Use of THRIVE for Apneic Oxygenation in Transoral Laser Microlaryngeal Surgery: A Scoping Review.

OBJECTIVES: Trans-nasal humidified rapid insufflation ventilatory exchange (THRIVE) has demonstrated utility in extending the apneic window in the perioperative setting. Its benefits in facilitating tubeless anesthesia are recognized during elective laryngotracheal surgeries. The use of THRIVE and administering higher fractional inspired oxygen concentrations in laser laryngeal surgery (LLS) remains controversial due to the theoretical risk of airway fires. A scoping review of the literature describing institutional experiences with THRIVE during LLS was conducted. DATA SOURCES AND REVIEW METHODS: A systematic scoping review of the literature was performed including PubMed, Medline, Embase, Scopus, JBI EBP Database, and Cochrane Library from inception to April 2023. RESULTS: From the 472 articles identified in our review, nine articles were included representing 271 cases. THRIVE was used for preoxygenation and to maintain apneic oxygenation during LLS. Different institutional practices related to THRIVE parameters and intraoperative modifications during lasing were described in the literature, including cessation of THRIVE, reduction of FiO2 to 30%, and continuous 100% FiO2 oxygenation. One study described a brief ignition of the coating of a KTP laser fiber without injury to the patient. No adverse patient outcomes have been documented in the literature with THRIVE during LLS. CONCLUSION: THRIVE is a safe and effective form of tubeless anesthesia and apneic oxygenation during LLS, with no adverse patient safety events reported in the literature. Key determinants to maintain safety include optimal patient and team selection, effective surgeon-anesthetist cooperation, and institutional protocols that govern intraoperative practice. Laryngoscope, 2024.

Trans-nasal Humidified Rapid Insufflation Ventilatory Exchange (THRIVE) and its Utility in Otolaryngology, Head and Neck Surgery: A Literature Review.

High-flow nasal oxygen (HFNO) therapy is extensively used in critical care units for spontaneously breathing patients. Trans-nasal humidified rapid insufflation ventilatory exchange (THRIVE) is a method of apnoeic oxygenation with continuous nasal delivery of warmed, humidified oxygen at high-flow rates up to 70L/min. THRIVE extends the apnoeic window before desaturation occurs so that tubeless anaesthesia is possible. The advent of THRIVE has had a monumental impact on anaesthetic practice, with a diverse range of clinical applications and it has been incorporated into difficult airway guidelines. THRIVE has many applications in otolaryngology and head and neck surgery. It is used as a pre-oxygenation tool during induction in both anticipated and unanticipated difficult airway scenarios and as a method of oxygenation for tubeless anaesthesia in elective laryngotracheal and hypopharyngeal surgeries and during emergence from anaesthesia. In this scoping review of the literature, we aim to provide an overview on the utility of THRIVE in otolaryngology, including the underlying physiologic principles, current indications and limitations, and its feasibility and safety in different surgical contexts and specific population groups.

Primary Management of Operable Locally Advanced Oral Cavity Squamous Cell Carcinoma: Current Concepts and Strategies.

INTRODUCTION: Locally advanced oral cavity carcinoma (LAOCSCC) is primarily treated with surgery followed by radiotherapy with or without chemotherapy. METHODS: A review of literature using PubMED was performed for studies reporting the management of LAOCSCC. Based on the reviewed literature and opinions of experts in the field, recommendations were made. RESULTS: Studies have shown that outcomes following resection of T4a and infranotch (inferior to mandibular notch) T4b are comparable. We discuss the concept of compartmental resection of LAOCSCC and issues concerning the management of the neck. Further, patients who refuse or are unable to undergo surgery can be treated with chemoradiotherapy with uncertain outcomes. The role of neoadjuvant chemotherapy has shown promise for organ (mandibular) preservation in a select subset of patients. CONCLUSION: The management strategy for LAOCSCC should be determined in a multidisciplinary setting with emphasis on tumor control, functional preservation, and quality of life of the patient.

When should patients with T1N0 oral squamous cell carcinoma be considered for elective neck dissection?

AIMS: To identify adverse pathological features (APF) predicting nodal failure in clinically node negative T1 oral squamous cell carcinoma (OSCC). METHODOLOGY: This study evaluated patients with T1N0 (≤5 mm depth of invasion (DOI) and ≤2 cm diameter) oral cancers from a prospectively maintained database between 1988 and 2020. All patients underwent surgical excision of the primary lesion without neck dissection. Patients underwent three monthly clinical surveillance and salvage neck dissection was performed if nodal relapse was diagnosed. RESULTS: Overall, 141 patients were included. Nodal relapse was reported in 16/141 (11.3%) patients. Factors impacting regional recurrence-free survival were DOI ≥3 mm (HR: 2.4, P < 0.001), maximum tumour diameter ≥12 mm (HR: 1.1, P = 0.009), perineural invasion (PNI) (HR 7.5, P = 0.002) and poor differentiation (HR 5.3, P = 0.01). Rates of nodal relapse increased from 2% amongst patients with no APFs to 100% for those with four APFs. Patients with two or more APFs had significantly poorer 5-year regional recurrence-free survival (94.8% vs. 56.3%, P < 0.001). CONCLUSION: Patients with T1N0 OSCC with two or more APFs (DOI ≥3 mm, diameter ≥12 mm, PNI or poor differentiations) should be considered for elective neck dissection.

Prognostic and predictive biomarkers in head and neck cancer: something old, something new, something borrowed, something blue and a sixpence in your shoe.

A biomarker is a measurable indicator of biological or pathological processes or the response to an exposure or intervention and is used to guide management decisions. In head and neck pathology, biomarkers are assessed by histological criteria and immunohistochemical and molecular studies. Surgical resection remains the mainstay of management of many head and neck malignancies. Adjuvant radiotherapy and/or systemic therapy may be administered depending on the presence of adverse prognostic factors identified on histopathological or immunohistochemical examination. In this review, we outline the clinically relevant prognostic and predictive factors in head and neck malignancies including conventionally recognised factors such as tumour size, depth of invasion, lymphovascular and perineural invasion and margin status as well as novel evolving factors such as recurrent genetic rearrangements and assessment of immune checkpoints. Practical issues are discussed to assist with recognising and reporting of these factors. A summary of useful tools such as structured pathology report formats is also included to assist with comprehensive reporting of all clinically relevant parameters, minimise risk and improve workflow efficiencies.

Associations between patient-level health literacy and diagnostic time intervals for head and neck cancer: A prospective cohort study.

BACKGROUND: Health literacy (HL) comprises skills and knowledge required to understand, access, and make decisions about healthcare. Our aim was to examine associations between patient HL and time intervals (defined in the Aarhus statement) along the pathway to treatment of head and neck cancer (HNC). METHODS: A prospective cohort study was conducted from October 2018 to March 2020. Participants completed the Health Literacy Questionnaire (HLQ®) and described key events and dates along the pathway to treatment using validated questionnaires. Correlations between six diagnostic time intervals and domains of HL were explored, and factors predicting exceeding maximum acceptable timeframes were assessed using logistic regression. RESULTS: One hundred patients with a diagnosis of HNC within the preceding 6 months were recruited. HLQ® Domain 2 (sufficient information to manage health) was significantly negatively associated with four intervals: the patient interval (first symptom to first presentation), primary care interval (first presentation to referral to secondary care), diagnostic interval (first presentation to diagnosis), and total interval (first symptom to treatment onset); correlation coefficients -0.25 to -0.27 (P < 0.05). Domain 8 (ability to find good information) was significantly negatively associated with three intervals (primary care interval, diagnostic interval, and total interval; correlation coefficients -0.23 to -0.34; P < 0.05). Higher education, age, and comorbidity levels were associated with shorter patient and diagnostic intervals. CONCLUSIONS: HL may be a potential target to improve timeliness of HNC diagnosis and reduce disparities in outcomes.

Ex vivo tissue modelling informs drug selection for rare cancers.

The identification and therapeutic targeting of actionable gene mutations across many cancer types has resulted in improved response rates in a minority of patients. The identification of actionable mutations is usually not sufficient to ensure complete nor durable responses, and in rare cancers, where no therapeutic standard of care exists, precision medicine indications are often based on pan-cancer data. The inclusion of functional data, however, can provide evidence of oncogene dependence and guide treatment selection based on tumour genetic data. We applied an ex vivo cancer explant modelling approach, that can be embedded in routine clinical care and allows for pathological review within 10 days of tissue collection. We now report that ex vivo tissue modelling provided accurate longitudinal response data in a patient with BRAFV600E -mutant papillary thyroid tumour with squamous differentiation. The ex vivo model guided treatment selection for this patient and confirmed treatment resistance when the patient's disease progressed after 8 months of treatment.

Management of Parastomal Recurrence Following Total Laryngectomy.

Parastomal recurrence occurs in around 5% of patients undergoing total laryngectomy for laryngeal squamous cell carcinoma. It carries a poor prognosis which has changed little over the last 50 years, and poses a significant challenge to the head and neck surgeon. At present, surgical excision offers the only realistic chance of cure, although patients must be selected carefully following thorough work-up and in-depth multidisciplinary team discussion. This article provides a review of the literature on the management of parastomal recurrence following total laryngectomy.

Patient-reported experiences and satisfaction with head and neck surgery outreach clinics in regional New South Wales, Australia: A cross-sectional survey.

RATIONALE: Head and neck surgery services are increasingly being centralised in Australia. Outreach models can overcome burdens of travel that patients in regional and rural areas experience when attending routine appointments, by providing services closer to home. AIM: To explore patient-reported experiences and satisfaction with regional outreach services for head and neck surgery in Australia. METHODS: Patients who attended two regional outreach clinics in New South Wales (NSW), Australia, were surveyed over a 6-month period. Patients completed the Outpatient Cancer Clinics Survey (2020 version) that explored perceptions and experiences of the clinic. Patients with cancer were asked to complete the Edmonton Symptom Assessment System and the Communication and Attitudinal Self-Efficacy scale. Descriptive statistics and analysis of data was performed, and results were compared to the NSW statewide Outpatient Cancer Clinics Survey (2020). Content analysis of free text responses was performed. RESULTS: Some 128 patients responded (56% response rate; mean age 67.2 years, 46.1% female). Compared to the 2020 NSW survey, a higher proportion of patients in our cohort responded positively to 14 of the 26 questions, with the greatest differences observed for questions regarding waiting area comfort (+12.1%, p = 0.008), being informed about different treatment options (+9.5%, p = 0.04), and issues relating to parking (+9.5%, p = 0.03). A lower proportion of our sample responded positively to the question about whether health professionals knew enough about their medical history (-19.3%, p < 0.001). Respondents appreciated having a local clinic that helped them avoid travel to major cities and associated expenses and highlighted benefits of expert consultation and timeliness of investigations. However, cost of appointments and level of reimbursements remain barriers for some patients. CONCLUSIONS: Patients had a high level of satisfaction with regional outreach clinics for head and neck surgery across most domains, indicating patients highly value this service.

Travel-associated cost savings to patients and the health system through provision of specialist head and neck surgery outreach clinics in rural New South Wales, Australia.

INTRODUCTION: Centralisation of head and neck surgical services means that patients in regional and remote Australia need to travel long distances for treatment and follow-up, imparting a significant financial burden on patients and the health system. OBJECTIVE: To estimate costs of travel to local outreach clinics and determine potential cost savings to patients and the health system by avoiding patient travel to major cities for head and neck surgical care. DESIGN: Retrospective audit of three head and neck surgery outreach clinics in New South Wales, Australia over 4 years (2017-2020). Direct costs of travel from a patient's residence to their local outreach clinic were estimated. Costs of travel and accommodation to Sydney for an appointment were calculated for different travel modes. Estimated reimbursements for travel through government support schemes were calculated based on published rates. FINDINGS: Some 657 patients attended the three clinics, accounting for 1981 appointments. Depending on mode of travel, the estimated median cost of return travel (including accommodation) to Sydney was $379 to $739 per patient per trip and the median government reimbursement ranged from $182 to $279 per trip. In comparison, the cost of return travel by car to local outreach clinics ranged from $28 to $163 per appointment. Outreach clinics were estimated to save patients a median of $285 per trip and avoided government reimbursements of $215 per trip. DISCUSSION: Despite uptake in telehealth, outreach medical services remain an important asset for people living in regional areas to address inequities in access. However, the cost benefits are likely to be underestimated as our approach did not account for indirect costs associated with travel. CONCLUSION: Outreach head and neck surgical services located in regional areas can reduce the financial burden on both patients and the healthcare system. Greater investment in outreach clinics could ensure sustainability of services to promote equitable access to specialised surgical services.

Persisting facial nerve palsy or trigeminal neuralgia - red flags for perineural spread of head and neck cutaneous squamous cell carcinoma (HNcSCC).

BACKGROUND: Perineural spread (PNS) of head and neck cutaneous squamous cell carcinoma (HNcSCC) is a unique diagnostic challenge, presenting with insidious trigeminal (CN V) or facial nerve (CN VII) neuropathies without clinically discernible primary masses. These patients are often sub-optimally investigated and misdiagnosed as Bell's palsy or trigeminal neuralgia. This case series highlights the red flags in history and pitfalls that lead to delays to diagnosis and treatment. METHODS: A retrospective case series of 19 consecutive patients with complete clinical histories with HNcSCC PNS without an obvious cutaneous primary lesion at time of presentation to a quaternary head and neck centre in Australia were identified and included for analysis. RESULTS: Fifteen had CN VII PNS, 17 had CN V PNS, and 13 had both. The overall median symptom-to-diagnosis time was 12-months (IQR-15 months). Eight patients had CN VII PNS and described progressive segmental facial nerve palsy with a median symptom-to-diagnosis time of 9-months (IQR-11.75 months). Eleven patients had primary CN V PNS and described well localized parathesia, formication or neuralgia with a median symptom-to-diagnosis time of 19-months (IQR 27.5 months). CONCLUSION: PNS is often mistaken for benign cranial nerve dysfunction with delays in diagnosis worsening prognosis. Red flags such as progressive CN VII palsy or persistent CN V paraesthesia, numbness, formication or pain, particularly in the presence of immuno-compromise and/or a history of facial actinopathy should raise suspicion for PNS. Gadolinium-enhanced MR Neurography should be obtained expediently in patients with persistent/progressive CN V/CN VII palsies in patients with red flags, with low threshold for referral to a Head and Neck Surgeon.

Pathologically Negative Excision for Biopsy-Proven Early Glottic Carcinoma.

In certain instances, patients who underwent endoscopic laser excision (ELE) for biopsy-proven early glottic carcinoma do not show any evidence of carcinomatous cells on histopathologic analysis. Our study aims to determine the incidence of this phenomenon. A retrospective analysis of patients with biopsy-proven early glottic squamous cell carcinoma who underwent ELE was conducted. 121 patients with a mean age of 68.2 ± 10.7 were included in this study. Initial biopsy showed carcinoma in situ in 38 patients, (31.4%), T1a in 41 patients (33.9%), and T1b in 42 patients (34.7%). Following ELE, a pathologically negative excision was seen in 26 patients (21.5%). Disease recurrence occurred in 3 patients who had a pathologically negative excision (11.5%). Following repeat ELE, all patients remained disease free. A significant number of early glottic carcinoma present with small volume disease which may be eradicated with diagnostic biopsy alone.

Treatment of Early Glottic cancer with Transoral Laser Microsurgery: An Australian Experience.

Introduction: Early laryngeal carcinomas may be treated by transoral laser microsurgery (TLM) or external beam radiotherapy. We review our experience of surgical treatment of laryngeal pre-malignant and malignant lesions over the past 15 years in a high-volume head neck unit. Methods: A review of a prospective patient database of patients with laryngeal SCC, who were treated with CO2 TLM between 2004 and 2019 was carried out. Results: 83 patients with a mean age of 67.7 (SD: 10.6) years underwent primary curative TLM for T1a/b SCC. 5-year overall survival was 93.2% (95%CI 86.9-100%), disease free survival was 86.0% (95%CI 78.1-94.6%), locoregional control was 91.2% (95%CI: 85.1-97.7%) and larynx preservation rate of 95.1% at 5 years. Conclusion: TLM is an excellent treatment modality for T1 early glottic SCC, with excellent locoregional control and disease-free survival. It is minimally invasive, outpatient-based, and cost-effective procedure preserving upper aerodigestive tract dysfunction for all activities of daily living.

The Utility of Near-Infrared Autofluorescence for Parathyroid Gland Identification During Thyroid Surgery: A Single-Center Experience.

Parathyroid gland injury during thyroid surgery is common and can lead to postoperative hypocalcemia. This study aims to determine the utility of near-infrared autofluorescence (NIRAF) technology for parathyroid gland identification in thyroid surgery. A prospective case series of patients who underwent thyroid surgery between March and June 2021 were examined. Following intra-operative visualisation, parathyroid glands and surrounding tissues were exposed to near-infrared light with a wavelength of approximately 800 nm using the Storz® Near-Infrared Range/Indocyanine Green (NIR/ICG) endoscopic system. Parathyroid glands were expected to show autofluorescence following exposure. Twenty patients who underwent thyroid surgery were included. Eighteen patients (90%) were female, with a median age of 50.0 (IQR 41.0 - 62.5). Surgeries performed include hemithyroidectomy (9 patients; 45.0%), total thyroidectomy (8 patients; 40.0%), completion thyroidectomy (2 patients; 10.0%) and right inferior parathyroidectomy (1 patient; 5.0%). Attempts were made to identify 56 parathyroid glands in this case series. There were 46/56 (82.1%) surgeon-identified parathyroid glands through direct visualisation. Using NIRAF technology, 39/46 (84.8%) were identified as parathyroid glands. There was no inadvertent resection of parathyroid glands or post-operative hypocalcaemia. NIRAF technology has the potential to be a useful tool in confirming the presence of parathyroid glands following direct visualisation intra-operatively.

Smell-related quality of life changes after total laryngectomy: a multi-centre study.

PURPOSE: A total laryngectomy creates an alternate airway for gas exchange that bypasses the upper aerodigestive tract. The subsequent reduction in nasal airflow, and therefore, reduction in deposition of particles to the olfactory neuroepithelium leads to hyposmia or anosmia. The aim of this study was to assess the quality of life impairment conferred by anosmia following laryngectomy and identify any specific patient-related risk factors that are associated with poorer outcomes. METHODS: Consecutive patients with a total laryngectomy presenting for review at three tertiary head and neck services (in Australia, the United Kingdom and India) over a 12-month period were recruited. Patient demographic and clinical data were collected, and each subject completed the validated assessment of self-reported olfactory functioning and olfaction-related quality of life questionnaire (ASOF). Dichotomous comparisons were performed using the student's unpaired t-test for continuous variables (SRP), a chi-squared test for categorical variables, and a Kendall's tau-b for ordinal variables (SOC) to assess for a correlation with poorer questionnaire scores. RESULTS: A total of 66 laryngectomees (13.4% female; age 65.7 ± 8.6 years) were included in the study. The mean SRP score of the cohort was found to be 15.6 ± 7.4, while the mean ORQ score was noted to be 16.4 ± 8.1. No other specific risk factors associated with poorer quality of life were identified. CONCLUSION: A significant quality of life detriment from hyposmia is conferred following laryngectomy. Further research to assess treatment options and the patient population that would best benefit from these interventions is required.

Comparing Genomic Landscapes of Oral and Cutaneous Squamous Cell Carcinoma of the Head and Neck: Quest for Novel Diagnostic Markers.

Squamous cell carcinoma is the most common head and neck malignancy arising from the oral mucosa and the skin. The histologic and immunohistochemical features of oral squamous cell carcinoma (OSCC) and head and neck cutaneous squamous cell carcinoma (HNcSCC) are similar, making it difficult to identify the primary site in cases of metastases. With the advent of immunotherapy, reliable distinction of OSCC and HNcSCC at metastatic sites has important treatment and prognostic implications. Here, we investigate and compare the genomic landscape of OSCC and HNcSCC to identify diagnostically useful biomarkers. Whole-genome sequencing data from 57 OSCC and 41 HNcSCC patients were obtained for tumor and matched normal samples. Tumor mutation burden (TMB), Catalogue of Somatic Mutations in Cancer (COSMIC) mutational signatures, frequent chromosomal alterations, somatic single nucleotide, and copy number variations were analyzed. The median TMB of 3.75 in primary OSCC was significantly lower (P < .001) than that of 147.51 mutations/Mb in primary HNcSCC. The COSMIC mutation signatures were significantly different (P < .001) between OSCC and HNcSCC. OSCC showed COSMIC single-base substitution (SBS) mutation signature 1 and AID/APOBEC activity-associated signature 2 and/or 13. All except 1 HNcSCC from hair-bearing scalp showed UV damage-associated COSMIC SBS mutation signature 7. Both OSCC and HNcSCC demonstrated a predominance of tumor suppressor gene mutations, predominantly TP53. The most frequently mutated oncogenes were PIK3CA and MUC4 in OSCC and HNcSCC, respectively. The metastases of OSCC and HNcSCC demonstrated TMB and COSMIC SBS mutation signatures similar to their primary counterparts. The combination of high TMB and UV signature in a metastatic keratinizing squamous cell carcinoma suggests HNcSCC as the primary site and may also facilitate decisions regarding immunotherapy. HNcSCC and OSCC show distinct genomic profiles despite histologic and immunohistochemical similarities. Their genomic characteristics may underlie differences in behavior and guide treatment decisions in recurrent and metastatic settings.

MYB RNA detection by in situ hybridisation has high sensitivity and specificity for the diagnosis of adenoid cystic carcinoma.

Adenoid cystic carcinoma (ACC) is one of the most common primary salivary gland cancers. ACC has several benign and malignant mimics amongst salivary gland neoplasms. An accurate diagnosis of ACC is essential for optimal management of the patients and their follow-up. Upregulation of MYB has been described in 85-90% of ACC, but not in other salivary gland neoplasms. In ACC, MYB upregulation can occur as a result of a genetic rearrangement t(6;9) (q22-23;p23-24), MYB copy number variation (CNV), or enhancer hijacking of MYB. All mechanisms of MYB upregulation result in increased RNA transcription that can be detected using RNA in situ hybridisation (ISH) methods. In this study, utilising 138 primary salivary gland neoplasms including 78 ACC, we evaluate the diagnostic utility of MYB RNA ISH for distinguishing ACC from other primary salivary gland neoplasms with a prominent cribriform architecture including pleomorphic adenoma, basal cell adenoma, basal cell adenocarcinoma, epithelial myoepithelial carcinoma, and polymorphous adenocarcinoma. Fluorescent in situ hybridisation and next generation sequencing were also performed to evaluate the sensitivity and specificity of RNA ISH for detecting increased MYB RNA when MYB gene alterations were present. Detection of MYB RNA has 92.3% sensitivity and 98.2% specificity for a diagnosis of ACC amongst salivary gland neoplasms. The sensitivity of MYB RNA detection by ISH (92.3%) is significantly higher than that of the FISH MYB break-apart probe (42%) for ACC. Next generation sequencing did not demonstrate MYB alterations in cases that lacked MYB RNA overexpression indicating high sensitivity of MYB RNA ISH for detecting MYB gene alterations. The possibility that the sensitivity may be higher in clinical practice with contemporary samples as compared with older retrospective tissue samples with RNA degradation is not entirely excluded. In addition to the high sensitivity and specificity, MYB RNA testing can be performed using standard IHC platforms and protocols and evaluated using brightfield microscopy making it a time and cost-efficient diagnostic tool in routine clinical practice.

Outcomes of immediate dental implants in vascularised bone flaps for mandibular reconstruction.

BACKGROUND: The aim of this study is to assess the outcomes of immediate implant placement for dental rehabilitation following mandibular reconstruction with vascularised bone flaps in a single Australian tertiary cancer centre. METHODS: A retrospective analysis of patients who underwent immediate dental implant or delayed placement in vascularised bone flaps was performed. Primary outcome measures assessed included the number of implants placed, operative time, complication rates, time to radiotherapy initiation, dental rehabilitation rates and time to dental rehabilitation. RESULTS: In total, 187 dental implants were placed in 52 patients, of which 34 patients underwent immediate implant placement and 18 had delayed implant placement. There were no significant differences in the postoperative complication rate (32% immediate vs. 33% delayed, P = 0.89) or time to postoperative radiotherapy (median 42 days immediate vs. 47 days delayed, P = 0.24). Dental rehabilitation was achieved in 62% of the immediate cohort versus 78% of the delayed cohort. The time to be fitted with a dental prosthesis was significantly shorter in the immediate cohort (median 150 days immediate vs. 843 days delayed, P = 0.002). CONCLUSIONS: The placement of immediate dental implants at the time of primary reconstruction of the mandible is a safe procedure and facilitates timely dental rehabilitation.

Interventions to reduce times to diagnosis and treatment of head and neck cancer: A systematic review and narrative synthesis.

BACKGROUND: We systematically reviewed evidence of health system interventions to reduce diagnostic and treatment intervals for people with head and neck cancer (HNC). METHODS: Electronic databases were searched from inception to 30 April 2020 for controlled or uncontrolled comparative studies. Primary outcome was any time interval between first clinical presentation and treatment onset. RESULTS: Thirty-seven studies were included. Four types of interventions were identified: single clinic-based (N = 4), multidisciplinary clinic-based (N = 15), hospital or service re-design (N = 12), and health system re-design (N = 6). There was some evidence that multidisciplinary interventions improve timeliness of diagnosis and treatment; however, evidence of long-term effectiveness was lacking. Study quality was assessed as either low or moderate. CONCLUSIONS: Interventions to reduce times to diagnosis and treatment of HNC are heterogeneous, with limited evidence of effectiveness. Future interventions should account for the complex and dynamic nature of health systems and adhere to best-practice principles for early-diagnosis research.