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INTRODUCTIONThe incidence and mortality rates of laryngeal cancer are high worldwide, with an estimated 184 615 new cases diagnosed and 99 840 deaths occurring in 2020.1 Laryngeal cancer affects the glottis in 70% of cases, but can also affect the supraglottis and subglottis. Squamous cell carcinoma (SCC) is its main histopathological type.2,3The application of the American Joint Committee on Cancer's TNM staging system for glottic cancer is crucial for the selection of the most appropriate treatment option.4 Glottic SCC can be treated with the individual or combined application of surgery, radiotherapy (RT), and chemotherapy. Surgery and RT are the two options for early‐stage (T1–T2) glottic cancer and, because nodal disease at these stages is rare, survival rates are high (90% for patients receiving RT, 93% for those undergoing transoral microsurgery).5,6 Although treatment choices depend on institutional human and technological resources and patient factors, transoral microsurgery with preservation of the larynx yields better functional and quality of life (QoL) outcomes.5,7 Traditional oncological protocols for advanced (stage III–IV) glottic cancer include techniques such as total laryngectomy and postoperative RT or non‐surgical therapy (chemotherapy). Overall and disease‐specific survival rates have been better following total laryngectomy than after non‐surgical therapy,8 but current evidence shows that induction chemotherapy followed by RT yields superior clinical outcomes due to decreased morbidity and organ preservation.7,9The National Comprehensive Cancer Network (NCCN) has developed clinical practice guidelines for the screening, prevention, diagnosis, treatment, and follow‐up of different types of cancer, including head and neck cancers. Recommendations in these guidelines are updated frequently following the critical review of newly published high‐level evidence and the establishment of consensus by multidisciplinary panels of experts, thereby providing appropriate orientation for decision making about oncological care.10,11 Head and neck cancer treatment protocol recommendations may differ according to country‐specific conditions, but the overall standardization of recommendations underpinned by high‐level scientific evidence and improvements in clinical outcomes is needed to reduce discrepancies in patients' clinical responses.12Clinical scenarios for decision making about glottic cancer treatment, including patient preferences and institutional conditions, often reveal challenges. The possibility of the occurrence of morbidities associated with essential functions, such as the loss of the natural voice, breathing, and airway protection during swallowing, should be evaluated carefully.13 Divergent survival and clinical outcomes of various oncological protocols have been reported, creating controversy about treatment choices, especially regarding organ preservation in patients with advanced (T3–T4) glottic cancer and well‐documented reductions in survival rates.8,14–17 Thus, the main goal of the present review was to describe the main changes made to the NCCN guidelines for glottic cancer treatment published between 2011 and 2022, as these guidelines serve as the reference in many institutions treating head and neck cancer worldwide. Secondary objectives were to describe the main features of references used in NCCN guideline development and relevant PubMed‐registered literature from 2011 to 2022, to provide an overview of published evidence for glottic cancer treatment types and oncological outcomes.METHODSSearch strategyThe NCCN Clinical Practice Guidelines (NCCN Guidelines®) for Head and Neck Cancers published between 2011 and 2022 in the Journal of the National Comprehensive Cancer Network were obtained by a search using keywords such as “guidelines,” “head and neck,” “larynx,” and “glottis.” Archived guidelines that were not available in the journal were requested via the NCCN website (www.NCCN.org).A systematic search of the PubMed database was performed to identify reports on randomized controlled trials (RCTs), systematic reviews (SRs), and meta‐analyses (MAs) published between 2011 and 2022 that provided data on functional (voice, swallowing, QoL) and survival outcomes for glottic SCC by treatment modality (Table A1). Exclusion criteria were applied for: (1) studies other than treatment of glottic cancer; (2) glottic cancer treatment focusing on recurrence or rehabilitation; (3) studies without functional (voice, swallowing, QoL) and survival outcomes; (4) non‐SCC on the glottic larynx or SCC involving other than glottis; and (5) observational studies, case reports, series reports, narrative literature reviews, guidelines, and letters to the editor.Data extractionData recording and descriptive analysis were performed using Excel software (Microsoft Corporation, Redmond, WA, USA). The following information was extracted from the NCCN guidelines: year, version, updates, characteristics of the references on glottic cancer treatment used (authors, publication year, country, study design), and recommended treatment algorithms for all clinical stages of glottic cancer. For the publications obtained by PubMed database search, the authors, publication year, country, study design, clinical stage, outcomes, treatment modality, and main results were extracted.RESULTSIn total, 24 updates of the NCCN guidelines were published between 2011 and 2022, with the number published varying among years. They contained mainly workup recommendations; descriptions of the principles of surgery, RT, and systemic therapy (ST); wording on clinical stages; primary and neck treatment pathways; descriptions of adverse features; and categories of evidence and preference. The largest numbers of changes occurred between 2013 and 2014 and between 2018 and 2019 (Table 1).1TABLEMajor changes in NCCN guideline recommendations for glottic cancer treatment, 2011–2022.Type of changeEarlyAdvancedVery advancedCarcinoma in situAmenable to larynx‐preserving (conservation) surgery (T1–T2, N0 or select T3, N0)T3 requiring (amenable to) total laryngectomy (N0–1)T3 requiring (amenable to) total laryngectomy (N2–3)T4a diseaseT4b, N0–3 or unresectable nodal disease or unfit for surgeryMetastatic (M1) disease at initial presentationClinical staging‐2012, 2013, 2015, 201920132013‐20192019Primary and neck treatmentTreatment pathway options2012‐2013, 2014‐‐2013, 2020, 20212013, 2021, 2022Surgical pathway recommendations‐2014, 2015, 20162011, 2013, 2015, 2018, 20192013, 2016, 20182012, 2018, 2019, 2020‐‐Category of evidence and preference2014‐2019201420142019‐Response after induction chemotherapy‐‐‐2014, 2017, 20182014, 2017, 2018‐‐Adjuvant treatmentNo adverse/adverse features‐2012, 2013, 20142017‐2018‐‐Pathway recommendations‐‐‐‐2012, 2017‐‐GeneralWorkup (2012, 2019, 2022), principles of surgery (2016, 2018, 2019, 2021, 2022), principles of radiation therapy (2011, 2014, 2019), principles of systemic therapy (2012, 2013, 2018, 2019, 2021, 2022).The main changes to workup recommendations pertain to the need for radiological imaging according to the clinical stage of glottic cancer. Currently, chest computed tomography (CT, with or without contrast), fluorodeoxyglucose positron emission tomography/CT, and pulmonary function evaluation are recommended for conservation surgery candidates. Diagnosis still requires full history taking and physical examination, biopsy of the primary tumor site or fine needle aspiration of the neck, CT with contrast and thin angled cuts through larynx, and/or magnetic resonance imaging of the primary site and neck.The main changes in glottic cancer treatment pathways are described by clinical stage in Table 2. For carcinoma in situ (Tis), clinical trials were removed as an option for treatment delivery, and endoscopic resection was deemed the preferred treatment. For stage T1–T2 and select stage T3 N0 cases, neck dissection (as indicated) was recommended and a new pathway based on adverse features was provided. For stage T3 N0–1 cases, two new pathways for primary and neck treatment (involving induction chemotherapy and clinical trials) were provided and the surgical recommendations were modified to favor pretracheal and ipsilateral paratracheal lymph‐node dissection. For patients receiving concurrent ST and RT, the adjuvant therapy pathway was removed. For stage T3 N2–3 cases, pretracheal and ipsilateral paratracheal lymph‐node dissection was recommended. The evidence category for induction chemotherapy was changed from 3 to 2A, and clinical trials have been recommended as an option for treatment delivery since 2015. Treatment pathways according to induction chemotherapy responses were modified significantly, and the evidence categories for RT in cases of complete response and ST/RT in cases of partial response were changed to 1 and 2B, respectively. For T4a N0–3 cases, the surgical and adjuvant treatment recommendations were changed considerably, with pretracheal and ipsilateral paratracheal lymph‐node dissection recommended and postoperative adjuvant treatment pathways provided according to adverse features. The category of evidence for induction chemotherapy for patients declining surgery was changed from 2B to 2A. For T4b N0–3 cases, recommendations based on patients' performance status (PS) were changed, and the evidence categories for concurrent ST and RT and induction ST followed by RT or concurrent ST and RT for patients with PSs of 0–1 were changed from 1 and 3, respectively, to 2A. Palliative RT was added as an option for patients with PSs of 3. For glottic cancer that is metastatic (M1) at initial presentation, a new algorithm was provided in 2015.2TABLENCCN guideline recommendations for glottic cancer treatment, 2011–2022.StagePrimary treatmentYearsNeck treatmentYearsAdjuvant treatmentYearsTis1. ER2011–2022‐‐‐‐Preferred2014–20222. RT2011–20223 Clinical trial2011–2012T1–2 N0, selected T31. RT2011–2022Follow‐up:2014–20222. Partial laryngectomy with ER or open resection (as indicated)2011–2022Neck dissection as indicated2015–2022No adverse feature: observation2014–2022Adverse features:Extranodal extension: ST/RT (category 1)Positive margins: re‐resection or RTOther risk features: RT2014–2022T3 N0–11. Concurrent ST/RT or, if not candidate, RT2011–2022Follow‐up neck evaluation:2017–20222. Laryngectomy2011–2022N0: ipsilateral thyroidectomy (as indicated), pretracheal and ipsilateral paratracheal lymph‐node dissectionN1: also ipsilateral or bilateral neck dissection2018–2022No adverse feature: observationAdverse features:Extranodal extension and/or positive margins: ST/RT (category 1)Other risk features: RT or consider ST/RT2011–20223. Induction chemotherapy2014–2022CT or MRI (with contrast) of primary site and neck2014–2022CR: definitive RT (category 1)PR: RT (category 1) or ST/RT (category 2B)<PR: laryngectomy or unresectable nodal disease2014–20224. Clinical trials2013–2022T3 N2–31. Concurrent ST/RT2011–2022Follow‐up neck evaluation:2018–20222. Laryngectomy2011–2022Thyroidectomy, ipsilateral or bilateral neck dissection, pretracheal and ipsilateral paratracheal lymph‐node dissection2018–2022No adverse feature: follow‐upAdverse features:Extranodal extension and/or positive margins: ST/RT (category 1)Other risk features: RT or consider ST/RT2011–20223. Induction chemotherapy2011–2022CT or MRI (with contrast) of primary site and neck2018–2022CR: definitive RT (category 1)PR: RT (category 1) or ST/RT (category 2B)<PR: laryngectomy or unresectable nodal disease2017–20224. Clinical trials2015–2022T4a, N0–31. Surgery: Total laryngectomy2. For selected T4a patients who decline surgery:Consider concurrent ST/RTClinical trial for function‐preserving surgical or nonsurgical managementInduction chemotherapy2011–20222011–20222015–2022N0: thyroidectomy ± unilateral or bilateral neck dissection, pretracheal and ipsilateral paratracheal lymph‐node dissectionN1: thyroidectomy, ipsilateral or bilateral neck dissection, pretracheal and ipsilateral paratracheal lymph‐node dissectionN2–3: total laryngectomy with thyroidectomy, ipsilateral or bilateral neck dissection, pretracheal and ipsilateral paratracheal lymph‐node dissection2018–2022No adverse features: follow‐upAdverse features:Extranodal extension and/or positive margins: ST/RT (category 1)Other risk features: RT or consider ST/RT2018–2022T4b any N, unresectable nodal disease or unfit for surgery1. Clinical trial preferred2. Standard therapyPS 0–1: concurrent ST/RT or induction ST + RT or ST/RTPS 2: RT or concurrent ST/RTPS 3: palliative RT, single‐agent ST, or best supportive care2011–20222011–20222021–2022Individual decisionTumor board discussionMetastatic (M1) disease at initial presentation1. Clinical trial preferred2. Consider locoregional treatment based on primary site algorithms3. Standard STPS 0–1: combination ST, single‐agent ST, surgery or RT, ST/RT for selected cases with limited metastases, or best supportive carePS 2: single‐agent ST, best supportive care, palliative RT, or palliative surgeryPS 3: best supportive care, palliative RT, or palliative surgery2015–20222015–20222021–2022Individual decisionTumor board discussionST, clinical trial preferred or palliative RT or best supportive careBest supportive care, alternate single‐agent ST, or palliative RT2022Abbreviations: CR, complete response; CT, computed tomography; ER, endoscopic resection; MRI, magnetic resonance imaging; PR, partial response; PS, performance status; RT, radiation therapy; ST, systemic therapy.A total of 19 studies [8 RCTs,9,18–24 4 observational studies,25–28 3 SRs,29–31 2 cohort studies,32,33 1 narrative review,34 and 1 MA35] contributed to the updating of the NCCN guidelines between 2011 and 2022. The SRs and MA were included as references in the guidelines in recent years. The studies were performed in the United States,9,19–21,33,34 United Kingdom,26,29,30 Switzerland,18,25,28 Germany,27,32 France,22,23 China,35 Canada,31 and Japan24 (Figure 1).1FIGUREOverview of countries in which researchers have contributed to the scientific literature on laryngeal glottic cancer treatment identified by PubMed search (A) and cited in the NCCN guidelines (B), 2011–2022.The PubMed database search yielded a total of 260 studies (Table A1), of which 68 (26 MAs, 24 RCTs, and 18 SRs) fulfilled the selection criteria.9,13–15,29–31,33,35–94 The countries in which the largest numbers of studies were performed were China (n = 18), the United Kingdom (n = 6), and Italy (n = 5; Figure 1). The main characteristics of the included publications are summarized in Table 3. The treatment of early‐stage glottic cancer, was examined in 44 studies,29–31,35–38,40,41,45,46,48,50–59,62,64,65,71,72,74–77,79–82,89–94 mainly with transoral laser microsurgery and RT modalities (Figure 2).3TABLEMain characteristics of glottic cancer treatment publications registered in the PubMed database, 2011–2022.Authors, yearCountryDesignClinical stageIntervention(s)/treatment(s)Outcome(s)Main finding(s)García‐León et al. 201713SpainSRAdvanced laryngeal cancerOrgan preservation (chemotherapy), surgeryQoLTreatment‐related differences in QoL of patients with advanced laryngeal cancer cannot be established due to insufficient number of studiesForastiere et al. 20139USARCTAdvanced laryngeal cancerInduction chemotherapy (cisplatin/fluorouracil) and RT, concomitant cisplatin/RT, RT aloneLaryngectomy‐free survivalLocoregional control and larynx preservation significantly improved with concomitant cisplatin/RT compared with induction chemotherapy and RT aloneMannelli et al. 201814ItalyMAAdvanced laryngeal cancerTransoral laser, open partial laryngectomySurvival, local controlBoth techniques valid conservative surgical options for advanced laryngeal cancer treatmentLi et al. 201966ChinaMAAdvanced laryngeal cancerPostoperative adjuvant RTSurvivalPostoperative adjuvant RT improved survival of patients with surgically managed locally advanced laryngeal cancerFrancis et al. 201415LebanonSRAdvanced laryngeal cancerPrimary total laryngectomy, neck dissection with adjuvant therapy (chemotherapy, RT) when indicatedSurvivalHigh survival rate for primary total laryngectomy for pT4a casesKhoueir et al. 201563LebanonSRAdvanced laryngeal cancerPrimary total laryngectomySurvivalSurvival better for T4a N0 than T3 N+, especially T3 N2, despite grouping in the same TNM stage IVaBadwal 201839IndiaSRAdvanced laryngeal cancerTotal laryngectomySurvivalTotal laryngectomy remains gold standard for T4a laryngeal cancer managementSingh et al. 201883IndiaRCTAdvanced laryngeal cancerConcurrent chemotherapy/RT‐‐Luo et al. 201567ChinaMAAdvanced laryngeal cancerTotal laryngectomy followed by RT, three larynx‐preserving strategiesSurvivalDisease‐free survival better for laryngectomy than for chemotherapy and RT, overall survival similar in all groupsRiga et al. 201778GreeceSRAdvanced laryngeal cancerOpen partial laryngectomy, transoral laser microsurgery, RT with/without chemotherapySurvivalSurvival, organ preservation rates high with partial laryngectomy, microsurgery; preoperative induction chemotherapy compromises overall survivalTang et al. 201887ChinaMAAdvanced laryngeal cancerTotal laryngectomy, nonsurgical organ‐preservation strategiesSurvival, local controlResults support total laryngectomy for T4 tumors, no advantage of primary organ preservation, no difference in overall survival for T3 tumorsMa et al. 201369ChinaMAAdvanced laryngeal cancerInduction chemotherapySurvivalNo difference in overall survival, disease‐free survival, locoregional recurrence with/without induction chemotherapyNutting et al. 202173United KingdomRCTAdvanced laryngeal cancerDose‐escalated, standard‐dose intensity‐modulated RTLocal controlDose escalation did not improve locoregional control of laryngeal or hypopharyngeal cancerSwiecicki et al. 202286USARCTAdvanced laryngeal cancerInduction chemotherapy (platinum, docetaxel, novel Bcl‐xL inhibitor)Organ preservationNo difference in laryngeal preservation between one and two cyclesBonner et al. 201642Spain, Germany, USARCTAdvanced laryngeal cancerCetuximab/RT, RT aloneLaryngeal preservation, laryngectomy‐free survival2‐year laryngeal preservation rates 87.9% with, 85.7% without cetuximab; no difference in overall QoL, feeding tube requirement, or speechMesía et al. 201770SpainRCTAdvanced laryngeal cancerInduction chemotherapy (docetaxel, cisplatin, 5‐fluorouracil) followed by bio‐RTFunctional larynx preservationSurvival with functional larynx better than critical value with acceptable toxicity; cetuximab with RT could improve functional larynx preservation in patients with stage III, IVA laryngeal cancer who respond to induction chemotherapyStokes et al. 201733USARCTAdvanced laryngeal cancerSurgical, organ‐preservation modalities (RT, chemotherapy)SurvivalOverall survival better with surgery/adjuvant RT than with concurrent chemotherapy/RT but not different from induction chemotherapy/RT; findings require validation, surgery with adjuvant RT should remain standard of care; organ preservation with induction chemotherapy and RT may be reasonable alternative for certain patientsFu et al. 201649ChinaMAAdvanced laryngeal cancerTotal laryngectomy, nonsurgical organ‐preservation (chemotherapy, RT)Local control, survivalTrend toward better overall, disease‐specific survival for total laryngectomy, but no clear difference in oncological outcomes; other factors (T‐stage, tumor size, lymph node metastasis, physical condition) also important indicators for treatment choicesJanssens et al. 201660NetherlandsRCTAdvanced laryngeal cancerAccelerated RT with/without carbogen, nicotinamideQoLGood local tumor control, speech, swallowing function with accelerated RT; one‐quarter of patients have long‐term dry mouth, sticky saliva, taste/smell changesBottomley et al. 201443BelgiumRCTAdvanced laryngeal cancerSequential induction, alternating chemotherapy/RTQoLTrend toward worse scores with alternating chemoradiotherapy but very few significant differences; most patients' health‐related QoL scores returned to baseline after therapyShapira et al. 202281IsraelMAEarly glottic cancerOpen, trans‐oral salvage partial laryngectomyLaryngectomy‐free survivalHigh survival rates for open (90.4%) and trans‐oral (78.6%) techniques in well‐selected patients after RT failureCampo et al. 202245ItalySREarly glottic cancerOpen partial laryngectomy, total laryngectomySurvivalHigh success of open partial laryngectomy for selected pT3 cases, accurate selection of cases amenable to conservative surgery importantKachhwaha et al. 202162IndiaRCTEarly glottic cancerHypofractionated, conventional RTSurvivalNo difference in overall survival, hypofractionated regimen provides better local control, symptomatic relief with shorter treatment timeFeng et al. 201148ChinaMAEarly glottic cancerLaser surgery, RTOncological outcomesNo difference in cure rate, inconclusive voice preservation resultsRodrigo et al. 201979Spain, Germany, Belgium, Slovenia, Italy, USASREarly glottic cancerTransoral laser microsurgerySurvival5‐year disease‐specific survival 95%, overall survival 68%, laryngectomy‐free survival 88%; procedure safe and effective for cases with few complications, good local control (>85%) and disease‐specific survival (>90%)Mo et al. 201735ChinaMAEarly glottic cancerTransoral laser microsurgery, RTOncological outcomes, QoLBetter overall survival and laryngeal preservation with laser surgery than with RT, no difference in local controlvan Loon et al. 201292NetherlandsSREarly glottic cancerLaser surgery, RTFunctional outcomes, QoLOnly voice, QOL outcomes reported; heterogeneity of outcome measures prevented data pooling; uncertainty about tumor comparability (depth, extent), small samples, poor reporting hindered interpretationPakkanen et al. 202275FinlandRCTEarly glottic cancerTransoral laser microsurgery, RTSurvival, larynx preservationSimilar results for both treatment modalitiesGioacchini et al. 201750ItalySREarly glottic cancerTransoral laser microsurgery, RT, open partial laryngectomySurvivalBetter disease‐free survival with RT (87%), open partial laryngectomy (83%) than with transoral laser microsurgery (77%)Reinhardt et al. 202277SwitzerlandRCTEarly glottic cancerSingle vocal cord irradiation, transoral CO₂‐laser microsurgical cordectomyFunctional, oncological outcomes‐Huang et al. 202258ChinaMAEarly glottic cancerLaser surgery, RTSurvivalBetter survival of T1a N0 M0 glottic cancer with laser surgeryHuang et al. 201755ChinaMAEarly glottic cancerLaser surgery, RTOncological outcomesIncreased larynx preservation with laser surgery, no difference in local control, overall survival, or disease‐specific survivalZhou et al. 202194ChinaMAEarly glottic cancerTransoral laser microsurgery with/without anterior commissure involvementSurvivalMore local recurrence, less laryngeal preservation likely with anterior commissure involvement, no difference in 5‐year overall survivalWarner et al. 201429United KingdomSREarly glottic cancerRT, open surgery, endolaryngeal surgery with/without laserSurvivalNo difference in 5‐year survival after RT and surgery (91.7% and 100% for T1 tumors, 88.8% and 97.4% for T2 tumors); 5‐year disease‐free survival after RT and surgery 71.1% and 100.0% for T1 tumors, 60.1% and 78.7% for T2 tumorsTulli et al. 202090ItalyMAEarly glottic cancerSurgery with anterior commissure involvementLocal controlAnterior commissure involvement negative prognostic factor for local control of T1 tumors at 5 years, needs to be considered in T staging of glottic tumorsWarner et al. 201730United KingdomSREarly glottic cancerTransoral laser microsurgery, external beam RTLocal control5‐year local control similar (weighted averages, 75.81% for RT, 77.26% for microsurgery)Benson et al. 202041IndiaMAEarly glottic cancerModerately hypofractionated RTLocal control, survivalSignificantly improved local control vs. conventional fractionation, no impact on overall survivalCampo et al. 202146ItalySREarly glottic cancerCO₂ transoral laser microsurgery, RT, open partial laryngectomySurvivalBetter local control at 5 years posttreatment with open partial laryngectomy (94.4%), no difference between RT (75.6%) and laser surgery (75.4%); better laryngeal preservation with primary open partial laryngectomy (95.8%) and laser surgery (86.9%) than with RT (82.4%) primary treatmentHuang et al. 201757ChinaMAEarly glottic cancerLaser surgery, RTLarynx preservation, local control, survivalBetter larynx preservation with RT for T1a tumors, no difference in overall or disease‐ specific survivalAbdurehim et al. 201237ChinaMAEarly glottic cancerTransoral laser surgery, RTOncological, functional outcomesNo difference in local control, overall survival, disease‐specific survival, posttreatment voice quality; better larynx preservation with laser surgery as initial treatmentHendriksma et al. 201853NetherlandsSREarly glottic cancerTransoral CO₂ laser microsurgery, RTFunctional outcomesBetter laryngeal preservation with microsurgery for T2 tumors (88.8% vs. 79.0%); differentiation of tumors with normal (T2a), impaired (T2b) mobility important because the latter have poorer prognosis with microsurgery and RT; with adequate staging and treatment, anterior commissure involvement does not compromise oncological outcomesYoo et al. 201431CanadaSREarly glottic cancerEndolaryngeal surgery with/without laser, RTLocal control, survivalNo difference in likelihood of local control, overall survival; less measurable voice perturbation with RT, no difference in patient perception; initial surgical treatment may increase likelihood of laryngeal preservationGreulich et al. 201551USAMAEarly glottic cancerTransoral laser microsurgery, RTVoice outcomesNo difference in VHI scores for T1 tumors, suggesting no clinically significant difference in functional voice outcomesVaculik et al. 201991CanadaMAEarly glottic cancerCO₂ transoral laser microsurgery, RTOncological outcomesBetter overall survival, disease‐specific survival, laryngeal preservation with microsurgeryO'Hara et al. 201374United KingdomSREarly glottic cancerTransoral laser surgery, RTLocal control3‐year local control rates with laser surgery and RT 88.9% and 89.3% for T1a tumors, 76.8% and 86.2% for T1b tumorsBahig et al. 202140Canada, USARCTEarly glottic cancerVocal cord–only, complete laryngeal radiationVoice outcomes‐Huang et al. 201756ChinaMAEarly glottic cancerLaser surgery, RTVoice outcomesRT increased maximum phonation time, decreased fundamental frequency; no difference in VHI score, jitter, shimmer, or airflow rateHuang et al. 201759ChinaMAEarly glottic cancerLaser surgeryVoice outcomesReduced postoperative VHI, GRABS scores; improved overall postoperative vocal‐cord function and QoL, but not early postoperative vocal‐cord function or physiologySapienza et al. 201980Brazil, USA, JapanMAEarly glottic cancerAltered, conventional fractionation RTLocal controlHypofractionation, hyperfractionation improved local control of T1 tumors and with anterior commissure involvement, but benefit may not persist for T2 tumors (consider alternative strategies)Guimarães et al. 201852BrazilMAEarly glottic cancerTransoral laser surgery, RTOncological, functional outcomesBetter overall survival, disease‐specific survival, laryngeal preservation with laser surgery, no difference in local controlKodaira et al. 201864JapanRCTEarly glottic cancerAccelerated‐, standard‐fractionation RTSurvivalNo difference in 3‐year overall survivalAaltonen et al. 201436FinlandRCTEarly glottic cancerCO₂ laser surgery, external beam RTVoice outcomesSimilar overall voice quality; RT may be treatment of choice for patients with demanding voice quality requirementsNasef et al. 201672EgyptRCTEarly glottic cancerTransoral laser microsurgery, external vertical hemilaryngectomyFunctional outcomesBetter overall postoperative outcome with microsurgery, with shorter hospital stays, less need for tracheostomy, nasogastric tube, ICU admissionShe et al. 201582ChinaMAEarly glottic cancerCO₂ laser surgeryOncological outcomesPostoperative local recurrence rate related to anterior commissure involvementZhang et al. 201893ChinaRCTEarly glottic cancerCO₂ laser microsurgery, low‐temperature plasma radiofrequency ablationVoice outcomesBoth treatments effective for T1a tumors; potential advantages of radiofrequency ablation for voice functionTrotti et al. 201489Canada, USARCTEarly glottic cancerHyperfractionation, conventional fractionation RTLocal controlNonsignificantly better 5‐year local control with hyperfractionation for T2 tumorsHiggins 201154CanadaMAEarly glottic cancerTransoral CO₂ laser excision, external beam RTLocal control, voice outcomesNo difference in local control, laryngectomy‐free survival, or voice qualityAl Afif et al. 202238CanadaRCTEarly glottic cancerHyaluronic acid injection during transoral laser microsurgeryVoice outcomesNo significant impact on subjective, objective voice outcomesQu et al. 201276ChinaMAEarly glottic cancerExternal radiation, transoral laser surgery‐Transoral laser surgery much less expensive, could be completed in the clinicMoon et al. 201471Republic of KoreaRCTEarly glottic cancerHypofractionation, conventional fractionation RTLocal control, survivalHypofractionation RT not inferior, similar toxicity profile, potentially better local control, shortened overall treatment time for T1–2 tumorsLahav et al. 202065IsraelRCTEarly glottic cancerCO₂ laser cordectomy, KTP laser surgeryOncological, functional outcomesKTP ablation has similar curative outcome, potentially better preservation of vocal fold architecture and function; clinical significance of findings unclearThomas et al. 201288United KingdomSREarly laryngeal cancerOpen partial laryngectomyLocal control, survival89.8% local control at 24 months, 79.7% overall survival, 84.8% disease free survival (n = 5061)Ding & Wang 201947ChinaMAGlottic cancerLaser surgery, RTLocal control, survivalBetter laryngeal preservation, overall survival with laser surgery, no difference in local control, recurrence, or disease‐specific survivalBoyle & Jones 202244United KingdomSREarly laryngeal cancerEndoscopic laser surgery, external beam RTFunctional outcomes, QoLNo clear advantage of either treatment; prospective studies with standardized assessment needed for valid comparisonJanssens et al. 201261NetherlandsRCTLaryngeal cancerAccelerated RT with/without carbogen inhalation, nicotinamideLocal control, larynx preservation, toxicity, survivalBetter 5‐year regional control with carbogen inhalation and nicotinamide, equivalent toxicityStrieth et al. 201985GermanyRCTEarly laryngeal cancerTransoral microsurgery with microvessel‐ablative KTP laser, gold‐standard cutting CO₂ laserVoice outcomesSignificantly reduced VHI scores, no relapse with KTP laser; one recurrence within 6 months with CO₂ laserSjogren et al. 202284EuropeSRGlottic cancerCO₂ transoral laser microsurgeryVoice outcomesVHI scores increased gradually (range 14.2–21.5) but similar for all cordectomy types, dysphonia grade increased gradually with increasing resection depth (range 1.0–1.9), maximum phonation time decreased gradually (range 15.2–7.2)Lyhne et al. 201568DenmarkRCTGlottic cancerModerately accelerated, conventional fractionated RTLocal controlModerately accelerated radiotherapy improved locoregional of glottic SCCAbbreviations: Bcl‐xL, B‐cell lymphoma‐extra large; ICU, intensive care unit; KTP, potassium titanyl phosphate; MA, meta‐analysis; QoL, quality of life; RCT, randomized controlled trial; RT, radiation therapy; SCC, squamous cell carcinoma; SR, systematic review; VHI, Vocal Handicap Index.2FIGURECharacteristics of studies registered in the PubMed database (2011–2022). CT, chemotherapy; MA, meta‐analysis; LS, laser surgery; RT, radiotherapy; RCT, randomized controlled trial; ST, systemic therapy; SR, systematic review.DISCUSSIONThe clinical landscape of glottic cancer has changed over the years, and, as shown by this review, new treatment modalities, mainly for organ function preservation, are being assessed. The NCCN guidelines, based on the most recent evidence generated throughout the world, provide recommendations that support clinicians' and patients' decision making. This study provides an overview of changes made to the guidelines and current recommendations for glottic cancer treatment. Over the study period, clinical stage–specific surgical principles and non‐surgical therapy for glottic cancer evolved in response to the development of new techniques, human and technological resources, and, mainly, a greater understanding of therapeutic modalities and corresponding survival rates. The intention to preserve the larynx and obtain better locoregional control and survival led to the performance of several studies of different clinical stages, mainly early, of glottic cancer (Figure 2, Table 3).According to the NCCN categories of evidence and consensus, all recommendations appearing in the NCCN guidelines are category 2A (lower‐level evidence, uniform NCCN consensus) unless otherwise indicated. An example of a category 1 recommendation (high‐level evidence, uniform NCCN consensus) is that for the concurrent administration of ST and RT in the presence of extranodal extension of T1–T2 N0 and select T3 N0 cases. The category of evidence for induction chemotherapy recommendations for advanced glottic cancer changed considerably over the period of this study, from 2B (lower‐level evidence, nonuniform NCCN consensus) and 3 (any level of evidence, major disagreement) to 2A. These changes are broadly supported by evidence linking laryngeal preservation to clinical outcomes, and they reflect the increasing clinical relevance of such non‐surgical strategies.9,49RT and surgery (including endoscopic resection or open partial laryngectomies) remain the two main recommendations for early‐stage glottic cancer in the NCCN guidelines. Advances in surgical techniques with different laser modalities and robotic‐assisted transoral surgery were observed, however, not only surgical techniques improved, as RT is using intensity‐modulated radiation to precisely select normal tissues and targets for treatment, providing curative treatment with less toxicities.44,58,75,77 As T1–T2 glottic cancer survival outcomes rates of laryngeal preservation are good and similar following laser surgery and RT,6 recent studies have focused on the improvement of functional voice outcomes.5,85 Relative to transoral laser microsurgery using a CO₂ laser, that performed with an angiolytic potassium titanyl phosphate laser for early‐stage glottic cancer yielded significantly better functional voice results with adequate oncological safety, and the researchers have encouraged further studies with larger samples to inform the selection of the best surgical laser technique for patients with this disease.85 Other therapeutic modalities for early‐stage glottic cancer that have been assessed include intraoperative hyaluronic acid injection during transoral laser microsurgery, which had no significant effect on survival,38 and altered (hypo‐ and hyper‐) fractionation RT, which was found to result in fewer local failure events than did conventional RT.80 The selection of the appropriate treatment modality is individualized by assessing clinicopathological factors, patient characteristics, as well as preferences and expectations and, finally, the availability of human and technological resources, however, the larynx preservation approaches have become the standard of care for early‐stage glottic cancer.Induction chemotherapy and clinical trials were the pathways added over time as treatment options for primary and neck in advanced glottic cancer. In this sense, the two previous modalities along with concomitant ST/RT or RT alone in patients whose performance status is not sufficient to tolerate this treatment, and surgery with or without adjuvant therapy, are the pathways provided by the last algorithm (2022) of the NCCN guideline. Although RCTs with a robust analysis between surgical and non‐surgical therapy comparing oncologic and functional outcomes in a homogeneous clinicopathological population are needed, retrospective studies performed in a population‐based database analyzing surgery with or without adjuvant treatment versus chemoradiation found superior oncological outcomes in those surgically treated.8,33 Despite the controversies in the oncological results between studies comparing surgical and non‐surgical modalities,13,67,69,87 it is noteworthy that induction chemotherapy, which has been gaining more evidence in recent years, is an excellent option for those patients with advanced cancer who are not candidates for surgery or those patients who, after careful evaluation by a multidisciplinary team, the decision to larynx preservation with dysfunction‐free survival through non‐surgical protocols is chosen according to good survival prognosis and patients' QoL. A current study on induction chemotherapy assessing other alternative agents with bioselection and two cycles with platinum, 5‐fluorouracil plus docetaxel, and a B‐cell lymphoma 2 protein inhibitor to increase the organ preservation rate have shown that the non‐surgical approach had better tolerability but did not improve oncological outcomes.86Based on the literature search strategy outlined in the NCCN guidelines,95 we conducted a PubMed database search to identify key literature in the field of glottic cancer treatment. The largest proportions of identified studies were conducted in Asian and European countries, consistent with the references cited in the NCCN guidelines. Notably, although the NCCN guidelines serve as a reference in American countries, no study cited therein was conducted in Latin America. Thus, the inclusion of data from low‐ and middle‐income American countries with different human and technological resources available in future NCCN evidence reviews would be particularly important for the comprehensive assessment of differences in treatment protocols and clinical outcomes.In general, the changes made to the NCCN glottic cancer treatment guidelines have been consistent with published research results, especially with the accumulation of clinical data for new techniques such as transoral laser microsurgery and induction chemotherapy.5,9,35 The guidelines support decision making about glottic cancer treatment that is individualized and focused on functional outcomes and patients' QoL.AUTHOR CONTRIBUTIONSConceptualization: Lady Paola Aristizabal Arboleda, Aline Borburema Neves, Maria Paula Curado, Luiz Paulo Kowalski; Methodology, Lady Paola Aristizabal Arboleda, Aline Borburema Neves. Formal Analysis: Letícia Miliano Candelária, Matheus Ferraz Borges, Gisele Aparecida Fernandes. Writing—original draft: Lady Paola Aristizabal Arboleda. Writing—review & editing: Hugo Fontan Kohler, José Guilherme Vartanian, Genival Barbosa de Carvalho, Alan Roger Santos‐Silva, Luiz Paulo Kowalski, Maria Paula Curado. Visualization: All authors. Supervision: Alan Roger Santos‐Silva, Luiz Paulo Kowalski, Paul Brennan, Maria Paula Curado. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.CONFLICT OF INTEREST STATEMENTThe authors declare that they have no conflict of interest related to this work.DATA AVAILABILITY STATEMENTData sharing is not applicable to this article as no new data were created or analyzed in this study.ETHICS STATEMENTThis is a literature review study, and no ethical approval is required according to the Ethics Committees of A.C.Camargo Cancer Center. 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J Natl Compr Canc Netw. 2022;20(3):224‐234.AAPPENDIXA1TABLESearch strategy and number of studies identified from Medline/PubMed.Database search strategy search date (October 26, 2022)ResultsFilters appliedTotal(“Cancer of Larynx” OR “Larynx Cancer*” OR “Laryngeal Cancer” OR “Cancer of the Larynx” OR “glottis cancer” OR “glottic cancer” OR “glottic carcinoma”) AND (“conservative treatment”[MeSH Terms] OR “neoadjuvant therapy”[MeSH Terms] OR “Radiotherapy”[MeSH Terms] OR “induction chemotherapy”[MeSH Terms] OR “chemotherapy, adjuvant”[MeSH Terms] OR Surgery OR Surgical OR “robotic surgical procedures”[MeSH Terms] OR “Laryngectomy”[MeSH Terms] OR “endoscopic resection” OR “palliative care”[MeSH Terms] OR Treatment OR Management OR “Clinical Protocols”[Mesh] OR “Treatment Protocol*” OR “Antineoplastic Protocols”[Mesh] OR “Cancer Treatment Protocol*”)7536Results by year:2011–2022Results by article type:‐Clinical trial‐Controlled clinical trial‐Meta‐analysis‐Randomized controlled trial‐Systematic review260 results
Cancer Reports – Wiley
Published: Aug 1, 2023
Keywords: glottic cancer; laryngeal cancer; NCCN guidelines; review; treatment
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