Invasiediepte (negatieve hals)

Uitgangsvraag

Welke rol speelt de mate van invasiediepte (of tumordikte) van het primaire plaveiselcelcarcinoom van de mondholte voor de behandelbeslissing van de klinisch negatieve hals?

Aanbeveling

Aanbeveling-1

Gebruik invasiediepte bij het bepalen van de kans op occulte lymfekliermetastasen van mondholtecarcinomen.

Aanbeveling-2

Overweeg geen watchful waiting in te zetten bij een invasiediepte hoger dan 3 tot 4 millimeter door een toenemend risico op lymfekliermetastasen.

Overwegingen

De zekerheid in het bewijs uit de geïncludeerde studies met multivariabele modellen was laag voor het risico op de aanwezigheid van metastasen. De geïncludeerde studies bevatten in geen enkel geval vooraf gedefinieerde confounders en de betrouwbaarheidsintervallen waren breed. Voor het classificeren van de aan- of afwezigheid van (occulte) halskliermetastasen aan de hand van een afkapwaarde voor invasiediepte (of tumordikte) was er een redelijk vertrouwen in het gevonden bewijs, met uitzondering van een zeer laag vertrouwen op specifieke afkappunten waar zeer weinig data voor beschikbaar was.

Invasiediepte is voorspellend voor de aanwezigheid van lymfekliermetastasen. In de beschreven studies werd een verhoogd risico gevonden voor lymfekliermetastasen bij een invasiediepte boven de gekozen afkapwaarde. Wanneer deze studies vergeleken worden, is geen duidelijke trend richting een hogere odds ratio te zien bij een hogere afkapwaarde. De studiepopulaties kunnen echter sterk verschillen.

Wanneer invasiediepte of tumordikte gebruikt wordt om de aanwezigheid van lymfekliermetastasen te voorspellen, nemen met een lagere afkapwaarde de sensitiviteit en negatief voorspellende waarde toe. Bij de veel gebruikte afkapwaarde van 4 mm voor het verrichten van een electieve halsklierdissectie is de sensitiviteit 70 tot 95% en de negatief voorspellende waarde 61 tot 99%. Dit betekent dat als een electieve halsklierdissectie alleen wordt verricht wanneer de invasiediepte groter is dan 4 millimeter, het risico op aanwezigheid van (occulte) lymfekliermetastasen 1 tot 39% is in de groep met een invasiediepte kleiner dan 4 millimeter. De sensitiviteit en negatief voorspellende waarde voor een afkapwaarde van 3 mm zijn 71-96% en 67 tot 98%.

Na de zoekactie voor deze module is nog een studie verschenen waarin de waarde van invasiediepte voor het voorspellen van lymfekliermetastasen is onderzocht bij 222 patiënten met een T1-2 mondholtecarcinoom (Aaboubout, 2021). De referentiestandaard was een electieve halsklierdissectie (n=166) of observatie (n=56). Hierbij werd een odds ratio van 1,3 per mm invasiediepte gevonden en was bij een afkapwaarde van 4 mm de sensitiviteit 74% en de negatief voorspellende waarde 81% (zie tabel 6).

Tabel 6 Sensitiviteit en negatief voorspellende waarde, uit Aaboubout 2021

Accuratesse parameter	Afkapwaarde (millimeter)
Accuratesse parameter	1	2	3	4	5	6	7	8	9	10
Sensitiviteit	1.00	1.00	0.90	0.74	0.59	0.54	0.46	0.28	0.13	0.00
Negatief voorspellende waarde	1.00	1.00	0.88	0.81	0.80	0.81	0.82	0.79	0.77	0.77

Belangrijke factoren die van invloed kunnen zijn op de gevonden waarde zijn de onderzoeken die verricht zijn voordat gesproken wordt over een klinisch negatieve hals, de daarmee samenhangende incidentie van lymfekliermetastasen.

Indien de hals na uitgebreid beeldvormend onderzoek negatief is, is de kans dat toch lymfekliermetastasen aanwezig zijn kleiner dan wanneer de hals na palpatie alleen als negatief beschouwd wordt. Aangezien het risico op lymfekliermetastasen ook afhankelijk is van vele andere factoren als T-stadium en tumor lokalisatie, kan de incidentie van lymfekliermetastasen verschillen indien de samenstelling van in studies onderzochte cohorten anders is. De incidentie van lymfekliermetastasen kan invloed hebben op de negatief voorspellende waarde.

Ook de referentiestandaard kan van invloed zijn op de resultaten. Bij routinematig onderzoek van een halsklierdissectiepreparaat kunnen namelijk tot 15% van de (micro)metastasen gemist worden. Door stapsgewijze doorsnijdingen en immunohistochemie kunnen bij de schildwachtklierprocedure micrometastasen beter gedetecteerd worden. Het is alleen te arbeidsintensief om dit routinematig bij alle lymfeklieren in een halsklierdissectiepreparaat te doen. Bij een watch and wait strategie (observatie) van een onbehandelde hals zullen alle lymfekliermetastasen tijdens follow-up uiteindelijke manifest worden. Derhalve is observatie van de onbehandelde hals de beste referentiestandaard, gevolgd door de schildwachtklierprocedure (die indien negatief gevolgd wordt door observatie) en daarna het histopathologisch onderzoek van een electieve halklierdissectie.

In de beschreven studies zijn met name tumoren van de tong onderzocht. Het is goed mogelijk dat de gevonden resultaten bij andere tumorlokalisaties als de mondbodem anders zullen zijn.

In de beschreven studies wordt invasiediepte op twee verschillende manieren gemeten: van een denkbeeldig intact (alsof er geen ulceratie of exofytische groei aanwezig is) mucosale oppervlak tot het diepste punt van tumorinfiltratie of van de basaalmembraan tot het diepste punt van tumorinfiltratie. Daarnaast is in andere studies tumordikte in plaats van invasiediepte gebruikt. Dikte kan mogelijk als surrogaat voor invasiediepte gebruikt worden aangezien Dirven (2017) in een cohort van 456 patiënten met een mondholtecarcinoom een gemiddeld verschil van 0,7 mm vonden.

Invasiediepte is voorspellend voor het optreden van lymfekliermetastasen. De sensitiviteit en negatief voorspellende waarde (per afkapwaarde) verschilt echter sterk per studie. Naast invasiediepte zijn er andere voorspellende factoren voor aanwezigheid van lymfekliermetastasen. Toch kan invasiediepte gebruikt worden bij de keuze voor het al dan niet electief behandelen van de hals. Invasiediepte kan histopathologisch bepaald worden op het resectiepreparaat en is derhalve voor de patiënt niet belastend. Nadeel is dat de uitslag niet voor of tijdens de operatie van de primaire tumor beschikbaar is, zodat dan in tweede instantie eventueel een halsklierdissectie verricht zou moeten worden. Aangezien een incisiebiopt slechts sample van de hele tumor is, zal onduidelijk zijn of de gemeten invasiediepte in het biopt ook de maximale invasiediepte van de tumor is. Preoperatief kan de invasiediepte met MRI en echografie betrouwbaar bepaald worden. MRI en echografie van de hals worden vaak al routinematig gemaakt waardoor het weinig belastend voor de patiënt is. Voor bepaling van invasiediepte met echografie is alleen wel een speciale probe voor in de mondholte nodig. Dit laatste is het enige dat extra aangeschaft hoeft te worden. De overige onderzoeken worden routinematig verricht. De metingen zijn gemakkelijk te aan te leren.

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Aanbeveling-1

Invasiediepte is een voorspeller voor de kans op lymfekliermetastasen. Gezien de grote variatie in sensitiviteit en negatief voorspellende waarde kan moeilijk een keuze gemaakt worden voor een optimale afkapwaarde waaronder voor een afwachtend beleid en waarboven voor een electieve halsklierdissectie gekozen dient te worden. Dit is onder andere afhankelijk van incidentie van lymfekliermetastasen, welke deels bepaald wordt door de accuratesse voor het detecteren van (occulte) lymfekliermetastasen van de tevoren verrichte diagnostische onderzoeken.

Aanbeveling-2

Gezien de grote variatie in sensitiviteit en negatief voorspellende waarde kan moeilijk een keuze gemaakt worden voor een optimale afkapwaarde waaronder voor een afwachtend beleid en waarboven voor een electieve halsklierdissectie gekozen dient te worden. Wanneer de hals alleen op basis van palpatie als klinisch negatief beoordeeld wordt zal waarschijnlijk voor een lagere afkapwaarde gekozen moeten worden om een acceptabel risico op gemiste metastasen te houden. In het algemeen lijken afkapwaarden tussen 3 en 4 mm acceptabel te zijn.

Onderbouwing

Achtergrond

De mate van invasiediepte (en tumordikte) van het primaire plaveiselcelcarcinoom van de mondholte is geassocieerd met de ontwikkeling van cervicale lymfekliermetastasen. Wanneer lymfekliermetastasen klinisch niet gedetecteerd worden, maar de kans aanzienlijk is dat deze wel aanwezig zijn, ontstaat een dilemma om de hals uit voorzorg (electief) te behandelen of af te wachten totdat deze eventueel manifest worden. Het verwijderen van lymfeklieren in de hals kan echter, naast pijn, oedeemvorming en bloedingen, ook potentieel gevolgen hebben voor de nek- en schouderfunctie van de patiënt. Wanneer gewacht wordt totdat de nog niet gedetecteerde (occulte) lymfekliermetastasen manifest worden, is de behandeling vaak uitgebreider of zelfs soms niet meer mogelijk. Het is daarom belangrijk om te bepalen aan de hand van de invasiediepte (en tumordikte) van de primaire tumor hoe hoog het risico op lymfekliermetastasen is, zodat voor een patiënt het beste beleid ten aanzien van het beleid van de hals (electief behandelen of afwachten en observeren) gekozen kan worden.

Conclusies

LOW

GRADE

The evidence is uncertain about the risk of lymph node metastasis as at various cut-off points of depth of invasion of oral tongue carcinomas using a sentinel node biopsy, elective neck dissection and/ or a watch and wait strategy as reference standard. There was no data included for other subsites of oral cavity carcinomas.

Sources: (Faisal, 2018; Wu, 2019; Xu 2020)

MODERATE GRADE

There is moderate certainty about the sensitivity at various cut-off points of depth of invasion (or tumor thickness) with enough data in oral cavity carcinomas using a sentinel node biopsy, elective neck dissection, or a watch and wait strategy as reference standard for the prediction of lymph node metastases. However, the evidence is very uncertain about specific cut-off points where there is a lack of data (1.5 mm/ 1.6mm/ 2.2mm/ 2.7mm/ 3.8mm).

Sources: (den Toom, 2019; Goerkem, 2010; Melchers, 2012; Sahoo, 2020; van Lanschot, 2020; Warburton, 2007; Yeh, 2014; Zhang, 2014)

MODERATE GRADE

There is moderate certainty about the negative predictive value at various cut-off points of depth of invasion (or tumor thickness) with enough data in oral cavity carcinomas using a sentinel node biopsy, elective neck dissection, or a watch and wait strategy as reference standard for the prediction of lymph node metastases. However, the evidence is very uncertain about specific cut-off points where there is a lack of data (1.5 mm/ 1.6mm/ 2.2mm/ 2.7mm/ 3.8mm).

Sources: (Goerkem, 2010; Melchers, 2012; van Lanschot, 2020; Warburton, 2007; Yeh, 2014)

Samenvatting literatuur

Description of studies

Den Toom (2019) included patients with cT1-2N0 oral carcinomas who underwent transoral excision and sentinel lymph node biopsy (examined with histopathology). Exclusion criteria were not reported. Patients (n=199, 100 males, 99 females) had a median age of 63 years (range 27 to 87). Tumor site in the sample was at the tongue (n=121), floor of mouth (n=53), buccal mucosa (n=160), inferior alveolar process (n=5), or other (n=4). T-stage was either T1 (n=132) or T2 (n=67). Persons with a negative sentinel lymph node biopsy were considered positive for metastasis when metastases developed during follow-up (i.e. the SLNB was false negative). There was a follow-up in the sample of 19 months (central tendency measure was unclear, range: 1 to 104). Depth of invasion was measured as being the mass beneath the basement membrane. A theoretical reconstruction of the basement membrane was made for exophytic lesions or ulceration. Depth of invasion was correlated with (true positive and false negative) lymph node metastatic rate. It was argued that the combination of sentinel node biopsy and follow-up was a better reference standard than routine histopathological examination of neck dissections specimens.

Faisal (2018) selected patients with histopathologically proven T1-2 tongue carcinomas from a database. Patients had to have a clinically negative neck and had to be treated with surgery (including level I-III/IV elective neck dissection) followed by adjuvant (chemo)radiotherapy. Exclusion criteria were not reported. Patients (n= 179, 57% male, 43% female) had a mean age of 57.92 years (SD: 11.93). Pathological T-stage was either T1 (63.69%) or T2 (36.31%), with a tumor differentiation of poor (5.59%), moderate (39.66%), or well (54.75%). Postoperative radiotherapy was provided for patients with pathologically involved lymph nodes or close (< 5mm) resection margins. Three patients received re-excision followed by radiotherapy. Patients with extranodal extension received chemoradiation. Depth of invasion was measured from the basement membrane of adjacent normal mucosa to the deepest point of invasion by a pathologist.

Goerkem (2010) selected patients from a database with biopsy-proven cT1-2 oral cavity carcinomas without evidence of lymph node metastases after physical examination and imaging. Exclusion criteria were not reported. Transoral tumor resection and sentinel lymph node biopsy was performed in all patients. Patients (n=78, 52 males, 26 females) had a mean age of 60 years (range: 34 to 87). T-stage was either T1 (n=40) or T2 (n=38) with the tumor location at the tongue (n=55) or floor of mouth (n=23). Lymphatic invasion was observed in 10 persons, perineural invasion in 15 persons, vascular invasion in 3 persons, and muscular invasion in 55 patients. Mode of infiltration was observed to be grade 1 (n=11), grade 2 (n=12), grade 3 (n=25), grade 4C (n=16), or grade 4D (n=14). Lymphoplasmacytic infiltration in the sample was grade 1 (n=31), grade 2 (n=41), or grade 3 (n=6). Tumor depth was measured from the mucosal surface to the deepest point of infiltration. Tumor thickness was measured from a virtual line (tangentially placed at the most exophytic tumor area) to the deepest point of infiltration.

Melchers (2012) selected patients with a histologically proven T1-2 oral squamous cell carcinoma from a database. Patients had to be treated by resection of the primary tumor without prior head-neck systemic oncological treatment. All clinicopathologic data regarding the nodal status had to be available. Patients were excluded when there were synchronous tumors, when HE-slides were irretrievable, or when there was an unreliable assessment of depth of invasion. Included patients (n=212, 119 males, 93 females) had a mean age of 61.5 years (range: 25 to 94) with tumors at the tongue (n=108), gum (n=15), floor of mouth (n=64), cheek mucosa (n=7), retromolar area (n=12), or other (n=6). Pathological T-stage was T1 9n=123) or T2 (n=89). The patients were treated with neck dissection (n=174, with n=106 with cN0) or underwent an observation period of at least 2 years (n=38). Clinical nodal stage was assessed with palpation and imaging (CT or MRI, while PET or ultrasound could be performed on indication). Patients with cN0 (n=106) were selected for the accuracy analyses. Pathological N-stage was considered as the true N-stage, after neck dissection. Patients who received the observation strategy were examined for the development of nodal metastases in the follow-up with return visits every 6 weeks. Maximum infiltration depth of the tumor below the mucosal surface was considered as the depth of invasion. The mucosal surface was reconstructed for ulcerated or exophytic tumors when measuring the depth of invasion. Of note is that the group of patients who underwent elective neck dissection differs from the observation group, e.g. true N0 status 58% versus 82%. This difference in incidence may affect negative predictive values.

Sahoo (2020) selected patients older than 35 years with histologically proven oral squamous cell carcinomas from a database. Patients had to be treated with a wide excision of the primary tumor and with elective neck dissection. Patients who had metastatic tumors, recurrent tumors in the oral cavity, immune-compromised diseases and tumors, or who were under treatment with chemotherapy or radiotherapy were excluded. The sample (n=150) consisted of 88 men and 51 females, where 110 patients were younger than 40 years old. The tumor stage was either cT1 (n=27) or cT2 (n=41), with a tumor differentiation of well (n=27), moderate (n=60), or poor (n=3). Lymphovascular invasion was present in 35 patients, while perineural invasion was present in 41 patients. Tumor thickness was measured from the level of the surface of the mucosa or the ulcer base to the deepest point of invasion (without superficial keratin or inflammatory debris). Depth of invasion was measured in two ways from the bottom of the adjacent dysplastic rete ridge to the deepest point of invasion and from the epithelial junction of most superficial adjacent connective tissue papilla to the deepest point of invasion

Van Lanschot (2020) included patients with pT1-2 primary oral squamous cell carcinomas from a database. Patients with synchronous multiple tumors or with clinically positive neck nodes were excluded. Patients (n=300, 158 males, 142 females) were surgically treated and received an elective neck dissection (n=173) or observation (n=127). Median age was 66.5 years (range: 25 to 94). Tumor site was at the tongue (n=162), floor of mouth (n=77), buccal mucosa (n=27), lower (n=12) or upper (n=7) alveolus and gingiva, lip (n=7), retromolar area (n=5), or hard palate (n=3). Infiltrative grows was present in 179 patients, vasoinvasion in 28 patients, and perineural invasion in 52 patients. Pathological T-stage according to the TNM7-staging system was pT1 (n=197) and pT2 (n=90). Some patients were staged according to the TNM8-staging system (pT1: n=5, pT2: n=8). Patients were surgically treated. Elective neck dissection was performed when the depth of invasion of the primary tumor was ≥ 4 millimeters. Patients staged with clinically negative lymph nodes and < 4 millimeters depth of invasion received an observation strategy. The mean follow-up in the observation group was 23.4 months (range: 0 to 62) and consisted of physical examinations and regular ultrasound of the neck in the first two years. Depth of invasion was measured from the basement membrane of the adjacent normal mucosa to the deepest point of infiltration.

Warburton (2007) selected patient with T1-2N0M0 tongue or floor of mouth carcinomas from a database. Patients had to be treated with resection of the primary tumor, without neck dissection or irradiation. Cases were excluded when there was insufficient tumor tissue on the archived slides. The sample consisted of 27 patients (18 males, 9 females) with a mean age of 64 years (range: 39 to 86). T-stage was either T1 (n=19) or T2 (n=8) with tumors located at the floor of mouth (n=15) or tongue (n=12). Depth of invasion was measured from the surface of the epithelium to the deepest points of invading tumor island or cell by using a reconstructed line, excluding exophytic components and including thickness lost to ulceration.

Wu (2019) Included patients with pathologically confirmed tongue squamous cell carcinoma by biopsy. Patients with T1-2 tumors and without cervical lymph node relapse (N0) were included. TNM stage was assessed with a clinical check, CT, and ultrasound. Exclusion criteria were not reported. Patients received neck dissection (n=69) or observation (n=72) after tumor resection. The sample (n=141, 75 males, 66 females) had a mean age of 55 years. Tumor location carcinoma was on the anterior (n=14), middle (n=103) or back (n=24) of the tongue. Tumor differentiation was well (n=48), moderate/poor (n=93). Eighteen patients had neurovascular invasion. Patients were followed for a maximum of 60 months and examined every 3 months (first 24 months), then every 6 months (for the following 36 months). Examination consisted of physical inspection and CT or MRI. Nodal relapses were pathologically proven. It was unclear how the depth of invasion was measured.

Xu (2020) selected adult patients (≥ 18 years) with primary cT1N0M0 tongue squamous cell carcinoma. Patients were selected when MRI and follow-up data were available. Exclusion criteria were not reported. Elective neck dissection was routinely provided after primary tumor excision, while patients with very early-stage disease did not undergo neck dissection. After therapy, the patients were examined every 3 months (in the first 12 months), every 6 months (in the following 12 months), and once yearly thereafter (mean follow-up: 70.4 months, range: 8 to 103). The sample (n=151, 111 males, 40 females) had a mean age of 57.1 years (range: 30 to 78). A portion of the sample had perineural invasion (n=23) and/or lymphovascular invasion (n=19). The observed growth pattern was either ulcerative (n=71), invasive (n=20), or exogenous (n=49). Depth of invasion as measured on MRI was defined as the distance between the deepest point of invasion and the simulated normal mucosal junction. The depth of invasion was determined by at least two radiologists. Pathological depth of invasion was measured from the level of normal adjacent mucosa to the deepest point of infiltration.

Yeh (2014) recruited 272 consecutive patients with newly diagnosed T1-2 cN0 oral squamous cell carcinoma who underwent curative surgery. Patients were excluded when there was previous cancer, unless the patient was more than 2 years disease-free. Nineteen patients (who underwent observation) were excluded because of adjuvant therapy was provided (n=7), there was local recurrence before neck recurrence (n=1), or the follow-up period was too short (n=11). Included patients (n=253) had either pT1 (n=128) or pT2 (n=125) with a well (n=171) or moderate/poor (n=82) tumor differentiation. The clinically negative neck status was determined with clinical examination and imaging (MRI or CT). A total of n=176 received neck dissection and n=77 received observation. Node positivity was defined as the pathological diagnosis of lymph node metastasis (for neck dissection) or the neck recurrence within 2 years without antecedent or synchronous local recurrence (for observation). Patients with high-risk features in the neck dissection group received postoperative adjuvant treatment (n=31). Patients were followed every month (first year), every 2 months (following year), and every 3 months (thereafter). Persons who received the observation strategy and remained free from neck recurrence had a mean follow-up of 61.9 months (range: 24 to 130). Tumor thickness was measured vertically from the tumor surface or ulcer base to the deepest point of invasion on serial sections.

Zhang (2014) selected patients with a biopsy proven cT1N0M0 squamous cell carcinoma of the tongue without previous treatment. Patients had to be treated with surgery, the staging of the neck was performed with palpation and contrast-enhanced CT, no other malignancies were present in the head and neck, and sufficient data was recorded. Cases were excluded when there was a carcinoma in situ, verrucous carcinoma, or carcinoma at the base of the tongue. The sample (n=65, 32 males, 33 females) had a mean age of 60.7 years (range: 24 to 91). Tumor was located at the dorsal (n=2), lateral (n=54), or ventral (n=9) part of the tongue with a poor (n=5), moderate (n=18), well (n=37), or unknown (n=5) tumor differentiation. Perineural invasion was present in four patients. Patients received observation when biopsy results showed < 3 millimeters depth of invasion. Delayed neck dissection was recommended within 4 to 6 weeks when pathological depth of invasion was ≥ 3 millimeters (while the biopsy showed < 3 mm). When the depth of invasion was ≥ 3mm on biopsy, the patients received selective neck dissection. Thirty-six patients received simultaneous or delayed neck dissection, while the other (n=29) did not receive neck dissection. Pathological tumor depth was measured from the normal adjacent mucosa to the deepest point of invasion.

Overviews of how depth of invasion was measured, whether tumor thickness was measured, and which reference standard(s) were used in the included studies are reported in Tables 1 and 2.

Table 1 Overview of how depth of invasion measured in the included studies and whether tumor thickness was measured

Author, year	Depth of invasion		Tumor thickness
Author, year	From basement membrane of intact mucosa	From surface of intact mucosa	Tumor thickness
Den Toom 2019	x
Faisal 2018	x
Goerkem 2010		x	x
Melchers 2012		x
Sahoo 2020	x		x
Van Lanschot 2020	x
Warburton 2007		x
Wu 2019	Unclear	Unclear
Xu 2020		x
Yeh 2014			x
Zhang 2014		x

Table 2 Overview of how the included studies assessed the occurrence (i.e. presence or development) of neck metastases

Author, year	Reference standard
Author, year	Follow-up	Sentinel node biopsy	Sentinel node + follow-up	Neck dissection
Den Toom 2019			x
Faisal 2018	x			I - III/IV
Goerkem 2010		x
Melchers 2012	x			x
Sahoo 2020				x
Van Lanschot 2020	x			x
Warburton 2007	x
Wu 2019	x			x
Xu 2020	x			x
Yeh 2014	x			x
Zhang 2014	x			x

Results

Risk of lymph node metastases

Three studies used a multivariable model (Faisal, 2018; Wu, 2019; Xu 2020). All studies solely included patients with oral tongue carcinomas. Results are summarized in Table 3.

Table 3 Adjusted odds ratios from multivariable models at specific cut-off points

Author, year, tumor sites	Reference strategy	TT / DOI*	Adjusted risk per cut-off (millimeters
Author, year, tumor sites	Reference strategy	TT / DOI*	4 mm	5 mm	7.5 mm
Faisal 2018 Tongue	ND	DOI		≤5 mm (ref) versus 6-10mm OR not reported (95%CI: 0.52 – 2.00) Other variables in the model: cT-stage, perineural invasion, extracapsular spread ≤5mm (ref) versus >10mm OR = 1.69 (95%CI: 0.80 – 3.58) Other variables in the model: cT-stage, perineural invasion, extracapsular spread
Wu 2019 Tongue	ND/WW*	DOI	<4 mm (ref) versus ≥4 mm OR = 12.23 (95%CI: 1.31 – 113.90) Other variables in the model: gender, age, mode of invasion, pathological differentiation, neurovascular invasion, location, T-stage, smoking, drinking, treatment
Xu 2020 Tongue	ND/WW*	DOI		≤5 mm(ref) versus >5 mm (pathological DOI) OR = 3.112 (95%CI: 1.812 – 9.668) Other variables in the model: lymphovascular invasion, pathologic tumor grade, MRI-measured depth of invasion.	<7.5mm (ref) versus ≥7.5 mm (MRI-measured DOI) OR = 2.978 (95%CI: 1.574 – 7.332) Other variables in the model: lymphovascular invasion, pathologic tumor grade, pathologic depth of invasion.
DOI: Depth of invasion mm: millimeter(s) ND: Neck dissection SLNB: Sentinel lymph node biopsy TT: Tumor thickness WW: Watch and wait *: ND and WW were not separately distinguishable from the reported results

Sensitivity

Study results for sensitivity using several reference strategies at specific cut-off points are summarized in Table 4. Overall the sensitivity ranged from 0.13 to 1.00, depending on the reference strategy and the cut-off point. Studies used tumor thickness measurements and/or depth of invasion measurements for specific cut-off points in millimeters.

Using watch and wait as the reference strategy, the sensitivity ranged from 0.375 to 1.00 (Warburton, 2007; Melchers 2012) depending on the cut-off point.

Two studies reported the sensitivity for both the neck dissection and observation strategies combined as one group (Zhang, 2014; Van Lanschot 2020). From another study, the sensitivity for the group receiving neck dissection or watch and wait could be calculated from the presented data (Yeh, 2014). The sensitivity ranged from 0.545 to 1.00, depending on the cut-off.

When using neck dissection as a reference strategy, two studies reported the sensitivity at various cut-off points (Melchers, 2012; Sahoo, 2020). Depending on the cut-off point, the sensitivity ranged from 0.50 to 1.00.

Sentinel lymph node biopsy was used as a reference strategy in two studies (Goerkem, 2010; Den Toom 2010). The sensitivity ranged from 0.13 to 1.00, depending on the different cut-off points.

Negative predictive value

Study results for the negative predictive value are summarized in Table 5. Overall, the negative predictive value using different reference strategies at specific cut-off points ranged from 0.464 to 1.00 in five studies (Warburton, 2007; Goerkem, 2010; Melchers, 2012; Yeh, 2014; Van Lanschot, 2020). Studies used tumor thickness measurements and/or depth of invasion measurements for specific cut-off points in millimeters.

When using watch and wait as a reference strategy in two studies (Warburton, 2007; Melchers, 2012), the negative predictive value ranged from 0.783 to 1.00 depending on the cut-off point.

In two studies, the study samples received neck dissection or watch and wait as a reference strategy which could not be distinguished (Yeh, 2014; Van Lanschot, 2020). One study reported the negative predictive value (Van Lanschot, 2020), while the negative predictive value could be calculated from the reported data in the other study (Yeh, 2014). Depending on the cut-off points, the negative predictive value ranged from 0.815 to 1.00.

One study also used neck dissection as the reference strategy in a study group (Melchers, 2012). The negative predictive value ranged from 0.889 (at the 7 millimeters cut-off point) to 1.00 (at the 1 millimeter cut-off point).

Sentinel lymph node biopsy was used as a reference strategy in one study reporting the negative predictive value (Goerkem, 2010). Here, the negative predictive value ranged from 0.649 to 1.00 (tumor thickness) and from 0.464 to 0.75 (depth of invasion), depending on the cut-off points.

Table 4 Summary of the sensitivity for predicting of lymph node metastasis using several reference standards at specific cut-off points of tumor thickness or depth of invasion

Author, year, tumor sites	Reference strategy	TT / DOI	Sensitivity at specific cut-off points
Author, year, tumor sites	Reference strategy	TT / DOI	1 mm	1.5 mm	1.6 mm	2 mm	2.2 mm	2.7 mm	3 mm	3.4 mm	3.8 mm	4 mm	4.59 mm	5 mm	6 mm	7 mm	7.64 mm	8 mm	8.64 mm	9 mm	10 mm
Warburton 2007 Floor of mouth, tongue	WW	DOI	-	1.00	1.00	0.875	0.875	0.75	0.5	-	0.375	-	-	-	-	-	-	-	-	-	-
Melchers 2012 Tongue, gum, floor of mouth, cheek mucosa, retromolar area, other (oral)	WW	DOI	1.00	-	-	0.857	-	-	0.714	-	-	0.714	0.714	0.571	0.571	0.571	-	-	-	-	-
	ND	DOI	1.00	-	-	0.944	-	-	0.889	-	-	0.833	0.833	0.722	0.667	0.50	-	-	-	-	-
Sahoo 2020 Gingivobuccal sulcus, tongue, floor of mouth, retromolar area, maxilla	ND	DOI	-	-	-	-	-	-	-	-	-	-	-	-	-	-	0.727 (95%CI 0.575 –0.838)	-	-	-	-
	ND	TT	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	0.72 (95%CI 0.572 – 0.85)	-	-
Van Lanschot 2020 Tongue, Floor of mouth, buccal mucosa, lower and upper alveolus and gingiva, lip, retromolar area, hard palate	ND/WW*	DOI	1.00	-	-	1.00	-	-	0.951		-	0.951	-	0.878	0.805	-	-	-	-	-	-
Yeh 2014 Oral	ND/WW*	TT	-	-	-	-	-	-	-	-	-	-	-	-	0.545	-	-	-	-	-	-
Zhang 2014 Tongue	ND/WW*	DOI	-	-	-	1.00	-	-	0.929	-	-	0.786		0.643	-	-	-	-	-	-	-
Den Toom 2019 Tongue, floor of mouth, buccal mucosa, inferior alveolar process, other (oral)	SLNB+follow-up**	DOI	0.97	-	-	0.89	-	-	0.83	0.83	-	0.70	-	0.50	0.34	0.25	-	0.20	-	0.13	0.13
Goerkem 2010 Tongue, floor of mouth	SLNB	DOI	0.964	-	-	0.929	-	-	0.857	-	-	0.643	-	0.607	0.464	-	-	-	-	-	-
Goerkem 2010 Tongue, floor of mouth	SLNB	TT	1.00	-	-	1.00	-	-	0.964	-	-	0.786	-	0.679	0.536	-	-	-	-	-	-
DOI: Depth of invasion mm: millimeter(s) ND: Neck dissection SLNB: Sentinel lymph node biopsy TT: Tumor thickness WW: Watch and wait : ND and WW were not separately distinguishable from the reported results *: When a regional metastasis developed during follow-up after a negative SLNB, the negative SLNB was considered to be false-negative

Table 5 Summary of negative predictive values for the prediction of lymph node metastasis using several reference standards at specific cut-off points of tumor thickness or depth of invasion

Author, year, tumor sites	Reference strategy	TT / DOI	Negative predictive value at specific cut-off points
Author, year, tumor sites	Reference strategy	TT / DOI	1 mm	1.5 mm	1.6 mm	2 mm	2.2 mm	2.7 mm	3 mm	3.8 mm	4 mm	4.59 mm	5 mm	6 mm	7 mm
Warburton 2007 Floor of mouth, tongue	WW	TT	-	1.00	1.00	0.933	0.938	0.889	0.818	0.783	-	-	-	-	-
Melchers 2012 Tongue, gum, floor of mouth, cheek mucosa, retromolar are, other (oral)	WW	DOI	1.00	-	-	0.857	-	-	0.889	-	0.923	0.923	0.889	0.897	0.906
	ND	DOI	1.00	-	-	0.938	-	-	0.939	-	0.943	0.948	0.918	0.915	0.889
Van Lanschot 2020 Tongue, Floor of mouth, buccal mucosa, lower and upper alveolus and gingiva, lip, retromolar area, hard palate	ND/WW*	DOI	1.00	-	-	1.00	-	-	0.978	-	0.986	-	0.971	0.958	-
Yeh 2014 Oral	ND/WW*	TT	-	-	-	-	-	-	-	-	-	-	-	0.815	-
Goerkem 2010 Tongue, floor of mouth	SLNB	DOI	0.75	-	-	0.75	-	-	0.667	-	0.615	-	0.607	0.464	-
Goerkem 2010 Tongue, floor of mouth	SLNB	TT	1.00	-	-	1.00	-	-	0.80	-	0.625	-	0.625	0.649	-
DOI: Depth of invasion mm: millimeter(s) ND: Neck dissection SLNB: Sentinel lymph node biopsy TT: Tumor thickness WW: Watch and wait *: ND and WW were not separately distinguishable from the reported results

Level of evidence of the literature

The level of evidence regarding the outcome measure risk of lymph node metastases was downgraded by two levels because of study limitations (1 levels for risk of bias: confounders were not predefined, but models were developed based on significance as predictors in the model); imprecision (1 level for imprecision: wide confidence intervals); publication bias was not assessed.

The level of evidence regarding the outcome measure sensitivity was downgraded by one level because of study limitations (1 level for risk of bias: unclear whether there were inappropriate exclusions in most studies, and in some studies not every patient received the same reference standard); not downgraded for conflicting results (already downgraded for risk of bias: different reference tests used within one group may explain some heterogeneity); Not downgraded for overall number of included patients (There is imprecision due to a very low number of included patients (n=27) at: 1.5mm/ 1.6mm/ 2.2 mm/ 2.7 mm/ 3.8 mm); publication bias was not assessed.

The level of evidence regarding the outcome measure negative predictive value was downgraded by 1 level because of study limitations (1 level for risk of bias: unclear whether there were inappropriate exclusions in most studies, and in some studies not every patient received the same reference standard); conflicting results (already downgraded for risk of bias: different reference tests used within one group may explain some heterogeneity); number of included patients (There is imprecision due to a very low number of included patients (n=27) at: 1.5mm / 1.6mm / 2.2 mm / 2.7 mm / 3.8 mm); publication bias.

Zoeken en selecteren

A systematic review of the literature was performed to answer the following questions:

What is the risk of lymph node metastases, sensitivity, and negative predictive value per millimeter tumor depth of invasion (or tumor thickness) of the primary tumor for a sentinel lymph node biopsy, an elective neck dissection, or a watch and wait strategy in patients with cT1-2N0 oral cavity carcinomas?

P: patients with a cT1-2N0 oral cavity carcinoma;

I/R: watch and wait, sentinel lymph node biopsy or elective neck dissection;

C: -;

O: risk of lymph node metastases (radiologically or pathologically confirmed), sensitivity, and negative predictive value per millimeter depth of invasion (or tumor thickness) of the primary tumor.

Relevant outcome measures

The guideline development group considered sensitivity and negative predictive value as a critical outcome measure for decision making; and the risk of lymph node metastases as an important outcome measure for decision making.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

The working group defined a minimal clinically relevant difference as:

0.8 or 1.25 as borders for clinical decision-making for lymph node metastases risk or odds ratios.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms from 2000 until September 23^rd,2020. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 612 hits.

Studies reporting the risk of lymph node metastases to the neck were selected based on the following criteria: patients had a cT1-2N0 oral cavity carcinoma, sentinel lymph node biopsy/ elective neck dissection/ watch and wait was performed, at least one outcome of interest was reported at a specific cut-off (millimeter), and a multivariable model was used to estimate adjusted risk/odds ratios.

Studies reporting the accuracy (sensitivity/negative predictive value) were selected based on the following criteria: patients had a cT1-2N0 oral cavity carcinoma, sentinel lymph node biopsy / elective neck dissection/ watch and wait was performed, and at least one outcome of interest was reported at a specific cut-off (millimeter).

Seventy-one studies were initially selected based on title and abstract screening. After reading the full text, 60 studies were excluded (see the table with reasons for exclusion under the tab Methods) and 11 studies were included.

Results

Eleven studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.

Referenties

Aaboubout Y, van der Toom QM, de Ridder MAJ, De Herdt MJ, van der Steen B, van Lanschot CGF, Barroso EM, Nunes Soares MR, Ten Hove I, Mast H, Smits RWH, Sewnaik A, Monserez DA, Keereweer S, Caspers PJ, Baatenburg de Jong RJ, Bakker Schut TC, Puppels GJ, Hardillo JA, Koljenović S. Is the Depth of Invasion a Marker for Elective Neck Dissection in Early Oral Squamous Cell Carcinoma? Front Oncol. 2021 Mar 12;11:628320. doi: 10.3389/fonc.2021.628320. PMID: 33777774; PMCID: PMC7996205.
Den Toom IJ, Janssen LM, van Es RJJ, Karagozoglu KH, de Keizer B, van Weert S, Willems SM, Bloemena E, Leemans CR, de Bree R. Depth of invasion in patients with early stage oral cancer staged by sentinel node biopsy. Head Neck. 2019 Jul;41(7):2100-2106. doi: 10.1002/hed.25665. Epub 2019 Jan 28. PMID: 30688384; PMCID: PMC6618049.
Dirven R, Ebrahimi A, Moeckelmann N, Palme CE, Gupta R, Clark J. Tumor thickness versus depth of invasion - Analysis of the 8th edition American Joint Committee on Cancer Staging for oral cancer. Oral Oncol. 2017 Nov;74:30-33. doi: 10.1016/j.oraloncology.2017.09.007. Epub 2017 Sep 19. PMID: 29103748.
Faisal M, Abu Bakar M, Sarwar A, Adeel M, Batool F, Malik KI, Jamshed A, Hussain R. Depth of invasion (DOI) as a predictor of cervical nodal metastasis and local recurrence in early stage squamous cell carcinoma of oral tongue (ESSCOT). PLoS One. 2018 Aug 22;13(8):e0202632. doi: 10.1371/journal.pone.0202632. PMID: 30133515; PMCID: PMC6105019.
Goerkem M, Braun J, Stoeckli SJ. Evaluation of clinical and histomorphological parameters as potential predictors of occult metastases in sentinel lymph nodes of early squamous cell carcinoma of the oral cavity. Ann Surg Oncol. 2010 Feb;17(2):527-35. doi: 10.1245/s10434-009-0755-3. Epub 2009 Oct 16. PMID: 19834764.
Melchers LJ, Schuuring E, van Dijk BA, de Bock GH, Witjes MJ, van der Laan BF, van der Wal JE, Roodenburg JL. Tumour infiltration depth ≥4 mm is an indication for an elective neck dissection in pT1cN0 oral squamous cell carcinoma. Oral Oncol. 2012 Apr;48(4):337-42. doi: 10.1016/j.oraloncology.2011.11.007. Epub 2011 Nov 29. PMID: 22130455.
Van Lanschot CGF, Klazen YP, de Ridder MAJ, Mast H, Ten Hove I, Hardillo JA, Monserez DA, Sewnaik A, Meeuwis CA, Keereweer S, Aaboubout Y, Barroso EM, van der Toom QM, Bakker Schut TC, Wolvius EB, Baatenburg de Jong RJ, Puppels GJ, Koljenović S. Depth of invasion in early stage oral cavity squamous cell carcinoma: The optimal cut-off value for elective neck dissection. Oral Oncol. 2020 Dec;111:104940. doi: 10.1016/j.oraloncology.2020.104940. Epub 2020 Aug 5. PMID: 32769035.
Sahoo A, Panda S, Mohanty N, Jena D, Mishra N, Surabhi, Baisakh MR. Perinerural, lymphovascular and depths of invasion in extrapolating nodal metastasis in oral cancer. Clin Oral Investig. 2020 Feb;24(2):747-755. doi: 10.1007/s00784-019-02921-0. Epub 2019 May 28. PMID: 31139977.
Warburton G, Nikitakis NG, Roberson P, Marinos NJ, Wu T, Sauk JJ Jr, Ord RA, Wahl SM. Histopathological and lymphangiogenic parameters in relation to lymph node metastasis in early stage oral squamous cell carcinoma. J Oral Maxillofac Surg. 2007 Mar;65(3):475-84. doi: 10.1016/j.joms.2005.12.074. PMID: 17307596.
Wu K, Wei J, Liu Z, Yu B, Yang X, Zhang C, Abdelrehem A, Zhang C, Li S. Can pattern and depth of invasion predict lymph node relapse and prognosis in tongue squamous cell carcinoma. BMC Cancer. 2019 Jul 19;19(1):714. doi: 10.1186/s12885-019-5859-y. PMID: 31324174; PMCID: PMC6642545.
Xu C, Yuan J, Kang L, Zhang X, Wang L, Chen X, Yao Q, Li H. Significance of depth of invasion determined by MRI in cT1N0 tongue squamous cell carcinoma. Sci Rep. 2020 Mar 13;10(1):4695. doi: 10.1038/s41598-020-61474-5. PMID: 32170092; PMCID: PMC7070144.
Yeh CF, Li WY, Yang MH, Chu PY, Lu YT, Wang YF, Chang PM, Tai SK. Neck observation is appropriate in T1-2, cN0 oral squamous cell carcinoma without perineural invasion or lymphovascular invasion. Oral Oncol. 2014 Sep;50(9):857-62. doi: 10.1016/j.oraloncology.2014.06.002. Epub 2014 Jul 4. PMID: 24998199.
Zhang T, Lubek JE, Salama A, Dyalram D, Liu X, Ord RA. Treatment of cT1N0M0 tongue cancer: outcome and prognostic parameters. J Oral Maxillofac Surg. 2014 Feb;72(2):406-14. doi: 10.1016/j.joms.2013.05.028. Epub 2013 Sep 14. PMID: 24045188.

Evidence tabellen

Evidence table for intervention studies (randomized controlled trials and non-randomized observational studies (cohort studies, case-control studies, case series))¹

This table is also suitable for diagnostic studies (screening studies) that compare the effectiveness of two or more tests. This only applies if the test is included as part of a test-and-treat strategy - otherwise the evidence table for studies of diagnostic test accuracy should be used.

Research question:

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Den Toom 2019

Type of study:

Observational

Setting and country: head and neck centers, Netherlands

Funding and conflicts of interest:

Inclusion criteria:

cT1-2N0 oral cancer, underwent transoral excision, underwent sentinel lymph node biopsy

Exclusion criteria:

Not reported

N total at baseline:

N=199

Important prognostic factors²:

Age, median (range):

63 (27-87)

Sex:

100M/99F

Tumor location, n:

Tongue: 121

FOM: 53

Buccal mucosa: 16

Inferior alveolar process: 5

Other: 4

T-stage:

T1: 132

T2: 67

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Transoral excision of oral cancer and sentinel lymph node biopsy was performed. Biopsy was assessed with histopathology.

Persons with negative SLNB developing metastases during follow-up were considered positive for metastasis (false negative).

DOI was considered to be the mass between the basement membrane and for ulceration/exophytic lesions a theoretical basement membrane was constructed.

1: ≤1mm

2: ≤2mm

3: ≤3 mm

4: ≤3.4mm

5: ≤4mm

6: ≤5mm

7: ≤6mm

8: ≤7mm

9: ≤8mm

10: ≤9mm

11: ≤10mm

Describe control (treatment/procedure/test):

1: >1mm

2: >2mm

3: >3 mm

4: >3.4mm

5: >4mm

6: >5mm

7: >6mm

8: >7mm

9: >8mm

10: >9mm

11: >10mm

Length of follow-up:

19 months (range:1-104)

Loss-to-follow-up:

NA, database study

Incomplete outcome data:

Outcome measures and effect size (include 95%CI and p-value if available):

Sensitivity at DOI 1mm cut-off:

1mm: 0.97

2mm: 0.89

3mm: 0.83

≤3.4mm: 0.83

4mm: 0.70

5mm: 0.50

6mm: 0.34

7mm: 0.25

8mm: 0.20

9mm: 0.13

10mm: 0.13

Faisal 2018

Type of study:

Observational, database

Setting and country: Hospital, Pakistan

Funding and conflicts of interest: No funding was received. The authors declared that there were no competing interests.

Inclusion criteria:

Histopathologically proven T1-2 tongue cancer, clinically negative neck (cN0) with usually MRI and chest x-ray, radiotherapy or chemoradiation in adjuvant setting.

Exclusion criteria:

Not reported

N total at baseline:

N=179

Important prognostic factors²:

Age, mean (SD):

57.92 (11.93)

Sex:

57% M / 43% F

pT-stage, %:

pT1: 63.69%

pT2: 36.31%

Tumor differentiation, %:

Poor: 5.59%

Moderate: 39.66%

Well: 54.75%

Unclear how other characteristics were distributed: some numbers seem to be omitted from the table.

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Primary treatment modality was surgery. Elective neck dissection was performed in all cases. Postoperative radiotherapy was provided for pathologically involved nodes or close surgical margins (<5mm). Patients with extranodal extension received radiochemotherapy. Three patients were managed by re-excision followed by postoperative radiotherapy.

DOI was measured by a pathologist from deepest point of invasion to the basement membrane of adjacent normal mucosa.

1:≤5mm

2: ≤5mm

Describe control (treatment/procedure/test):

1: 6-10mm

2: >10mm

Length of follow-up:

Unclear

Loss-to-follow-up:

Incomplete outcome data:

Outcome measures and effect size (include 95%CI and p-value if available):

Risk of nodal metastases with DOI, multivariable model, ≤5mm(ref) versus 6-10mm:

Adjusted OR: not reported (only the 95%CI was reported: 0.52-2.02)

Other variables in the model: cT-stage, perineural invasion. Extracapsular spread

Risk of nodal metastases with DOI, multivariable model, ≤5mm(ref) versus >10mm:

Adjusted OR = 1.69 (95%CI: 0.80-3.58)

Other variables in the model: cT-stage, perineural invasion. Extracapsular spread

Group A: ≤5mm

Group B: 6-10mm

Group C: <10mm

Goerkem 2010

Type of study:

Observational / cross-sectional, database

Setting and country: Hospital, Switzerland

Funding and conflicts of interest: Not reported in the manuscript

Inclusion criteria:

Biopsy-proven cT1-2 oral cavity SCC, no evidence of lymph node metastases (cN0) after physical examination and imaging.

Exclusion criteria:

Not reported.

N total at baseline:

N=78

Important prognostic factors²:

Mean age (range):

60 (34-87

Sex:

52M / 26F

Tumor site, n:

Tongue: 55

FOM: 23

T-stage, n:

T1: 40

T2: 38

Lymphatic invasion, n:

Yes: 10

No:68

Perineural invasion:

Yes: 15

No: 63

Vascular invasion, n:

Yes: 3

No: 75

Muscle invasion, n:

Yes: 55

No: 23

Lymphoplasmacytic infiltration:

Grade 1: 31

Grade 2: 41

Grade 3: 6

Mode of invasion, n:

Grade 1: 11

Grade 2: 12

Grade 3: 25

Grade 4C: 16

Grade 4D: 14

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Patients received transoral tumor resection and SLNB.

Tumor depth was measured from the mucosal surface to the deepest point of infiltration.

Tumor thickness was measured from drawing a parallel line to the virtual mucosa (placed tangentially at the most exophytic tumor area) to the deepest point of infiltration.

1: <1mm

2: <2mm

3: <3mm

4: <4mm

5: <5mm

6: <6mm

Describe control (treatment/procedure/test):

1: ≥1mm

2: ≥2mm

3: ≥3mm

4: ≥4mm

5: ≥5mm

6: ≥6mm

Length of follow-up:

None, the study seems to be cross-sectional.

Loss-to-follow-up:

Incomplete outcome data:

Outcome measures and effect size (include 95%CI and p-value if available):

Tumor depth:

Cut-off 1 mm for tumor depth:

Sensitivity: 0.964

NPV: 0.75

Cut-off 2 mm for tumor depth:

Sensitivity: 0.929

NPV: 0.75

Cut-off 3 mm for tumor depth:

Sensitivity: 0.85.7

NPV: 0.667

Cut-off 4 mm for tumor depth:

Sensitivity: 0.643

NPV: 0.615

Cut-off 5 mm for tumor depth:

Sensitivity: 0.607

NPV: 0.656

Cut-off 6 mm for tumor depth:

Sensitivity: 0.464

NPV: 0.674

Tumor thickness:

Cut-off 1 mm for tumor thickness:

Sensitivity: 1.00

NPV: 1.00

Cut-off 2 mm for tumor thickness:

Sensitivity: 1.00

NPV: 1.00

Cut-off 3 mm for tumor thickness:

Sensitivity: 0.964

NPV: 0.80

Cut-off 4 mm for tumor thickness:

Sensitivity: 0.786

NPV: 0.625

Cut-off 5 mm for tumor thickness:

Sensitivity: 0.679

NPV: 0.625

Cut-off 6 mm for tumor thickness:

Sensitivity: 0.53.6

NPV: 0.649

Melchers 2012

Type of study:

Observational, database

Setting and country: Hospital, Netherlands

Funding and conflicts of interest: Funding not reported. The authors declare that there are no conflicts of interest.

Inclusion criteria:

Oral primary tumor location, histologically proven SCC, treated by resection of the primary tumor without prior head-neck or systemic oncological treatment, pT1-2 tumors, all clinicopathologic data regarding nodal status available.

Exclusion criteria:

Synchronous multiple tumors, irretrievable HE-slides, unreliable assessment of DOI.

N total at baseline:

N=212

Important prognostic factors²:

Median age (range):

61.5 (25-94

Sex:

119 M / 93 F

Tumor site, n:

Tongue: 108

Gum: 15

FOM: 64

Cheek mucosa: 7

Retromolar area: 12

Other: 6

pT-stage, n:

pT1: 123

pT2: 89

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Patients were treated by excision for their primary oral tumor. 174 patients received a neck dissection (n=106 with cN0), while 38 patients received a watchful waiting-strategy.

Clinical nodal stage was assessed with palpation combined with imaging (CT or MRI). PET or ultrasound may be performed on indication. Pathological N-stage was considered the ‘true’ N-stage after neck dissection. For patients in the watchful waiting-group, two years of follow-up were examined for the development of nodal metastases.

Watchful waiting consisted of return visits every 6 weeks.

Infiltration depth was measured as the maximum tumor infiltration below the mucosal surface. (mucosal surface was reconstructed for ulcerated or exophytic tumors)

1: 1mm

2: 2mm

3: 3mm

4: 4mm

5: 4.49 mm

6: 5mm

7: 6mm

8: 7mm

Describe control (treatment/procedure/test):

1: 1mm

2: 2mm

3: 3mm

4: 4mm

5: 4.49 mm

6: 5mm

7: 6mm

8: 7mm

Length of follow-up:

At least 2 years (for watchful waiting)

Loss-to-follow-up:

Incomplete outcome data:

NA, none other than the cases excluded from the sample

Outcome measures and effect size (include 95%CI and p-value if available):

Accuracy of neck dissection in cN0 (n=106)

Cut-ff 1 mm for DOI:

Sensitivity: 1.00

NPV: 1.00

Cut-ff 2 mm for DOI:

Sensitivity: 0.944

NPV: 0.938

Cut-ff 3 mm for DOI:

Sensitivity: 0.889

NPV: 0.939

Cut-ff 4 mm for DOI:

Sensitivity: 0.833

NPV: 0.94.3

Cut-ff 4.59 mm for DOI:

Sensitivity: 0.833

NPV: 0.948

Cut-ff 5 mm for DOI:

Sensitivity: 0.722

NPV: 0.918

Cut-ff 6 mm for DOI:

Sensitivity: 0.667

NPV: 0.915

Cut-ff 7 mm for DOI:

Sensitivity: 0.5

NPV: 0.889

Accuracy of watchful waiting in cN0 (n=38)

Cut-ff 1 mm for DOI:

Sensitivity: 1.00

NPV: 1.00

Cut-ff 2 mm for DOI:

Sensitivity: 0.857

NPV: 0.857

Cut-ff 3 mm for DOI:

Sensitivity: 0.714

NPV: 0.889

Cut-ff 4 mm for DOI:

Sensitivity: 0.714

NPV: 0.923

Cut-ff 4.59 mm for DOI:

Sensitivity: 0.714

NPV: 0.923

Cut-ff 5 mm for DOI:

Sensitivity: 0.571

NPV: 0.889

Cut-ff 6 mm for DOI:

Sensitivity: 0.571

NPV: 0.897

Cut-ff 3 mm for DOI:

Sensitivity: 0.571

NPV: 0.906

For the accuracy analyses, only cases with clinical negative neck nodes were used.

Sahoo 2020

Type of study:

Observational, database

Setting and country: Institute of dental sciences and a diagnostics center, India

Funding and conflicts of interest: Funding not reported. The authors declare that there are no conflicts of interest

Inclusion criteria:

histologically-proven oral SCC, patients >35 years, treated with wide excision of the primary tumor, treated with END

Exclusion criteria:

Metastatic tumor, recurrent tumors in the oral cavity, immune-compromised diseases and tumors, tumors under treatment of chemotherapy or radiotherapy.

N total at baseline:

N=150

Important prognostic factors²:

Age, n:

>60y: 40

<60y: 110

Sex:

99M / 51F

Tumor site, n:

GB sulcus: 113

Tongue: 29

FOM: 2

Retromolar area: 4

Maxilla: 2

cT-stage, n:

cT1: 27

cT2: 41

Note: unclear why there was missing data

Tumor differentiation, n:

Well: 87

Moderate: 60

Poor: 3

Lymphovscylar invasion, n:

Yes: 35

No: 115

Perineural invasion, n:

Yes: 41

No: 109

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Patients received excision for the primary tumor and underwent elective neck dissection.

Tumor thickness was measured from the level of adjacent normal mucosa to the deepest point of invasion without superficial keratin or inflammatory debris.

Depth of invasion was measured from the bottom of the most adjacent dysplastic abnormal rete ridge to the deepest point of invasion.

Tumor thickness: >8.64mm

DOI: >7.64mm

Describe control (treatment/procedure/test):

Tumor thickness: <8.64mm

DOI: <7.64mm

Length of follow-up:

unclear

Loss-to-follow-up:

Incomplete outcome data:

N=14 incomplete for tumor thickness measurements

N=27 incomplete for DOI measurements

Outcome measures and effect size (include 95%CI and p-value if available):

Accuracy of END, tumor thickness at 8.64mm cut-off (n=136):

Sensitivity: 0.72 (95%CI: 0.575-0.838)

Accuracy of END, DOI at 7.64mm cut-off (n=123):

Sensitivity: 0.727 (95%CI: 0.572-0.85)

Van Lanschot 2020

Type of study:

Observational, database

Setting and country: Hospital, Netherlands

Funding and conflicts of interest: work was supported by ATOS Medical B.V. (provided financial support for PhD student, no role in the study design). The authors declare there were no competing financial interests.

Inclusion criteria:

pT1-2 primary oral SCC

Exclusion criteria:

Synchronous multiple tumors, patients with clinically positive neck nodes

N total at baseline:

N=300 (n=173 END, 127 WW)

Important prognostic factors²:

Media age (range):

66.5 (24-94)

Sex:

158M / 142F

Smoking, n:

Active: 113

Quit smoking: 89

Non-smokers: 65

Alcohol, n:

Active: 163

Quit: 12

Non-consumer: 85

pT (tnm7),n:

T1: 197

T2: 90

pT (tnm8), n:

T1: 5

T2: 8

Tumor site, n:

Tongue: 162

FOM: 77

Buccal mucosa: 27

Lower alveolus and gingiva: 12

Upper alveolus and gingiva: 7

Lip: 7

Retromolar area: 5

Hard palate: 3

Infiltrative growth, n: 179

Vasoinvasion, n: 28

Perineural invasion, n: 52

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Patients were surgically treated. END was performed when DOI was ≥4mm. patient staged as cN0 wit DOI <4mm received a watch and wait strategy (5-year follow-up with physical examinations and regular ultrasound of the neck in the first 2 years)..

DOI measurement was taken from the basement membrane of the closest adjacent normal mucosa to the deepest point of infiltration.

1: <1mm

2: <2mm

3: <3mm

4: <4mm

5: <5mm

6: <6mm

Describe control (treatment/procedure/test):

1: 1mm

2: 2mm

3: 3mm

4: 4mm

5: 5mm

6: 6mm

Length of follow-up:

Mean follow-up: 23.4 months(range 0-62)

Loss-to-follow-up:

Incomplete outcome data:

Outcome measures and effect size (include 95%CI and p-value if available):

Accuracy of DOI (END+WW)

1mm cut-off for DOI, predicting lymph node metastases:

N (<1mm): 10

N (≥1mm): 290

Sensitivity: 1.00

NPV: 1.00

2mm cut-off for DOI, predicting lymph node metastases:

N (<2mm): 54

N (≥2mm): 246

Sensitivity: 1.00

NPV:1.00

3mm cut-off for DOI, predicting lymph node metastases:

N (<3mm): 93

N (≥3mm): 207

Sensitivity: 0.951

NPV: 0.978

4mm cut-off for DOI, predicting lymph node metastases:

N (<4mm): 139

N (≥4mm): 161

Sensitivity: 0.951

NPV: 0.986

5mm cut-off for DOI, predicting lymph node metastases:

N (<5mm): 171

N (≥5mm): 129

Sensitivity: 0.878

NPV: 0.971

6mm cut-off for DOI, predicting lymph node metastases:

N (<6mm): 190

N (≥6mm): 110

Sensitivity: 0.805

NPV: 0.958

Warburton 2007

Type of study:

Observational, database

Setting and country: Hospital, USA

Funding and conflicts of interest: Supported by the ivision of Intramural Researchm National Institute of Dental and Craniofacial Research, National Institutes of Health. Conflicts of interest were not declared in the manuscript.

Inclusion criteria:

Early stage (T1-2N0M0) tongue or floor of mouth carcinomas, treated by primary tumor resection without neck dissection or neck irradioation.

Exclusion criteria:

Lack of tumor tissue in the archived tissue

N total at baseline:

N=27

Important prognostic factors²:

Mean age (range):

64 (39-86)

Sex:

18 M / 9F

Alcohol use, n:

Yes: 15

No: 11

Tumor location, n:

FOM: 15

Tongue: 12

T-stage, n:

T1: 19

T2: 8

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Treated by primary tumor resection without neckdissection or irradiation.

Tumor thickness was measured from the surface of the epithelium to the deepest invading tumor island or cell using a reconstructed line (including the thickness lost due to ulceration) while excluding exophytic components.

Tumor thickness

1: >1.5mm

2: >1.6 mm

3: >2.0mm

4: >2.2mm

5: >2.7mm

6: >3.0mm

7: >3.8mm

Describe control (treatment/procedure/test):

Tumor thickness

1: ≤1.5mm

2: ≤1.6 mm

3: ≤2.0mm

4: ≤2.2mm

5: ≤2.7mm

6: ≤3.0mm

7: ≤3.8mm

Length of follow-up:

Unclear

Loss-to-follow-up:

Incomplete outcome data:

none

Outcome measures and effect size (include 95%CI and p-value if available):

Accuracy of tumor thickness cut-offs

>1.5mm versus ≤1.5mm tumor thickness:

TP: 8

FP: 10

FN: 0

TN: 9

Sensitivity: 1.00

NPV: 1.00

>1.6mm versus ≤1.6mm tumor thickness:

TP: 8

FP: 8

FN: 0

TN: 11

Sensitivity: 1.00

NPV: 1.00

>2mm versus ≤2mm tumor thickness:

TP: 7

FP: 5

FN: 1

TN: 14

Sensitivity: 0.875

NPV: 0.933

>2.2mm versus ≤2.2mm tumor thickness:

TP: 7

FP: 4

FN: 1

TN: 15

Sensitivity: 0.875

NPV: 0.938

>2.7mm versus ≤2.7mm tumor thickness:

TP: 6

FP: 3

FN: 2

TN: 16

Sensitivity: 0.75

NPV: 0.889

>3.0mm versus ≤3.0 mm tumor thickness:

TP: 4

FP: 1

FN: 4

TN: 18

Sensitivity: 0.5

NPV: 0.818

>3.8mm versus ≤3.8mm tumor thickness:

TP: 3

FP: 1

FN: 5

TN: 18

Sensitivity: 0.375

NPV: 0.783

NPV was calculated from the reported data

Wu 2019

Type of study:

Observational

Setting and country:

Hospital, China

Funding and conflicts of interest:

Inclusion criteria:

Pathologically confirmed tongue SCC (biopsy), T1-2 tumors, no cervical lymph node relapse (N0)

Exclusion criteria:

Not described.

N total at baseline:

N=141

Important prognostic factors²:

Age, n:

<55y: 59

≥55: 82

Average age = 55 years

Sex:

75M / 66F

Tumor differentiation, n:

Well: 48

Moderate /poor: 93

Neurovascular invasion, n:

Yes: 18

No: 123

Tumor location, n:

Anterior: 14

Middle: 103

Back: 24

T-stage, n:

T1: 60

T2: 81

Smoking, n:

Yes: 59

No: 82

Drinking, n:

Yes: 52

No: 89

Treatment, n:

Neck dissection: 69

Observation: 72

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Neck dissection and observation-strategy were randomly assigned.

For observation: patients were examined for cervical lymph nodes every 3 months (first 24 months), then every 6 months (for the following 36 months). Examination consisted of physical inspection and CT or MRI. Nodal relapses were pathologically proven.

Unclear how DOI was measured.

1: ≥4mm

Describe control (treatment/procedure/test):

1: <4mm

Length of follow-up:

Maximum of 60 months (observation)

Loss-to-follow-up:

None described

Incomplete outcome data:

None described

Outcome measures and effect size (include 95%CI and p-value if available):

Multivariable analysis of DOI

Risk of nodal metastases with DOI, multivariable model, <4mm(ref) versus ≥4mm:

N (<4mm): 43

N (≥4mm): 98

Adjusted OR: 12.23 (95%CI: 1.31-113.90)

Other variables in the model: gender, age, mode of invasion, pathological differentiation, neurovascular invasion, location, T-stage, smoking, drinking, treatment

No radiotherapy or chemotherapy had been provided before the collection of tumor samples

Xu 2020

Type of study:

Observational, database

Setting and country: Hospital, China

Funding and conflicts of interest: Funding not reported. Authors declare that there were no conflicts of interest.

Inclusion criteria:

≥18 years old, primary tongue SCC, cT1N0M0 carcinoma according to TNM 7, MRI data was available, follow-up data was available.

Exclusion criteria:

Not reported

N total at baseline:

N=151

Important prognostic factors²:

Mean age (range):

57.1 (30-78)

Smoker, n:

Yes: 101

No: 50

Alcohol users, n:

Yes: 61

No: 90

Perineural invasion, n:

Yes: 23

No:128

Lymphovascular invasion:

Yes: 19

No: 131

Growth pattern:

Ulcer: 72

Invasive: 20

Exogenous: 59

Sex:

111 M / 40F

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

MRI DOI was measured as the vertical distance between the deepest point of tumor infiltration and the simulated normal mucosal junction. DOI was determined by at least two radiologists.

Pathological DOI was measured from the level of adjacent normal mucosa to the deepest point of tumor infiltration.

Patients with very early stage disease did not undergo neck dissection. Elective neck dissection was routine for other stages. After therapy, the patients were examined every 3 months during the first 12 months, every 6 months during the following 12 months, and once yearly thereafter. Biopsy was performed when in suspicion of disease recurrence.

1: <7.5mm (MRI)

2: ≤5mm (path)

Describe control (treatment/procedure/test):

1: ≥7.5mm (MRI)

2: >5mm (path)

Length of follow-up:

Mean: 70.4 months (range: 8-103)

Loss-to-follow-up:

Incomplete outcome data:

Outcome measures and effect size (include 95%CI and p-value if available):

Risk of nodal metastases with MRI-measured DOI, multivariable model, <7.5mm versus ≥7.5mm(ref):

N (<7.5mm): 38

N (≥7.5mm): 113

Adjusted OR: 2.978 (95%CI: 1.574-7.332)

Other variables in the model: lymphovascular invasion, pathologic tumor grade, pathologic DOI

Risk of nodal metastases with pathology measured DOI, multivariable model, ≤5mm versus >5mm(ref):

N (≤5mm): 108

N (>5mm): 43

Adjusted OR: 3.112 (95%CI: 1.812-9.668)

Other variables in the model: lymphovascular invasion, pathologic tumor grade, MRI-measured DOI

Yeh 2014

Type of study:

Observational

Setting and country: Hospital, Taiwan

Funding and conflicts of interest: Funding not stated in the manuscript. Authors declare there were no CoI

Inclusion criteria:

Newly diagnosed T1-2 cN0 oral SCC, curative surgery

Exclusion criteria:

Previous cancer (unless disease-free >2 years).

N total at baseline:

N=272 (n=253 after excluding n=19 patients who received observation)

Important prognostic factors²:

pT-stage, n:

pT1: 128

pT2: 125

Tumor differentiation, n:

Well: 171

Moderate/poor: 82

Treatment, n:

Neck dissection: 176

Observation: 77

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

cN0 status was determined by clinical examination and imaging (including CT or MRI).

Patients received END or observation

pN+ was the pathological diagnosis of lymph node metastasis in the END group, or recurrence within 2 years without antecedent or synchronous local recurrence in the observation group.

Tumor thickness was measured vertically from the tumor surface or ulcer base to the deepest point of invasion on serial sections.

1: 0-6mm

Describe control (treatment/procedure/test):

1: >6mm

Length of follow-up:

2 year

Loss-to-follow-up:

Not described.

Incomplete outcome data:

n=19 patients who received observation

Reason: postoperative adjuvant therapy (n=7), local recurrence before neck recurrence (n=1), short follow-up period: <2 years (n=11).

Outcome measures and effect size (include 95%CI and p-value if available):

Accuracy of 0-6mm versus >6mm cut-off point for END+observation as one group:

TP: 30

FP: 88

FN: 25

TN: 111

Sensitivity: 0.545

Negative predictive value: 0.815

Sensitivity was calculated from the presented data

Zhang 2014

Type of study:

Observational

Setting and country: hospital, USA

Funding and conflicts of interest:

Inclusion criteria:

Biopsy proven cT1N0M0 SCC of the tongue, primary treatment with surgery, no previous treatment, staging of the neck with palpation and contrast enhanced CT, no other malignancies In the head and neck during treatment of tongue SCC, sufficient data recorded.

Exclusion criteria:

Carcinoma in situ, verrucous carcinoma, base of tongue carcinoma

N total at baseline:

N=65

Important prognostic factors²:

Mean age (range):

60.7 (24-91)

Sex:

32M / 33F

Smoking:

Yes: 19

No: 46

Non-drinkers / social drinkers: 50

Tumor location, n:

Dorsal: 2

Lateral: 54

Ventral: 9

Tumor differentiation, n:

Well: 37

Moderate: 18

Poor: 5

Unknown: 5

Perineural invasion, n:

Yes: 4

No: 58

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

Patients received observation if the tumor depth was <3 mm on biopsy. Patients received selective neck dissection when tumor depth was ≥3mm on biopsy. When pathologic tumor depth was ≥3mm after the biopsy tumor depth was <3mm, delayed neck dissection was recommended within 4-6 weeks.

Pathological tumor depth was measured from the level of the adjacent normal mucosa to the deepest point of invasion in to the tongue.

1: 2mm

2: 3mm

3: 4mm

4: 5mm

Describe control (treatment/procedure/test):

1: 2mm

2: 3mm

3: 4mm

4: 5mm

Length of follow-up:

Mean: 56.8 months (range: 4-148)

Loss-to-follow-up:

None other than due to death (see survival rates)

Incomplete outcome data:

None.

Outcome measures and effect size (include 95%CI and p-value if available):

Accuracy of tumor depth (WW/delayed ND/ND)

2mm cut-off for tumor depth, predicting lymph node metastases:

Sensitivity: 1.00

3mm cut-off for tumor depth, predicting lymph node metastases:

Sensitivity: 0.929

4mm cut-off for tumor depth, predicting lymph node metastases:

Sensitivity: 0.78.6

5mm cut-off for tumor depth, predicting lymph node metastases:

Sensitivity: 0.643

Notes:

Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures.
Provide data per treatment group on the most important prognostic factors ((potential) confounders).
For case-control studies, provide sufficient detail on the procedure used to match cases and controls.
For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders.

Risk of bias table for intervention studies (observational: non-randomized clinical trials, cohort and case-control studies)

Table of quality assessment - prognostic factor (PF) studies

Based on: QUIPS^A (Haydn, 2006; Haydn 2013)

Research question:

Study reference (first author, year of publication)	Study participation¹ Study sample represents the population of interest on key characteristics? (high/moderate/low risk of selection bias)	Study Attrition² Loss to follow-up not associated with key characteristics (i.e., the study data adequately represent the sample)? (high/moderate/low risk of attrition bias)	Prognostic factor measurement³ Was the PF of interest defined and adequately measured? (high/moderate/low risk of measurement bias related to PF)	Outcome measurement³ Was the outcome of interest defined and adequately measured? (high/moderate/low risk of measurement bias related to outcome)	Study confounding⁴ Important potential confounders are appropriately accounted for? (high/moderate/low risk of bias due to confounding)	Statistical Analysis and Reporting⁵ Statistical analysis appropriate for the design of the study? (high/moderate/low risk of bias due to statistical analysis)
Faisal 2018	Unclear	Low	Low	Unclear	High, stepwise regression method excluded non-significant predictors from the model. There are probably uncontrolled confounders.	low
Wu 2019	Low	Low	Unclear	Unclear	Unclear, confounders were not predefined. Nonetheless all variables seemed to be remained in the model (even when non-significant). There might be residual confounding.	Low
Xu 2020		Low	Low	Unclear	High, it seems that non-significant variables were excluded, instead of adding and keeping plausible confounders in the model. There are probably uncontrolled confounders.	Low

^Ahttps://methods.cochrane.org/sites/methods.cochrane.org.prognosis/files/public/uploads/QUIPS%20tool.pdf

¹Adequate description of: source population or population of interest, sampling and recruitment, period and place of recruitment, in- and exclusion criteria, study participation, baseline characteristics.

² Adequate response rate, information on drop-outs and loss to follow-up, no differences between participants who completed the study and those lost to follow-up.

³ Method of measurement is valid, reliable, setting of measurement is the same for all participants.

⁴ Important confounders are listed (including treatments), method of measurement is valid, reliable, setting of measurement is the same for all participants, important confounders are accounted for in the design (matching, stratification, initial assembly of comparable groups), or analysis (appropriate adjustment)

⁵ Enough data are presented to assess adequacy of the analysis, strategy of model building is appropriate and based on conceptual framework, no selective reporting.

Risk of bias assessment diagnostic accuracy studies (QUADAS II, 2011)

Research question:

Study reference

Patient selection

Index test

Reference standard

Flow and timing

Comments with respect to applicability

Den Toom 2019

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Probably yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: UNCLEAR

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

After discussion with the working group we decided that there was a low risk.

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW /HIGH/UNCLEAR

Goerkem, 2010;

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Probably yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

Unclear.

RISK: UNCLEAR

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

After discussion with the working group we decided that there was a low risk.

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Melchers, 2012;

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Probably yes (although a ROC was used to select 1 specific cut-off as well)

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes (two groups, separately reported)

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

After discussion with the working group we decided that there was a low risk.

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Sahoo, 2020

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

No (persons <35 years old were not included)

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Unclear

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: HIGH

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

After discussion with the working group we decided that there was a low risk.

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Van Lanschot, 2020;

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Probably yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

No (WW/ND)

Were all patients included in the analysis?

Unclear (probably eys)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

After discussion with the working group we decided that there was a low risk.

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

Two different reference standards were used.

RISK: HIGH

Warburton, 2007;

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Unclear

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Unclear (probably yes)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: UNCLEAR

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW /HIGH/UNCLEAR

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

After discussion with the working group we decided that there was a low risk.

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Yeh, 2014

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Unclear

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

No (ND/WW)

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: UNCLEAR

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

After discussion with the working group we decided that there was a low risk.

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: HIGH

Zhang, 2014

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Probably yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes/No/Unclear

Did patients receive the same reference standard?

No (ND/WW)

Were all patients included in the analysis?

Unclear (probably yes)

Are there concerns that the included patients do not match the review question?

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Are there concerns that the target condition as defined by the reference standard does not match the review question?

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: UNCLEAR

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

After discussion with the working group we decided that there was a low risk.

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: HIGH

Judgments on risk of bias are dependent on the research question: some items are more likely to introduce bias than others, and may be given more weight in the final conclusion on the overall risk of bias per domain:

Patient selection:

Consecutive or random sample has a low risk to introduce bias.
A case control design is very likely to overestimate accuracy and thus introduce bias.
Inappropriate exclusion is likely to introduce bias.

Index test:

This item is similar to “blinding” in intervention studies. The potential for bias is related to the subjectivity of index test interpretation and the order of testing.
Selecting the test threshold to optimise sensitivity and/or specificity may lead to overoptimistic estimates of test performance and introduce bias.

Reference standard:

When the reference standard is not 100% sensitive and 100% specific, disagreements between the index test and reference standard may be incorrect, which increases the risk of bias.
This item is similar to “blinding” in intervention studies. The potential for bias is related to the subjectivity of index test interpretation and the order of testing.

Flow and timing:

If there is a delay or if treatment is started between index test and reference standard, misclassification may occur due to recovery or deterioration of the condition, which increases the risk of bias.
If the results of the index test influence the decision on whether to perform the reference standard or which reference standard is used, estimated diagnostic accuracy may be biased.
All patients who were recruited into the study should be included in the analysis, if not, the risk of bias is increased.

Judgement on applicability:

Patient selection: there may be concerns regarding applicability if patients included in the study differ from those targeted by the review question, in terms of severity of the target condition, demographic features, presence of differential diagnosis or co-morbidity, setting of the study and previous testing protocols.

Index test: if index tests methods differ from those specified in the review question there may be concerns regarding applicability.

Reference standard: the reference standard may be free of bias but the target condition that it defines may differ from the target condition specified in the review question.

Table of excluded studies

Authors	Year	Reason for exclusion
Ahmed, S. Q. and Junaid, M. and Awan, S. and Kazi, M. and Khan, H. U. and Halim, S.	2018	risk was not adjusted
Al-Rajhi, N. and Khafaga, Y. and El-Husseiny, J. and Saleem, M. and Mourad, W. and Al-Otieschan, A. and Al-Amro, A.	2000	sample consists of oral and oropharynxcarcinomas
Alkureishi, Lee W. T. and Ross, Gary L. and Shoaib, Taimur and Soutar, David S. and Robertson, A. G. and Sorensen, Jens A. and Thomsen, Jorn and Krogdahl, Annelise and Alvarez, Julio and Barbier, Luis and Santamaria, Joseba and Poli, Tito and Sesenna, Enrico and Kovacs, Adorjan F. and Grunwald, Frank and Barzan, Luigi and Sulfaro, Sandro and Alberti, Franco	2008	risk was not adjusted
Bier-Laning, Carol M. and Durazo-Arvizu, Ramon and Muzaffar, Kamil and Petruzzelli, Guy J.	2009	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Brockhoff, H. C. and Kim, R. Y. and Braun, T. M. and Skouteris, C. and Helman, J. I. and Ward, B. B.	2017	Unclear whether patient initially presenting positive nodes were excluded or whether they had previously undetected nodes. (Zie tekst voor model C (tumor size en DOI), zie tabel 6 voor accuracy per mm)
Chandler, K. and Vance, C. and Budnick, S. and Muller, S.	2011	Unclear what surgical procedures were given (or whether observation strategy was provided)
Chen, Y. W. and Yu, E. H. and Wu, T. H. and Lo, W. L. and Li, W. Y. and Kao, S. Y.	2008	risk was not adjusted
De Silva, R. K. and Siriwardena, B. S. M. S. and Samaranayaka, A. and Abeyasinghe, W. A. M. U. L. and Tilakaratne, W. M.	2018	Not stated in the selection criteria that the sample must have had a cN0 neck at presentation
Dik, E. A. and Willems, S. M. and Ipenburg, N. A. and Rosenberg, A. J. W. P. and Van Cann, E. M. and van Es, R. J. J.	2016	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Ettl, Tobias and Irga, Serkan and Muller, Steffen and Rohrmeier, Christian and Reichert, Torsten E. and Schreml, Stephan and Gosau, Martin	2014	concerns resection margin instead of infoltration depth/tumorthickness
Feng, Z. and Cheng, A. and Alzahrani, S. and Li, B. and Han, Z. and Ward, B. B.	2020	Results reported in the text concern univariable analyses (See table 3)
Hakeem, Arsheed Hussain and Pradhan, Sultan Ahmed and Kannan, Rajan and Tubachi, Jagadish	2016	risk was not adjusted
Huang, C. and Zhuang, S. M. and Li, J. J. and Chen, S. W. and Zhang, X. W. and Song, M.	2017	Unadjusted results
Huang, C. and Zhuang, S. M. and Li, J. J. and Chen, S. W. and Zhang, X. W. and Song, M.	2017	risk was not adjusted
Imai, T. and Satoh, I. and Matsumoto, K. and Asada, Y. and Yamazaki, T. and Morita, S. and Saijo, S. and Okubo, J. I. and Wakamori, S. and Saijo, S. and Matsuura, K.	2017	Unadjusted results
Imai, T. and Satoh, I. and Matsumoto, K. and Asada, Y. and Yamazaki, T. and Morita, S. and Saijo, S. and Okubo, J. I. and Wakamori, S. and Saijo, S. and Matsuura, K.	2017	risk was not adjusted
Jacob, T. E. and Malathi, N. and Rajan, S. T. and Augustine, D. and Manish, N. and Patil, S.	2016	tumor depth, not tumor thicknes/DOI
Jayasankaran, S. C. and Chelakkot, P. G. and Karippaliyil, M. and Thankappan, K. and Iyer, S. and Moorthy, S.	2017	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Jin, W. L. and Ye, W. M. and Zheng, J. W. and Zhou, L. and Zhu, H. G. and Zhang, Z. Y. and Tian, J.	2008	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Jing, Jie and Li, Longjiang and He, Wei and Sun, Gang	2006	Did not exclude patients presenting with positive neck nodes
Jung, J. and Cho, N. H. and Kim, J. and Choi, E. C. and Lee, S. Y. and Byeon, H. K. and Park, Y. M. and Yang, W. S. and Kim, S. H.	2009	risk was not adjusted
Kozak, M. M. and Shah, J. and Chen, M. and Schaberg, K. and von Eyben, R. and Chen, J. J. and Bui, T. and Kong, C. and Kaplan, M. and Divi, V. and Hara, W.	2019	risk was not adjusted, does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest in multivriable analysis
Kumar, Tarun and Patel, Mahesh D.	2013	risk was not adjusted
Kunzel, J. and Psychogios, G. and Koch, M. and Mantsopoulos, K. and Kapsreiter, M. and Iro, H.	2013	Unadjusted results
Kurokawa, H. and Yamashita, Y. and Takeda, S. and Zhang, M. and Fukuyama, H. and Takahashi, T.	2002	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Li, Q. L. and Chen, F. J. and Zeng, Z. Y. and Yang, A. K. and Wu, Q. L. and Zhang, H. Z. and Wu, G. H. and Xu, G. P. and Guo, Z. M. and Zhang, Q.	2003	Article in Chinese
Lin, M. J. and Guiney, A. and Iseli, C. E. and Buchanan, M. and Iseli, T. A.	2011	Did not exclude patients presenting with positive neck nodes
Mair, M. D. and Shetty, R. and Nair, D. and Mathur, Y. and Nair, S. and Deshmukh, A. and Thiagarajan, S. and Pantvaidya, G. and Lashkar, S. and Prabhash, K. and Chaukar, D. and Pai, P. and Cruz, A. D. and Chaturvedi, P.	2018	Not all patients underwent radiology or histopathology to assess the nodal status of the neck at presentation: clinical or radiological detected metastases. From the article: "it is important to note that all patients did not underwent radiological examination for detection of occult metastasis as per our institute policy which would not insist for radiological neck assessment in early oral cancer unless essentially required"
Mark Taylor, S. and Drover, C. and MacEachern, R. and Bullock, M. and Hart, R. and Psooy, B. and Trites, J.	2010	risk was not adjusted
Mark Taylor, S. and Drover, C. and MacEachern, R. and Bullock, M. and Hart, R. and Psooy, B. and Trites, J.	2009	duplicate
Masood, M. M. and Farquhar, D. R. and Vanleer, J. P. and Patel, S. N. and Hackman, T. G.	2018	Did not exclude patients presenting with positive neck nodes
Mattalitti, S. F. O. and Kawazu, T. and Kawano, S. and Ikari, T. and Wada, H. and Yoshiura, K.	2017	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Melchers, L. J. and Schuuring, E. and Van Dijk, B. A. C. and De Bock, G. H. and Witjes, M. J. H. and Van Der Laan, B. F. A. M. and Van Der Wal, J. E. and Roodenburg, J. L. N.	2012	duplicate
Melkane, A. E. and Mamelle, G. and Wycisk, G. and Temam, S. and Janot, F. and Casiraghi, O. and Lumbroso, J.	2012	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Moe, J. and McHugh, J. B. and Udager, A. M. and Braun, T. M. and Helman, J. I. and Ward, B. B.	2019	does not report the outcomes of interest per millimeter DOI/tumor thickness
Morand, G. B. and Ikenberg, K. and Vital, D. G. and Cardona, I. and Moch, H. and Stoeckli, S. J. and Huber, G. F.	2019	Risk from DOI in the multivariable regression was continuous, risk from categorized DOI was not adjusted
Nair, A. V. and Meera, M. and Rajamma, B. M. and Anirudh, S. and Nazer, P. K. and Ramachandran, P. V.	2018	risk was not adjusted
Nayanar, Sangeetha Keloth and Tripathy, Jaya Prasad and Duraisamy, Karthickeyan and Babu, Sajith	2019	seems to be univariable, for the multivariable analysis it seems that only the risk scores were calculated/reported and not the model or per mm (or cutoff mm)
O'Brien, C. J. and Lauer, C. S. and Fredricks, S. and Clifford, A. R. and McNeil, E. B. and Bagia, J. S. and Koulmandas, C.	2003	Did not exclude patients presenting with positive neck nodes
Otsuru, M. and Ota, Y. and Yanamoto, S. and Okura, M. and Umeda, M. and Kirita, T. and Kurita, H. and Ueda, M. and Komori, T. and Yamakawa, N. and Kamata, T. and Hasegawa, T. and Shibahara, T. and Ohiro, Y. and Yamashita, Y. and Noguchi, K. and Noguchi, T. and Karakida, K. and Naito, H. and Aikawa, T. and Yamashita, T. and Kabata, D. and Shintani, A.	2019	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Pentenero, M. and Gandolfo, S. and Carrozzo, M.	2005	not a systematic review
Prabu, N. P. and Swaranapriya and Sargunar, B. and Shamugapriyan and Mohan, R.	2017	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Reddy, V. and Wadhwan, V. and Reddy, M. and Venkatesh, A.	2018	Figures and tables are not published on the journal's website and not printed in the fulltext PDF file
Seki, M. and Sano, T. and Yokoo, S. and Oyama, T.	2017	Did not exclude patients presenting with positive neck nodes
Sheahan, P. and O'Keane, C. and Sheahan, J. N. and O'Dwyer, T. P.	2003	logistic regression seems to be performed for composite outcomes ("occult metastases or outcome XYZ"), outcomes of the multiple regression do not seem to be reported besides a p-value
Shin, J. H. and Yoon, H. J. and Kim, S. M. and Lee, J. H. and Myoung, H.	2020	risk was not adjusted
Shin, Jung-Hyun and Yoon, Hye-Jung and Kim, Soung-Min and Lee, Jong-Ho and Myoung, Hoon	2020	Unadjusted results
Sparano, A. and Weinstein, G. and Chalian, A. and Yodul, M. and Weber, R.	2004	multivariable model uses TT as a continuous variable (no dichotomization/cut-off was used)
Subramaniam, N. and Balasubramanian, D. and Low, T. H. H. and Murthy, S. and Anand, A. and Prasad, C. and Vijayan, S. N. and Thankappan, K. and Iyer, S.	2018	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Subramaniam, N. and Balasubramanian, D. and Murthy, S. and Kumar, N. and Vidhyadharan, S. and Vijayan, S. N. and Nambiar, A. and Thankappan, K. and Iyer, S.	2019	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Suzuki, Mitsuya and Suzuki, Tsunemiti and Asai, Masao and Ichimura, Kei-Ichi and Nibu, Ken-Ichi and Sugasawa, Masashi and Kaga, Kimitaka	2007	Did not exclude patients presenting with positive neck nodes
Tai, S. K. and Li, W. Y. and Chu, P. Y. and Chang, S. Y. and Tsai, T. L. and Wang, Y. F. and Huang, J. L.	2012	Unadjusted results
Tam, Samantha and Amit, Moran and Zafereo, Mark and Bell, Diana and Weber, Randal S.	2019	multivariable model uses TT as a continuous variable (no dichotomization/cut-off was used)
Tanaka, K. and Hanai, N. and Eba, J. and Mizusawa, J. and Asakage, T. and Homma, A. and Kiyota, N. and Fukuda, H. and Hayashi, R.	2018	study protocol
Tarsitano, Achille and Del Corso, Giacomo and Tardio, Maria Lucia and Marchetti, Claudio	2016	risk was not adjusted
Terada, H. and Sasaki, E. and Suzuki, H. and Nishikawa, D. and Beppu, S. and Hanai, N.	2020	Only approximable from a figure
Tsai, C. Y. and Lai, Y. S. and Chen, M. K.	2014	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Tsang, R. K. Y. and Chung, J. C. K. and Howe To, V. S. and Chan, J. Y. W. and Ho, W. K. and Wei, W. I.	2011	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Veness, M. J. and Morgan, G. J. and Sathiyaseelan, Y. and Gebski, V.	2005	Participants were not clinically node-negative (cN0) in 43% at recruitment
Vijayakumar, M. and Burrah, R. and Sabitha, K. S. and Nadimul, H. and Rajani, B. C.	2011	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Wermker, Kai and Belok, Friederike and Schipmann, Stephanie and Klein, Martin and Schulze, Hans-Joachim and Hallermann, Christian	2015	postive neck nodes at presentation were not excluded
Zenga, J. and Divi, V. and Stadler, M. and Massey, B. and Campbell, B. and Shukla, M. and Awan, M. and Schultz, C. J. and Shreenivas, A. and Wong, S. and Jackson, R. S. and Pipkorn, P.	2019	does not report the outcomes of interest per millimeter DOI/tumor thickness for the outcomes of interest
Zou, H. and Zhang, W. F. and Lu, T. T. and Chen, X. M. and Zhao, Y. F.	2005	Did not seem to exclude patients presenting with positive neck nodes

Verantwoording

Autorisatiedatum en geldigheid

Laatst beoordeeld :

Laatst geautoriseerd :

Geplande herbeoordeling : 01-01-2027

De geldigheid van de richtlijnmodule komt te vervallen indien nieuwe ontwikkelingen aanleiding zijn een herzieningstraject te starten.

NB: Informatie over de autorisatiedatum, autoriserende partij(en), herbevestiging en regiehouder(s) worden ter zijne tijd na autorisatie toegevoegd aan deze alinea.

Module[1]	Regiehouder(s)[2]	Jaar van autorisatie	Eerstvolgende beoordeling actualiteit richtlijn[3]	Frequentie van beoordeling op actualiteit[4]	Wie houdt er toezicht op actualiteit[5]	Relevante factoren voor wijzigingen in aanbeveling[6]
Afkappunt invasiediepte cT1-2N0

[1] Naam van de module

[2] Regiehouder van de module (deze kan verschillen per module en kan ook verdeeld zijn over meerdere regiehouders)

[3] Maximaal na vijf jaar

[4] (half)Jaarlijks, eens in twee jaar, eens in vijf jaar

[5] regievoerende vereniging, gedeelde regievoerende verenigingen, of (multidisciplinaire) werkgroep die in stand blijft

[6] Lopend onderzoek, wijzigingen in vergoeding/organisatie, beschikbaarheid nieuwe middelen

Initiatief en autorisatie

Initiatief:

Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied

Geautoriseerd door:

Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied

Algemene gegevens

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten en werd gefinancierd uit de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

De richtlijn is ontwikkeld in samenwerking met:

Nederlandse Internisten Vereniging
Nederlandse Vereniging voor Mondziekten, Kaak- en Aangezichtschirurgie
Nederlandse Vereniging voor Nucleaire Geneeskunde
Nederlandse Vereniging voor Pathologie
Nederlandse Vereniging voor Plastische Chirurgie
Nederlandse Vereniging voor Radiologie
Nederlandse Vereniging voor Radiotherapie en Oncologie
Nederlandse Federatie van Kankerpatiëntenorganisaties | Patiëntenvereniging HOOFD-HALS
Verpleegkundigen en Verzorgenden Nederland | Oncologie

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodule is in 2019 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen die betrokken zijn bij de zorg voor patiënten met hoofd-halstumoren.

Werkgroep

Prof. Dr. R. de Bree, KNO-arts/hoofd-halschirurg, UMC Utrecht, Utrecht, NVKNO (voorzitter)
Dr. M.B. Karakullukcu, KNO-arts/hoofd-halschirurg, NKI, Amsterdam, NVKNO
Dr. H.P. Verschuur, KNO-arts/hoofd-halschirurg, Haaglanden MC, Den Haag, NVKNO
Dr. M. Walenkamp, AIOS-KNO, LUMC, Leiden, NVKNO
Dr. A. Sewnaik, KNO-arts/hoofd-halschirurg, Erasmus MC, Rotterdam, NVKNO
Drs. L.H.E. Karssemakers, MKA-chirurg-oncoloog/hoofd-hals chirurg, NKI, Amsterdam, NVMKA
Dr. M.J.H. Witjes, MKA-chirurg-oncoloog, UMC Groningen, Groningen, NVMKA
Drs. L.A.A. Vaassen, MKA-chirurg-oncoloog, Maastricht UMC+, Maastricht, NVMKA
Drs. W.L.J. Weijs, MKA-chirurg-oncoloog, Radboud UMC, Nijmegen, NVKMA
Drs. E.M. Zwijnenburg, Radiotherapeut-oncoloog, Radboud UMC, Nijmegen, NVRO
Dr. A. Al-Mamgani, Radiotherapeut-oncoloog, NKI, Amsterdam, NVRO
Prof. Dr. C.H.J. Terhaard, Radiotherapeut-oncoloog, UMC Utrecht, Utrecht, NVRO
Drs. J.G.M. Van den Hoek, Radiotherapeut-oncoloog, UMC Groningen, Groningen, NVRO
Dr. E. Van Meerten, Internist-oncoloog, Erasmus MC Kanker Instituut, Rotterdam, NIV
Dr. M. Slingerland, Internist-oncoloog, LUMC, Leiden, NIV
Drs. M.A. Huijing, Plastisch Chirurg, UMC Groningen, Groningen, NVPC
Prof. Dr. S.M. Willems, Klinisch patholoog, UMC Groningen, Groningen, NVVP
Prof. Dr. E. Bloemena, Klinisch patholoog, Amsterdam UMC, locatie Vumc, Amsterdam, NVVP
R.A. Burdorf, Voorzitter dagelijks bestuur patiëntenvereniging, Patiëntenvereniging HOOFD-HALS, PvHH
P.S. Verdouw, Hoofd infocentrum patiëntenvereniging, Patiëntenvereniging HOOFD-HALS, PvHH
A.A.M. Goossens, Verpleegkundig specialist oncologie, Haaglanden MC, Den Haag, V&VN
Dr. P. de Graaf, Radioloog, Amsterdam UMC, Amsterdam, NVvR
Dr. W.V. Vogel, Nucleair geneeskundige/radiotherapeut-oncoloog, NKI, Amsterdam, NVNG
Drs. G.J.C. Zwezerijnen, Nucleair geneeskundige, Amsterdam UMC, Amsterdam, NVNG

Klankbordgroep

Dr. C.M. Speksnijder, Fysiotherapeut, UMC Utrecht, Utrecht, KNGF
Ir. A. Kok, Diëtist, UMC Utrecht, Utrecht, NVD
Dr. M.M. Hakkesteegt, Logopedist, Erasmus MC, Rotterdam, NVvLF
Drs. D.J.M. Buurman, Tandarts-MFP, Maastricht UMC+, Maastricht, KNMT
W. Van der Groot-Roggen, Mondhygiënist, UMC Groningen, Groningen, NVvM
Drs. D.J.S. Dona, Bedrijfsarts/Klinisch arbeidsgeneeskundige oncologie, Radboud UMC, Nijmegen, NVKA
Dr. M. Sloots, Ergotherapeut, UMC Utrecht, Utrecht
J. Poelstra, Medisch maatschappelijk werkster, op persoonlijke titel

Met dank aan

Maarten Donswijk, Nucleair geneeskundig, AVL

Met ondersteuning van

Dr. J. Boschman, Senior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. C. Gaasterland, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. A. Van der Hout, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. L. Oostendorp, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Drs. M. Oerbekke, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Drs. A. Hoeven, Junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten

Belangenverklaringen

De Code ter voorkoming van oneigenlijke beïnvloeding door belangenverstrengeling is gevolgd. Alle werkgroepleden hebben schriftelijk verklaard of zij in de laatste drie jaar directe financiële belangen (betrekking bij een commercieel bedrijf, persoonlijke financiële belangen, onderzoeksfinanciering) of indirecte belangen (persoonlijke relaties, reputatiemanagement) hebben gehad. Gedurende de ontwikkeling of herziening van een module worden wijzigingen in belangen aan de voorzitter doorgegeven. De belangenverklaring wordt opnieuw bevestigd tijdens de commentaarfase.

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten.

Werkgroeplid	Functie	Nevenfuncties	Gemelde belangen	Ondernomen actie
*Bree, de*	KNO-arts/hoofd-halschirurg, UMC Utrecht	* Lid Algemeen Bestuur Patiëntenvereniging Hoofd-Hals (onbetaald) * Voorzitter Research Stuurgroep NWHHT * Lid Richtlijnen commissie NWHHT * Lid dagelijks bestuur NWHHT * Lid Clinical Audit Board van de Dutch Head and Neck Audit (DHNA) * Lid wetenschappelijk adviescommissie DORP * Voorzitter Adviescommissie onderzoek hoofd-halskanker (IKNL/PALGA/DHNA/NWHHT)	Geen	Geen
*Slingerland*	Internist-oncoloog, LUMC	* 2018-present: Treasurer of the "Dutch Association of Medical Oncology"(NVMO - vacancy fees) * 2018-present: Member of the "Dutch Working Group for Head-Neck Tumors" (NWHHT-Systemic therapy) * 2016-present: Member of the 'Dutch Working Group for Head-Neck Tumors" (NWHHT - study group steering group (coordinating)) * 2016-present: Member of the "Dutch Working Group for Head-Neck Tumors" (NWHHT - Elderly Platform) * 2012-present: Member "Working Group for Head-Neck Tumors" (WHHT) "University Cancer Centre"(UCK) Leiden - Den Haag * 2019: Member CAB DHNA	Deelname Nationaal expert forum hoofd-halskanker MSD dd 2-5-2018 * Deelname Checkmate studie, sponsor Bristol-Myers Squibb (BMS): An open label, randomized phase 3 clinical trial of nivolumab versus therapy of investigator's choice in recurrent or metastatic platinum-refractory squamous cell carcinoma of the head and neck (SCCHN) * Deelname Commence studie, sponsor Radboud University, in collaboration with Merck Serono International SA (among several Dutch medical centers): A phase lB-II study of the combination of cetuximab and methotrexate in recurrent of metastatic squamous cell carcinoma of the head and neck. A study of the Dutch Head and Neck Society, MOHN01/COMMENCE study. * Deelname HESPECTA studie: Phase I study: to determine the biological activity of two HPV16E6 specific peptides coupled to Amplivant®, a Toll-like receptor ligand in non-metastatic patients treated for HPV16-positive head and neck cancer. * Deelname PINCH studie (nog niet open): PD-L1 ImagiNg to predict durvalumab treatment response in HNSCC (PINCH) trial; patiënten met biopt bewezen locally recurrent of gemetastaseerd HNSCC * Deelname ISA 101b-HN-01-17 studie (nog niet open): A randomized, Double-blind, Placebo-Controlled, Phase 2 Study of Cemiplimab versus the combination of Cemiplimab with ISA101b in the Treatment of Subjects.	In de werkgroep participeren 2 internist-oncologen, zodat één van beide de voortrekker is van modules over systemische therapie. Actie: werkgroeplid is uitgesloten van besluitvorming bij modules die betrekking hebben op de onderwerpen van de gemelde onderzoeken: nivolumab, cetuximab + methotrexaat, Amplivant, durvalumab, cemiplimab.
*Meerten, van*	Internist-oncoloog, Erasmus MC Kanker Instituut	Geen	Op dit moment Principal Investigator voor NL van gerandomiseerde fase III trial naar toegevoegde waarde van pembrolizumab aan chemoradiotherapie bij patiënten met gevorderd hoofdhalskanker. Sponsor: GlaxoSmithKline Research & Development Ltd. Studie is nog lopend, resultaten zullen pas bekend zijn na verschijning van de richtlijn. In toekomst mogelijk participatie aan door industrie gesponsorde studies op gebied van behandeling van hoofdhalskanker	In de werkgroep participeren 2 internist-oncologen, zodat één van beide de voortrekker is van modules over systemische therapie. Actie: werkgroeplid is uitgesloten van besluitvorming bij modules die betrekking hebben op het onderwerp van het gemelde onderzoeken: de toegevoegde waarde van pembrolizumab bij patiënten met gevorderd hoofdhalskanker.
*Huijing*	Plastisch chirurg, UMC Groningen	Geen	Geen	Geen
*Sewnaik*	KNO-arts/hoofd Hals chirurg, Erasmus MC	Sectorhoofd Hoofd-Hals chirurgie	Geen	Geen
*Vaassen*	MKA-chirurg-oncoloog, Maastricht UMC+ / CBT Zuid-Limburg	Lid Bestuur NVMKA Waarnemend hoofd MKA-chirurgie MUMC	Geen	Geen
*Witjes*	MKA-chirurg-oncoloog, UMC Groningen	Geen	PI van KWF grant: RUG 2015 -8084: Image guided surgery for margin assessment of head & neck Cancer using cetuximab-IRDye800 cONjugate (ICON) geen financieel belang	Geen. Financiering door KWF werd niet als een belang ingeschat.
*Bloemena*	Klinisch patholoog, Amsterdam UMC (locatie Vumc) / Radboud UMC / Academisch Centrum voor Tandheelkunde Amsterdam (ACTA)	* Lid bestuur Nederlandse Vereniging voor Pathologie (NVVP) – vacatiegeld (tot 1-12-20) * Voorzitter Commissie Bij- en Nascholing (NVVP) * Voorzitter (tot 1-12-20) Wetenschappelijke Raad PALGA - onbezoldigd	Geen	Geen
*Willems*	Klinisch patholoog, UMC Groningen	Vice-vz PALGA, AB NWHHT, CAB DHNA, mede-vz en oprichter expertisegroep HH pathologie NL, Hoofdhalspathologie UMC Groningen	PDL1 trainer NL voor MSD Onderzoeksfinanciering van Pfizer, Roche, MSD, BMS, Lilly, Novartis, Bayer, Amge, AstraZeneca	Geen
*Karakullukcu*	KNO-arts/hoofd-hals chirurg, NKI/AVL	Geen	Geen	Geen
*Verschuur*	KNO-arts/Hoofd-hals chirurg, Haaglanden MC	* Opleider KNO-artsen * Dagvoorzitter	Geen	Geen
*Walenkamp*	AIOS KNO, LUMC	Geen	Geen	Geen
*Al-Mamgani*	Radiotherapeut-oncoloog, NKI/AVL	Geen	Geen	Geen
*Terhaard*	Radiotherapeut-oncoloog, UMC Utrecht	Niet van toepassing	Geen	Geen
*Hoek, van den*	Radiotherapeut-oncoloog UMCG	Niet van toepassing	Geen	Geen
*Zwijnenburg*	Radiotherapeut, Hoofd-hals Radboud UMC	Geen	Geen	Geen
*Burdorf*	Patiëntvertegenwoordiger	Geen	Geen	Geen
*Verdouw*	Hoofd Infocentrum patiëntenvereniging HOOFD HALS	Geen	Werkzaam bij de patiëntenvereniging. De achterban heeft baat bij een herziening van de richtlijn	Geen
*Karssemakers*	Hoofd-hals chirurg NKI/AVL MKA-chirurg-oncoloog Amsterdam UMC (locatie AMC) / vakgroep kaakchirurgie Amsterdam West	Niet van toepassing	Geen	Geen
*Goossens*	Verpleegkundig specialist, Haaglanden Medisch Centrum (HMC)	* Bestuurslid (penningmeester) PWHHT (onbetaald) * Lid Commissie voorlichting PVHH (onbetaald)	Geen	Geen
*Zwezerijnen*	Nucleair geneeskundige, Amsterdam UMC (locatie Vumc) PhD kandidaat, Amsterdam UMC (locatie Vumc)	Lid als nucleair geneeskundige in HOVON imaging werkgroep (bespreken van richtlijnen en opzetten/uitvoeren van wetenschappelijke studies met betrekking tot beeldvorming in de hematologie); onbetaald	Geen	Geen
*Vogel*	Nucleair geneeskundige/radiotherapeut-oncoloog, AVL	Geen	In de afgelopen jaren incidenteel advies of onderwijs, betaald door Bayer, maar niet gerelateerd aan hoofd-hals KWF-grant speekselklier toxiteit na behandeling. Geen belang bij de richtlijn	Geen
*Graaf, de*	Radioloog, Amsterdam UMC (locatie Vumc)	Bestuurslid sectie Hoofd-Hals radiologie (onbetaald)	Geen	Geen
*Weijs*	MKA-chirurg-oncoloog, Radboudumc	MKA-chirurg, Weijsheidstand B.V. Werkzaam als algemeen praktiserend MKA-chirurg, betaald (0,1 fte)	Geen	Geen

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door het uitnodigen van de patiëntenvereniging HOOFD-HALS (PVHH) voor de Invitational conference en met afgevaardigden van de PVHH in de werkgroep. Het verslag hiervan is besproken in de werkgroep. De verkregen input is meegenomen bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen. De conceptrichtlijn is tevens voor commentaar voorgelegd aan de patiëntenvereniging HOOFD-HALS en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

Methode ontwikkeling

Evidence based

Werkwijze

AGREE

Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).

Knelpuntenanalyse en uitgangsvragen

Tijdens de voorbereidende fase inventariseerden de werkgroep de knelpunten in de zorg voor patiënten met hoofd-halstumoren. De werkgroep beoordeelde de aanbeveling(en) uit de eerdere richtlijnmodule (NVKNO, 2014) op noodzaak tot revisie. Tevens zijn er knelpunten aangedragen door de patiëntenvereniging en genodigde partijen tijdens de Invitational conference (zie bijlagen). Op basis van de uitkomsten van de knelpuntenanalyse zijn door de werkgroep concept-uitgangsvragen opgesteld en definitief vastgesteld.

Uitkomstmaten

Na het opstellen van de zoekvraag behorende bij de uitgangsvraag inventariseerde de werkgroep welke uitkomstmaten voor de patiënt relevant zijn, waarbij zowel naar gewenste als ongewenste effecten werd gekeken. Hierbij werd een maximum van acht uitkomstmaten gehanteerd. De werkgroep waardeerde deze uitkomstmaten volgens hun relatieve belang bij de besluitvorming rondom aanbevelingen, als cruciaal (kritiek voor de besluitvorming), belangrijk (maar niet cruciaal) en onbelangrijk. Tevens definieerde de werkgroep tenminste voor de cruciale uitkomstmaten welke verschillen zij klinisch (patiënt) relevant vonden.

Methode literatuursamenvatting

Een uitgebreide beschrijving van de strategie voor zoeken en selecteren van literatuur en de beoordeling van de risk-of-bias van de individuele studies is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.

Beoordelen van de kracht van het wetenschappelijke bewijs

De kracht van het wetenschappelijke bewijs werd bepaald volgens de GRADE-methode. GRADE staat voor ‘Grading Recommendations Assessment, Development and Evaluation’ (zie http://www.gradeworkinggroup.org/). De basisprincipes van de GRADE-methodiek zijn: het benoemen en prioriteren van de klinisch (patiënt) relevante uitkomstmaten, een systematische review per uitkomstmaat, en een beoordeling van de bewijskracht per uitkomstmaat op basis van de acht GRADE-domeinen (domeinen voor downgraden: risk of bias, inconsistentie, indirectheid, imprecisie, en publicatiebias; domeinen voor upgraden: dosis-effect relatie, groot effect, en residuele plausibele confounding).

GRADE onderscheidt vier gradaties voor de kwaliteit van het wetenschappelijk bewijs: hoog, redelijk, laag en zeer laag. Deze gradaties verwijzen naar de mate van zekerheid die er bestaat over de literatuurconclusie, in het bijzonder de mate van zekerheid dat de literatuurconclusie de aanbeveling adequaat ondersteunt (Schünemann, 2013; Hultcrantz, 2017).

GRADE	Definitie
Hoog	er is hoge zekerheid dat het ware effect van behandeling dicht bij het geschatte effect van behandeling ligt; het is zeer onwaarschijnlijk dat de literatuurconclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Redelijk	er is redelijke zekerheid dat het ware effect van behandeling dicht bij het geschatte effect van behandeling ligt; het is mogelijk dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Laag	er is lage zekerheid dat het ware effect van behandeling dicht bij het geschatte effect van behandeling ligt; er is een reële kans dat de conclusie klinisch relevant verandert wanneer er resultaten van nieuw grootschalig onderzoek aan de literatuuranalyse worden toegevoegd.
Zeer laag	er is zeer lage zekerheid dat het ware effect van behandeling dicht bij het geschatte effect van behandeling ligt; de literatuurconclusie is zeer onzeker.

Bij het beoordelen (graderen) van de kracht van het wetenschappelijk bewijs in richtlijnen volgens de GRADE-methodiek spelen grenzen voor klinische besluitvorming een belangrijke rol (Hultcrantz, 2017). Dit zijn de grenzen die bij overschrijding aanleiding zouden geven tot een aanpassing van de aanbeveling. Om de grenzen voor klinische besluitvorming te bepalen moeten alle relevante uitkomstmaten en overwegingen worden meegewogen. De grenzen voor klinische besluitvorming zijn daarmee niet één op één vergelijkbaar met het minimaal klinisch relevant verschil (Minimal Clinically Important Difference, MCID). Met name in situaties waarin een interventie geen belangrijke nadelen heeft en de kosten relatief laag zijn, kan de grens voor klinische besluitvorming met betrekking tot de effectiviteit van de interventie bij een lagere waarde (dichter bij het nuleffect) liggen dan de MCID (Hultcrantz, 2017).

Overwegingen (van bewijs naar aanbeveling)

Om te komen tot een aanbeveling zijn naast (de kwaliteit van) het wetenschappelijke bewijs ook andere aspecten belangrijk en worden meegewogen, zoals aanvullende argumenten uit bijvoorbeeld de biomechanica of fysiologie, waarden en voorkeuren van patiënten, kosten (middelenbeslag), aanvaardbaarheid, haalbaarheid en implementatie. Deze aspecten zijn systematisch vermeld en beoordeeld (gewogen) onder het kopje ‘Overwegingen’ en kunnen (mede) gebaseerd zijn op expert opinion. Hierbij is gebruik gemaakt van een gestructureerd format gebaseerd op het evidence-to-decision framework van de internationale GRADE Working Group (Alonso-Coello, 2016a; Alonso-Coello, 2016b). Dit evidence-to-decision framework is een integraal onderdeel van de GRADE-methodiek.

Formuleren van aanbevelingen

De aanbevelingen geven antwoord op de uitgangsvraag en zijn gebaseerd op het beschikbare wetenschappelijke bewijs en de belangrijkste overwegingen, en een weging van de gunstige en ongunstige effecten van de relevante interventies. De kracht van het wetenschappelijk bewijs en het gewicht dat door de werkgroep wordt toegekend aan de overwegingen, bepalen samen de sterkte van de aanbeveling. Conform de GRADE-methodiek sluit een lage bewijskracht van conclusies in de systematische literatuuranalyse een sterke aanbeveling niet a priori uit, en zijn bij een hoge bewijskracht ook zwakke aanbevelingen mogelijk (Agoritsas, 2017; Neumann, 2016). De sterkte van de aanbeveling wordt altijd bepaald door weging van alle relevante argumenten tezamen. De werkgroep heeft bij elke aanbeveling opgenomen hoe zij tot de richting en sterkte van de aanbeveling zijn gekomen.

In de GRADE-methodiek wordt onderscheid gemaakt tussen sterke en zwakke (of conditionele) aanbevelingen. De sterkte van een aanbeveling verwijst naar de mate van zekerheid dat de voordelen van de interventie opwegen tegen de nadelen (of vice versa), gezien over het hele spectrum van patiënten waarvoor de aanbeveling is bedoeld. De sterkte van een aanbeveling heeft duidelijke implicaties voor patiënten, behandelaars en beleidsmakers (zie onderstaande tabel). Een aanbeveling is geen dictaat, zelfs een sterke aanbeveling gebaseerd op bewijs van hoge kwaliteit (GRADE-gradering HOOG) zal niet altijd van toepassing zijn, onder alle mogelijke omstandigheden en voor elke individuele patiënt.

Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers
	Sterke aanbeveling	Zwakke (conditionele) aanbeveling
Voor patiënten	De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet.	Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet.
Voor behandelaars	De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen.	Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren.
Voor beleidsmakers	De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid.	Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen.

Organisatie van zorg

In de knelpuntenanalyse en bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van zorg.

Commentaar- en autorisatiefase

De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.

Literatuur

Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.

Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.

Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.

Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.

Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.

Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. https://richtlijnendatabase.nl/over_deze_site/richtlijnontwikkeling.html.

Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55. doi: 10.1016/j.jclinepi.2015.11.017. Epub 2016 Jan 6. Review. PubMed PMID: 26772609.

Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. The GRADE Working Group, 2013. Available from http://gdt.guidelinedevelopment.org/central_prod/_design/client/handbook/handbook.html.

Schünemann HJ, Oxman AD, Brozek J, Glasziou P, Jaeschke R, Vist GE, Williams JW Jr, Kunz R, Craig J, Montori VM, Bossuyt P, Guyatt GH; GRADE Working Group. Grading quality of evidence and strength of recommendations for diagnostic tests and strategies. BMJ. 2008 May 17;336(7653):1106-10. doi: 10.1136/bmj.39500.677199.AE. Erratum in: BMJ. 2008 May 24;336(7654). doi: 10.1136/bmj.a139.

Schünemann, A Holger J (corrected to Schünemann, Holger J). PubMed PMID: 18483053; PubMed Central PMCID: PMC2386626.

Wessels M, Hielkema L, van der Weijden T. How to identify existing literature on patients' knowledge, views, and values: the development of a validated search filter. J Med Libr Assoc. 2016 Oct;104(4):320-324. PubMed PMID: 27822157; PubMed Central PMCID: PMC5079497.

Zoekverantwoording

Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.

Richtlijnendatabase

Hoofd-halstumoren

Hoofd-halstumoren

Invasiediepte (negatieve hals)

Uitgangsvraag

Aanbeveling

Overwegingen

Onderbouwing

Achtergrond

Conclusies

Samenvatting literatuur

Zoeken en selecteren

Referenties

Evidence tabellen

Verantwoording

Autorisatiedatum en geldigheid

Initiatief en autorisatie

Algemene gegevens

Samenstelling werkgroep

Belangenverklaringen

Inbreng patiëntenperspectief

Methode ontwikkeling

Werkwijze

Zoekverantwoording

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