, social eating, sexuality, mouth opening, dry mouth, and sticky saliva. Significantly better result was shown in nausea/vomiting.
Van Gemert, 2015 [48]	Cross-sectional study	The Netherlands	20	OC undergoing lateral segmental resection of the mandible	Sociodemographic: age (NOS); gender Disease/treatment: site (retromolar area vs. FOM vs. gingiva vs. cheek); neck dissection (no vs. unilateral NOS vs. bilateral NOS); reconstruction (of the bony defect [FFF vs. plate] and of soft tissue defect among plate group [primary closure vs. RFFF vs. PMMC]); adjuvant RT Other: cN stage (0 vs. +); horizontal defect size; occlusion (achieved vs. not achieved); accessory nerve sacrifice	Age: significant inverse relation with mouth opening (OVB or selection bias) Gender: relation NOS with feeding tube (OVB or selection bias) Reconstruction of the bony defect: significant relation NOS with functional scales and feeling ill Reconstruction of soft tissue defect: significant relation NOS with mouth opening and feeling ill Bilateral neck dissection NOS: significant relation NOS with social eating and contact, dental status, and feeding tube Horizontal defect size: significant relation NOS with feeding tube Accessory nerve sacrifice: significant relation with swallowing and speech troubles No statistical significance of other independent variables
Yoshimura, 2009 [49]	Prospective cohort study	Japan	30	OC undergoing primary low-dose-rate brachytherapy with no cervical lymph node or distant metastases, no other active malignancies	Time (baseline vs. 3 months vs. 6 months vs. 1 year) Sociodemographic: gender; age (<65 years or >65 years) Disease/treatment: site (tongue vs. others); T stage (T1 vs. T2–3) Other: brachytherapy source (iridium vs. cesium vs. gold)	Site: patients affected by cancer of the tongue scored worse results at baseline for swallowing, senses and sticky saliva. The latter two remained worse during the follow-up period (1 y), while swallowing item improved toward results comparable with those of the other group at 1 y assessment T stage: T1 stage patients demonstrated higher scores for global health status at baseline and at the 1-year evaluation No statistical significance of other independent variables
Tot			1833