Definitie resectiemarge mondholtecarcinomen

Beoordeeld: 20-09-2023

Uitgangsvraag

Hoe wordt een laag-, intermediair- en hoog-risico resectiemarge gedefinieerd voor plaveiselcelcarcinomen in de mondholte?

Aanbeveling

Gebruik de volgende indeling van de grootte van de chirurgische marge in relatie tot het risico op het optreden van tumor recidief van een carcinoom van de bovenste adem en voedingsweg:

Hoog risico: < 1mm.
Intermediair risico: 1 tot 5 mm.
Laag risico: > 5mm.

Overwegingen

Voor- en nadelen van de interventie en de kwaliteit van het bewijs

De meeste geïncludeerde studies gebruikten een afkapwaarde voor de resectie marge in millimeters, maar twee studies berekenden een marge-tumordikte ratio en onderzochten afkapwaarden voor deze methode (Heiduschka, 2016; Huang, 2019). Samenvattingen van de resultaten op elke uitkomstmaat zijn te vinden in Tabellen 11.3.1.1 tot 11.3.1.5 in de literatuursamenvattingen onder het tabblad ‘Onderbouwing’. Alle geïncludeerde studies in deze richtlijnmodule waren observationeel van aard. De zekerheid in het gevonden bewijs was zeer laag voor elke afkapwaarde op elke vooraf gedefinieerde uitkomstmaat, ongeacht of het een afkapwaarde in millimeters of in marge-tot-tumordikte ratio was. Verder werden er op elke afkapwaarde voor de resectiemarge weinig patiënten met elkaar vergeleken. Hierdoor nam de zekerheid in de gevonden schatters af. Daarnaast definieerden de meeste studies niet a priori de plausibele confounders en in een aantal studies werden alleen significante predictoren voor de uitkomst van interesse behouden in het multivariabele model ter correctie. Hierdoor is het vertrouwen in de gevonden uitkomsten uit de literatuur zeer laag.

Hoewel deze module zich specifiek richt op de definitie van de resectiemarge zijn er, naast de resectiemarge status, andere factoren die een rol spelen bij de lokale controle en overleving. Hierbij is, bijvoorbeeld, te denken aan lymfkliermetastase(n) met kapseldoorbraak, meerdere lymfkliermetastasen, lymfangio invasie, T3-4 tumoren, en/of perineurale groei.

Aanvaardbaarheid, haalbaarheid en implementatie

Het lijkt dat de onderbouwing ontbreekt om de bestaande indeling van de margestatus van hoog (< 1mm), intermediair (1 tot 5mm) en laag (> 5mm) risico op tumor recidief aan te passen. De gangbare definitie lijkt voor nu gehandhaafd te moeten blijven. Inschatting van het risicoprofiel op tumor recidief blijft voor de gemiddeld-risicogroep een individuele afweging.

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

Er lijkt geen verdere verfijning van het marge interval van 1 tot 5 mm mogelijk met de voor handen zijnde data. De literatuur ondersteunt onvoldoende de mogelijkheid van toepassen van een gradiënt in risico in het interval van 1 tot 5 mm marge. De betrouwbaarheid intervallen zijn te breed en daarnaast zijn de data van de studies niet samen te voegen. Vermoedelijk is de marge niet de enige voorspeller voor het risico op tumor recidief en is onvoldoende rekening gehouden hiermee in de voorhanden zijnde studies.

Onderbouwing

Achtergrond

De resectiemarge van mondholtecarcinomen wordt conventioneel gedefinieerd als laag risico op recidief tumor wanneer er infiltrerende tumorcellen worden gevonden op een afstand van 5 millimeter of meer ten opzichte van het sneevlak. Dit wordt beschreven als een radicale of complete tumor resectie. Er wordt vanuit gegaan dat er een gemiddeld risico aanwezig is op recidief tumor wanneer er infiltrerende tumorcellen worden gevonden tussen de één en vijf millimeter ten opzichte van het sneevlak. Dit wordt beschreven als een krappe marge. Een hoog risico op recidief tumor zou bestaan als er infiltrerende cellen worden waargenomen binnen één millimeter ten opzichte van de resectiemarge en wordt derhalve geduid als een positieve marge. Chirurgen streven naar een radicale resectie marge van minimaal 5 mm bij het verwijderen van de tumor. Minder dan één mm marge heeft een hoog risico op recidief en behoeft adjuvante behandeling in geval van een curatieve behandeling. Het is onduidelijk of een marge tussen de 1 en 5 mm wellicht tot hetzelfde risicoprofiel zou kunnen hebben als een radicale resectie van 5 mm of meer wat betreft de kans op recidief van tumoren en de overleving van patiënten.

Conclusies

Very low

GRADE

We are unsure of the effects of different cut-off values for the resection margin on the local recurrence of tumors in patients with a resected oral cavity tumor.

Sources: (Brinkman, 2020; Heiduschka, 2016; Tsai, 2011; Wong, 2012; Yamada, 2016; Yanamoto, 2012)

Very low GRADE

We are unsure of the effects of different cut-off values for the resection margin on the (local) recurrence-free survival of patients with a resected oral cavity tumor.

Sources: (Zanoni, 2017)

Very low GRADE

We are unsure of the effects of different cut-off values for the resection margin on the disease-specific survival of patients with a resected oral cavity tumor.

Sources: (Brinkman, 2020; Heiduschka, 2016; Tsai, 2011; Wong, 2012)

Very low

GRADE

We are unsure of the effects of different cut-off values for the resection margin on the disease-free survival of patients with a resected oral cavity tumor.

Sources: (Chiou, 2010; Huang, 2019; Tsai, 2011)

Very low GRADE

We are unsure of the effects of different cut-off values for the resection margin on the overall survival of patients with a resected oral cavity tumor.

Sources: (Brinkman, 2020; Nason, 2009; Tsai, 2011)

Samenvatting literatuur

Description of studies

Brinkman (2020) selected patients who underwent primary surgery for oral cavity carcinomas between 2009 and 2018 from a database. Patients that had a second primary tumor, had a previous history of radiotherapy or head and neck cancer, or resection without curative intent were excluded. The sample consisted of 224 patients (164 males; 80 females) with a median age of 63 years (range 27-93). Primary tumor locations were at the tongue (n=105), floor of the mouth (n=71), buccal (n=20), alveolus/retromolar trigone/palate (n=37), or lip (n=11). Of the 244 patients, 149 had a bone resection and 196 had a neck dissection (unilateral: n=142, bilateral: n=54). Patients had either T1 (n=59), T2 (n=91), T3 (n=38), or T4 (n=56) carcinomas. Nodal stage in the sample was N0 (n=103), N1 (n=30), N2a (n=9), N2b (n=13), N2c (n=4), N3b (n=37), or cN0 (n=48). The 8^th edition of the AJCC TNM-staging system was used. Surgical margins were extracted from pathology reports, without taking intraoperative frozen sections or extra tumor bed margins in to account. Multivariable analyses were conducted for a resection margin at 3 millimeters, where < 3 millimeters was a close margin and ≥ 3 millimeters was a clear margin.

Chiou (2010) selected 110 patients from a database. To be eligible, patients with buccal mucosa carcinoma had to be treated between 2000 and 2008. Patients were excluded when solely treated with radiotherapy or concurrent chemoradiotherapy, had neoadjuvant treatment and surgery, or had a second synchronous primary tumor. The 110 patients (103 males; 7 females) had a pT-stage of pT1-2 (n=70) or pT3-4 (n=40), and a pN-stage of pN0 (n=84) or pN1-3 (n=26). The 6^th edition of the AJCC TNM-staging system was used. Sixty-six participants were aged above 50 years old. Tumor differentiation was well (n=6), moderate (n=90), poor (n=12), or was not specified (n=2). Other characteristics were tobacco use (n=93 smoked) and betel nut chewing (n=93 chewed betel nuts, n=2 unknown). Patients underwent surgery alone (n=32), surgery with radiotherapy (n=38), or surgery with concurrent chemoradiotherapy (n=40). Pathology reports were reviewed. Cut-offs of 1 millimeter (close: ≤ 1mm, clear: >1mm), 2 millimeter (close: ≤ 2mm, clear: > 2mm), 3 millimeter (close: ≤ 3mm, clear: > 3mm), 4 millimeter (close: ≤ 4mm, clear: > 4mm) and 5 millimeter (close: ≤ 5mm, clear: > 5mm).

Heiduchka (2016) selected patients treated for oral squamous cell carcinoma between 1987 and 2014 from a database. Patients were excluded when insufficient data was available. A total of 501 participants (289 males; 212 females) with a median age of 63.6 years (IQR: 53.2-72.9) were included. Tumor differentiation was well (n=81), moderate (n=307), or poor (n=77). There was perineural invasion (in n=151), lymphovascular invasion (in n=69), and extracapsular spread (in n=83) in the sample. The patients had a T1 (n=170), T2 (n=180), T3 (n=43), or T4 (n=108). The nodal stage was N0 (n=303), N1 (n=140), or N3 (n=2). It was unclear which staging system was used. Radiotherapy was given for 225 patients, and 29 patients received chemotherapy. A resection margin to tumor size ratio (margin/tumor diameter in millimeters) and a resection margin to tumor thickness ratio (margin/tumor thickness in millimeters) was calculated. A margin to thickness cut-off (MTR) of 0.3 was used in a multivariable analysis to compare MTR< 0.006 with MTR> 0.3, and MTR 0.06-0.3 with MTR> 0.3.

Huang (2019) selected 302 patients from a database. To be eligible, patients should have had a newly diagnosed oral squamous cell carcinoma, underwent radical surgery (either with or without adjuvant treatment), and had sufficient pathologic data available. Patients that were treated with chemotherapy or radiotherapy as an initial treatment were excluded. Furthermore, patients with previous cancer in their history or distant metastases upon diagnoses were excluded as well. A resection margin to tumor thickness ratio (MTR) was calculated by: margin +0.1/tumor thickness +0.1 in millimeters. The log(MTR) of 33% was used as a cut-off in multivariable analyses (close: log(MTR)≤ 33%, clear: log(MTR)> 33%). There were 100 patients (93 males; 7 females) in the log(MTR)≤33% group with a median age of 51 years (range: 33-88). In this group, the tumor site was at the tongue (n=41) or buccal mucosa (n=59). There was perineural invasion (in n=48) and lymphovascular invasion (in n=14). Tumor differentiation was well (n=7), moderate (n=79), or poor (n=14). Other characteristics were tobacco use (in n=88) and alcohol use (in n=70). This group received no adjuvant therapy (n=35), radiotherapy (n=35), chemotherapy (n=7), or chemoradiotherapy (n=28). The pT-stage in the log(MTR)≤33% group was T1 (n=8), T2 (n=43), T3 (n=10), or T4 (n=39), while the pN-stage was N0 (n=44), N1 (n=41) or N2 (n=41). The log(MTR)>33% group consisted of 202 patients (187 males; 15 females) with a median age of 54 years (range: 28-92). The tumor site was either the tongue (n=88) or buccal mucosa (n=114). Perineural invasion was present in 6 patients and lymphovascular invasion in 6 patients as well. Tumor differentiation was well (n=38), moderate (n=150), or poor (n=14). There was tobacco use in 179 patients and alcohol use in 150 patients. Patients in this group received no adjuvant treatment (n=107), radiotherapy (n=22), chemotherapy (n=22), or chemoradiotherapy (n=28). Their pT-stage was T1 (n=63), T2 (n=91), T3 (n=10), or T4 (n=36), while their pN-stage was N0 (n=136), N1 (n=22), or N2 (n=44). The 7^th edition of the AJCC TNM-staging system was used. There were proportional differences between the groups on the following characteristics: perineural invasion, lymphovascular invasion, pT-stage, pN-stage, tumor differentiation, and adjuvant therapy.

Nason (2009) selected patients from a database which had biopsy-proven and previously unteasted oral cavity squamous cell carcinoma and were managed with surgery (with or without adjuvant radiotherapy). Patients with incomplete data, which were seen in consultation only, were treated with radiotherapy only, or were treated with palliative intent were excluded. The sample consisted of 277 patients with a mean age of 63.3 years (SD: 12). Ninety percent used alcohol and seventy percent used tobacco. Other relevant sample characteristics were not described. Staging was performed with the 6^th edition of the IUAC TNM-staging system. Margin status was extracted from pathology reports. A cut-off value of 3 millimeter was used, where clear margins (> 3mm) were compared to close margins (≥3mm) and positive margins (undefined).

Tsai (2011) selected patients with a surgical margin ≤ 3 millimeter who underwent postoperative radiotherapy or concurrent chemoradiotherapy between 2000 and 2008 from a database. Patients were excluded when they had positive margins, had not received postoperative therapy, or when the radiotherapy dose was below 45 Gy. Thirty patients were selected (26 males; 4 females) with a median age of 51.5 years (range: 35 to 82). Medical record were reviewed. The EGOC-status was either 0 to 1 (in n=21) or > 2 (in n=9). Tumor differentiation was well to moderate (n=28) or poor (n=2). Twenty-four patients smoked and twenty-tree patients chewed betel nuts. The pT-stage was categorized in either T1-3 (n=20) or T4 (n=10). Similarly, the pN-stage was categorized in N0 (n=25) and N1-2 (n=5). The 6^th edition of the AJCC TNM-staging system was used. Sixteen patients received ≤66 Gy dose for radiotherapy and fourteen patients received > 66 Gy. A resection margin cut-off value of 1 millimeter was used in multivariable analyses (close: ≤ 1mm, clear: > 1mm).

Wong (2012) selected previously untreated patients with oral or oropharyngeal squamous cell carcinomas between 2001 and 2007 from a database. Paraffin-embedded sections of 4 micrometer were stained and measured under a microscope. The sample consisted of 192 patients (122 males; 70 females) with a mean age of 61 years (SD: 11). Tumor site was oral in 160 patients and oropharyngeal in 32 patients. Tumor differentiation was well (n=21), moderate (n=134), or poor (n=27). There was perineural invasion (in n=28), vascular invasion (in n=36), lymphatic invasion (in n=26), and bony invasion (in n=31). Invasive front was assessed as being either cohesive (n=56) or non-cohesive (n=105). The cT-stage was T1 (n=72), T2 (n= 38), T3 (n=16), or T4 (n=56). Nodal stage was cN0 (n=119), cN1 (n=28), cN2 (n=44), or cN3 (n=1). It remained unclear which staging system was used. ROC analyses identified a cut-off value of 1 (close: ≤ 1mm, clear: > 1mm) and 1.6 millimeter (close: ≤ 1.6mm; clear: > 1.6mm). The cut-off values were used un multivariable analyses.

Yamada (2016) selected previously untreated patients with oral squamous cell carcinomas who had planned radical resection (with or without adjuvant radiotherapy and/or chemotherapy) between 1990 and 2007. Patients with T4b tumors or dysplastic epithelium at the mucosal margin were excluded. Pathology reports were reviewed for the margin status. A total of 127 patients (73 males; 54 females) with a median age of 66 years (range 27-84) were selected. Tumor locations were the tongue (n=59), lower gum (n=2), upper gum (n=16), cheek mucosa (n=16), floor of the mouth (n=14), or hard palate (n=1). Tumor differentiation was micro-invasive (n=4), well (n=79), moderate (n=38), or poor (n=6). Furthermore, the mode of invasion was YK-2 (n=18), YK-3 (n=55), YK4C (n=41), or YK4D (n=13). Eighty-three patients received preoperative therapy, while thirty-five patients received postoperative radiotherapy > 50 Gy. T-stage was T1 (n=20), T2 (n=39), T3 (n=22), or T4a (n=46), while the N-stage was N0 (n=72), N1 (n=20), N2b (n=26), N2c (n=8), or N3 (n=1). It was unclear which staging system was used. Resection margin cut-offs of 0 (involved, clear: > 0), 1 (involved, close: ≤ 1mm, clear: > 1mm), 2 (involved, close: ≤ 2mm, clear: > 2mm), 4 (involved, close: ≤ 4mm, clear: > 4mm), and 5 millimeters (involved, close: ≤ 5mm, clear: > 5mm) were used in multivariable analyses. An involved margin was defined as evidence of carcinoma at the margin (including carcinoma in situ).

Yanamoto (2012) retrospectively reviewed 187 patients who underwent radical surgery for histologically confirmed oral squamous cell carcinoma between 2001 and 2010 and with a minimal follow-up period of 12 months (exclusion criteria were not reported). Mean age in the total sample (102 males; 85 females) was 67.3 years (range: 28-95). Tumor stage was T1 (n=52), T2 (n=92), T3 (n=14), or T4 (n=29). N-stage was N0 (n=141), N1 (n=26), N2a (n=2), N2b (n=12), or N2c (n=6). Staging was performed using the 6^th edition of the UICC staging system. Tumor differentiation was well in 166 patients, moderate in 20, and poor in 1 patient. A portion of the patients (n=63) received neoadjuvant chemotherapy and some patients received postoperative adjuvant radiotherapy (n=15). Tumor site was at the tongue (n=73), the oral floor (n=26), upper gingiva (n=36), lower gingiva (n=44), or buccal mucosa (n=63). Resection margin cut-off used was 4 millimeter (close: ≤4 mm, clear: > 4mm) for both the superficial and deep margin.

Zanoni (2017) selected patients who underwent primary surgery for squamous cell carcinoma of the tongue between 2000 and 2012 from a database. Histopathological slides had to be available to be included. Archived tumor specimens were assessed by head and neck pathologists. The pathologists were blinded for the patient outcomes. The sample consisted of 381 patients (222 males; 159 females) with a mean age of 58 years (SD: 14.7). One hundred and twenty-one patients had never used tobacco. The cT stage was T1 (n=193), T2 (n=135), T3 (n=34), T4 (n=15), or cTX (n=4). Nodal stage was cN0 (n=275), cN1 (n=40), cN2 (n=64), or cN3 (n=2). It was unclear which staging system was used. A 5-millimeter cut-off (positive, close: 0.01-2mm; clear: > 5mm) and 2.2 millimeter cut-off (positive, close: 0.01-2mm, clear: > 2mm) resection margin was used in multivariable analyses. Positive margins were defined as invasive carcinoma at the margin of the resected specimen.

Results

Local failure

Results of the included studies reporting the local recurrence in multivariable models are summarized in Table 11.3.1.1

Brinkman (2020) selected 224 patients, however it was unclear how large both groups were (i.e. < 3mm-group and ≥ 3mm-group) and how disease characteristics were distributed between groups. It was not completely clear which other variables were added to the model.

Heiduschka (2016) selected 501 patients and calculated the margin-to-thickness ratio (MTR). It was unclear how large groups were (i.e. < 0.06 MTR-group, 0.06 to 0.3 MTR-group, and MRR> 0.3-group) and how characteristics were distributed among the groups. Sub-analyses were performed, where patients with positive margins (n=79) were removed from analysis. Perineural invasion, lymphovascular invasion, and nodal status were other variables in the model besides the MTR.

Tsai (2011) selected 30 patients. It was unclear how large both groups were at the cut-off point (i.e. the ≤ 1mm-group and < 1mm-group) and how characteristics were distributed among the groups. Besides the resection margin, other variables in the model were age, gender, ECOG PD, smoking, betel nut chewing, tumor differentiation, invasion depth, perineural invasion, lymphovascular invasion, extracapsular spread, pT-stage, pathology stage, and radiotherapy dose.

Wong (2012) selected 192 patients, of which 107 had close margins (as defined by the standard definition of 1 to 5mm). It was unclear how large the groups were at the cut-off point and how disease characteristics were distributed among both groups. Other variables in the model were cN-stage, lymphatic invasion, histopathological involved nodes, extracapsular spread, and tumor depth.

Yamada (2016) selected 127 patients and reported group sizes at the 0 millimeter (involved: n=10, > 0mm: n=117), 1 millimeter (involved: n=10, 0-1mm: n=6, > 1mm: n=111), 2 millimeter (involved: n=10, 0-2mm: n=14, >2mm: n=103), 4 millimeter (involved: n=10, 0-4mm: n=19, > 4mm: n=98), and 5 millimeter cut-off values (involved: n=10, 0-5mm: n=24, > 5mm: n=93). It was unclear how disease characteristics were distributed among groups at the various cut-off points. The 2-year local recurrence was reported. Other variables in the model besides surgical margin were T-stage, tumor differentiation, mode of invasion, preoperative therapy, and postoperative therapy over 50 Gy.

Yanamoto (2012) reported the local recurrence using a cut-off value of 4 millimeter for the superficial margin (≤ 4mm: n=31, > 4mm: n=156) and deep margin (≤ 4mm: n=25, > 4mm: n=162). It was unclear how disease characteristics were distributed among groups. For superficial margin, other variables in the model were pattern of invasion, preoperative treatment, deep surgical margin, and postoperative adjuvant radiotherapy. For deep margin, Other variables in the model were pattern of invasion, preoperative treatment, superficial surgical margin, and postoperative adjuvant radiotherapy.

Table 11.3.1.1 Local recurrence at surgical margin cut-off values. The reference group is labeled with ‘(ref)’

Author, year (tumor locations)	Cut-off value in millimeters							Cut-off value for MTR*
Author, year (tumor locations)	>0 mm	>1 mm	>2 mm	>3 mm	≥3 mm	>4 mm	>5 mm	>0.3
Brinkman 2020 (tongue, FOM, buccal)	-	-	-	-	<3mm versus ≥3m(ref): HR = 1.63 (95%CI: 0.90-2.96)	-	-	-
Heiduschka 2016 (oral)	-	-	-	-	-	-	-	<0.06MTR versus >0.3MTR(ref): HR = 1.92 (95%CI: 1.02-3.61) <0.06MTR versus >0.3MTR(ref), (positive margins excluded): HR = 2.63 (95%CI: 1.05-6.63) 0.06-0.3MTR versus >0.3MTR(ref): HR = 1.22 (95%CI: 0.62-2.41)
Tsai 2011 (buccal mucosa)	-	≤1mm versus >1mm(ref): HR = 14.02 (95%CI: 1.13-29.76)	-	-	-	-	-	-
Wong 2012 (oral and oropharyngeal)	-	≤1mm versus >1mm(ref): HR = 2.86 (95%CI: 1.20-6.85)	-	-	-	-	-	-
Yamada 2016 (tongue, gums, cheek mucosa, FOM, hard palate)	Involved versus >0mm(ref): HR = 10.74 (95%CI: 3.07-37.54)	Involved versus >1mm(ref): HR = 17.00 (95%CI: 4.49-64.42) 0-1mm versus >5mm(ref): HR = 23.69 (95%CI: 3.38-166.15)	Involved versus >2mm(ref): HR = 13.22 (95%CI: 3.73-46-85) 0-2mm versus >5mm(ref): HR = 4.37 (95%CI: 1.04-18.42)	-	-	Involved versus >4mm(ref): HR = 14.42 (95%CI: 3.95-53.73) 0-4mm versus >4mm(ref): HR = 4.35(95%CI: 1.09-17.32)	Involved versus >5mm(ref): HR = 14.42 (95%CI: 3.82-54.36) 0-5mm versus >5mm(ref): HR = 3.32 (95%CI: 0.87-12.73)	-
Yanamoto 2012 (tongue, oral floor, upper and lower gingiva, buccal mucosa)	-	-	-	-	-	≤4mm versus >4mm(ref), (superficial margin): OR = 7.12 (95%CI: 2.28-22.35) ≤4mm versus >4mm(ref), (deep margin): OR = 4.90 (95%CI: 1.44-16.70)	-	-
*MTR: Margin to thickness ratio

(Local) recurrence-free survival

Results of the included study reporting the (local) recurrence-free survival in multivariable models are summarized in Table 11.3.1.2.

Zanoni (2017) selected 381 patients, however group size and the distribution of characteristics was unclear for the groups at the cut-off values. Local recurrence-free survival was reported for 2.2 millimeter and 5 millimeter cut-off values. At the 2.2 millimeter cut-off value, the other variables in the model were tumor size, perineural invasion, and pN-stage. Other variables in the model for the 5 millimeter cut-off value were tumors size and adjuvant therapy besides resection margin.

Table 11.3.1.2 (Local) recurrence-free survival at surgical margin cut-off values. The reference group is labeled with ‘(ref)’

Author, year (tumor locations)

Cut-off value in millimeters

>0 mm

>1 mm

>2 mm

>2.2mm

>3 mm

>4 mm

>5 mm

Zanoni 2017

(tongue)

Positive versus >2.2mm(ref):

HR = 5.73 (95%CI: 2.45-13.41)

0.01-2.2mm versus >2.2mm(ref):

HR = 2.00 (95%CI: 1.13-3.55)

Positive versus >5mm(ref):

HR = 5.71 (95%CI: 2.8-15.65)

0.01-2.2mm versus >5mm(ref):

HR = 2.25 (95%CI: 1.03-4.92)

2.3-5mm versus >5mm(ref):

HR = 1.17 (95%CI: 0.51-2.66)

Disease-specific survival

Results of the included studies reporting the disease-specific survival in multivariable models are summarized in Table 11.3.1.3.

Brinkman (2020) selected 224 patients, however it was unclear how large both groups were (i.e. < 3mm-group and ≥ 3mm-group) and how disease characteristics were distributed between groups. T-stage, N-stage, extracapsular spread, and postoperative radiotherapy were variables in the model besides surgical margin.

Heiduschka (2016) selected 501 patients and calculated the margin-to-thickness ratio (MTR). It was unclear how large groups were (i.e. < 0.06 MTR-group and MRR> 0.3-group) and how characteristics were distributed among the groups. Sub-analyses were performed, where patients with positive margins (n=79) were removed from analysis. Perineural invasion, lymphovascular invasion, and nodal status were other variables in the model besides the MTR.

Wong (2012) selected 192 patients, of which 107 had close margins (as defined by the standard definition of 1-5mm). It was unclear how large the groups were at the cut-off point and how disease characteristics were distributed among both groups. Other variables in the model were cT-stage, cN-stage, lymphatic invasion, vascular invasion, histopathological involved nodes, extracapsular spread, and tumor depth.

Table 11.3.1.3 Disease-specific survival at surgical margin cut-off values. The reference group is labeled with (ref)

Author, year (tumor locations)	Cut-off value in millimeters								Cut-off value for MTR*
Author, year (tumor locations)	>0 mm	>1 mm	>1.6mm	>2 mm	>3mm	≥3 mm	>4 mm	>5 mm	>0.3
Brinkman 2020 (tongue, FOM, buccal)	-	-	-	-	-	<3mm versus ≥3m(ref): HR = 1.86 (95%CI: 1.06-3.27)	-	-	-
Heiduschka 2016 (oral)	-	-	-	-	-	-	-	-	<0.06MTR versus >0.3MTR(ref), (positive margins excluded): HR = 2.27 (95%CI: 1.07-4.81)
Tsai 2011 (buccal mucosa)	-	≤1mm versus >1mm(ref): HR = 16.52 (95%CI: 0.88-36.46)	-	-	-	-	-	-	-
Wong 2012 (oral and oropharyngeal)	-	-	≤1.6mm versus >1.6mm(ref) HR = 2.43 (95%CI: 1.21-4.88)	-	-	-	-	-	-
*MTR: Margin to thickness ratio

Disease-free survival

Results of the included studies reporting the disease-free survival in multivariable models are summarized in Table 11.3.1.4.

Chiou (2010) selected 110 patients and reported the 3-year disease-free survival at various cut-off values for the resection margin. Group sizes and distribution of characteristics among the groups at the cut-off values were unclear. It was unclear which models were entered in the model besides surgical margin.

Huang (2019) selected 302 patients and separated the sample by using a margin-to-thickness ratio (MTR). Here, the sample was divided into log(MTR)≤ 33% (n=100) and log(MTR)> 33% (n=202). Groups differed in proportions on the following variables: perineural invasion, lymphovascular invasion, T-stage, N-stage, tumor differentiation, and adjuvant therapy. Variables in the model for 5-year disease-free survival other than surgical margin were perineural invasion, lymphovasculat invasion, pT-stage, pN-stage, and tumor differentiation. Sub-analyses were performed for a subsample of 97 patients with T3-4 tumors. Besides surgical margin, the multivariable model for 5-year disease-free for patients with T3-4 tumors contained pN-stage and adjuvant therapy.

Wong (2012) selected 192 patients, of which 107 had close margins (as defined by the standard definition of 1-5mm). It was unclear how large the groups were at the cut-off point and how disease characteristics were distributed among both groups. Other variables in the model were cN-stage, lymphatic invasion, histopathological involved nodes, extracapsular spread, and tumor depth.

Table 11.3.1.4 Disease-free survival at surgical margin cut-off values. The reference group is labeled with (ref)

Author, year (tumor locations)	Cut-off value in millimeters						Cut-off value for log(MTR)*
Author, year (tumor locations)	>0 mm	>1 mm	>2 mm	>3 mm	>4 mm	>5 mm	>33%
Chiou 2010 (buccal mucosa)	-	≤1mm(ref) versus >1mm: HR = 0.2 (95%CI: 0.06-0.72)	≤2mm(ref) versus >2mm: HR = 0.1 (95%CI: 0.01-0.60)	≤3mm(ref) versus >3mm: HR = 0.2 (95%CI: 0.03-1.86)	≤4mm(ref) versus >4mm: HR = 0.3 (95%CI: 0.04-2.16)	≤5mm(ref) versus >5mm: HR = 0.5 (95%CI: 0.07-4.22)	-
Huang 2019 (tongue, buccal)							Log(MTR)≤33% versus log(MTR)>33%(ref): HR = 1.73 (95%CI: 1.16-2.57) Log(MTR)≤33% versus log(MTR)>33%(ref), (T3-4 only): HR = 2.67 (95%CI: 4.95)
Tsai 2011 (buccal mucosa)	-	≤1mm versus >1mm(ref): HR = 12.78 (95%CI: 1.93-25.22)	-	-	-	-	-
*MTR: Margin to thickness ratio

Overall survival

Results of the included studies reporting the overall survival in multivariable models are summarized in Table 11.3.1.5.

Brinkman (2020) selected 224 patients, however it was unclear how large both groups were (i.e. < 3mm-group and ≥3mm-group) and how disease characteristics were distributed between groups. T-stage, N-stage, extracapsular spread, and postoperative radiotherapy were variables in the model besides surgical margin.

Nason (2009) selected 277 patients. Group sizes and distribution of characteristics between groups at the cut-off value were unclear. Variables in the multivariable models were gender, age, and tumor stage, besides resection margin.

Table 11.3.1.5 Overall survival at surgical margin cut-off values. The reference group is labeled with ‘(ref)’

Author, year (tumor locations)	Cut-off value in millimeters
Author, year (tumor locations)	>0 mm	>1 mm	>2 mm	>3 mm	≥3mm	>4 mm	>5 mm
Brinkman 2020 (tongue, FOM, buccal)	-	-	-	-	<3mm versus ≥3m(ref): HR = 1.78 (95%CI: 1.18-2.70)	-	-
Nason 2009 (oral)	-	-	-	Positive versus >3mm(ref): HR = 2.5 (95%CI: 0.95-2.70) ≤3mm versus >3mm(ref): HR = 1.54 (95%CI: 0.95-2.70)	-	-	-
Tsai 2011 (buccal mucosa)	-	≤1mm versus >1mm(ref): HR = 15.88 (95%CI: 0.54-35.98)	-	-	-	-	-

Level of evidence of the literature

GRADE for interventions starts at ‘LOW’ for a body of evidence with observational studies. The level of evidence regarding the outcome measure local failure was downgraded by 3 levels because of study limitations (1 level for risk of bias: 4/9 studies excluded non-significant variables from the model; most studies did not define plausible confounders a priori); number of included patients (2 levels for imprecision: individual cut-off values have a low number of participants).

GRADE for interventions starts at ‘LOW’ for a body of evidence with observational studies. The level of evidence regarding the outcome measure (local) recurrence-free survival was downgraded by 3 levels because of study limitations (1 level for risk of bias: 4/9 studies excluded non-significant variables from the model; most studies did not define plausible confounders a priori); number of included patients (2 levels for imprecision: individual cut-off values have a low number of participants).

GRADE for interventions starts at ‘LOW’ for a body of evidence with observational studies. The level of evidence regarding the outcome measure disease-specific survival was downgraded by 3 levels because of study limitations (1 level for risk of bias: 4/9 studies excluded non-significant variables from the model; most studies did not define plausible confounders a priori); number of included patients (2 levels for imprecision: individual cut-off values have a low number of participants).

GRADE for interventions starts at ‘LOW’ for a body of evidence with observational studies. The level of evidence regarding the outcome measure disease-free survival was downgraded by 3 levels because of study limitations (1 level for risk of bias: 4/9 studies excluded non-significant variables from the model; most studies did not define plausible confounders a priori); number of included patients (2 levels for imprecision: individual cut-off values have a low number of participants).

GRADE for interventions starts at ‘LOW’ for a body of evidence with observational studies. The level of evidence regarding the outcome measure overall survival was downgraded by 3 levels because of study limitations (1 level for risk of bias: 4/9 studies excluded non-significant variables from the model; most studies did not define plausible confounders a priori); number of included patients (2 levels for imprecision: individual cut-off values have a low number of participants).

Zoeken en selecteren

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

What are the (un)beneficial effects of alternatively defined surgical resection margins (i.e. other than < 1 mm, 1 tot 5mm, >5mm) on the recurrence-free survival, overall survival, local failure, and local recurrence-free survival in patients with surgically resected oral cavity carcinomas?

P: Patients with oral cavity squamous cell carcinomas where the carcinoma is surgically resected.

I: Surgical resection margin (cutoff point(s)) other than those defined as usual (usual definition: < 1mm, 1 tot 5mm, > 5mm).

C: Surgical resection margin (cut-off points) compared.

O: Local failure, (local) recurrence-free survival, disease-specific survival, disease-free survival, overall survival.

Relevant outcome measures

The guideline development group considered local failure and (local) recurrence-free survival as a critical outcome measures for decision making; and disease-specific survival, disease-free survival, and overall survival 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 risk/odds ratios for local failure.
5% difference or more (absolute) and HR< 0.7 in disease-specific survival, (local) recurrence-free survival, and overall survival.

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until the 4^th of June, 2020. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 411 hits. Studies were selected based on the following criteria: patients had an oral cavity carcinoma, a different definition (or cut-off) of the low/intermediate/high risk resection margins were used and compared, multivariable models were used to correct for confounding. Fifty-seven studies were initially selected based on title and abstract screening. After reading the full text, 49 studies were excluded (see the table with reasons for exclusion under the tab Methods), and 8 studies were included. One relevant study (Brinkman, 2020) was published shortly after the search date and was included. A systematic review (Bungum, 2020) published after the search date identified another relevant study which was not found in our search strategy. This study (Yanamoto, 2012) was included as well, resulting in a total of 10 included studies.

Results

Ten 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

Brinkman D, Callanan D, O'Shea R, Jawad H, Feeley L, Sheahan P. Impact of 3 mm margin on risk of recurrence and survival in oral cancer. Oral Oncol. 2020 Jul 10;110:104883. doi: 10.1016/j.oraloncology.2020.104883. Epub ahead of print. PMID: 32659737.
Bungum A, Jensen JS, Jakobsen KK, Christensen A, Grønhøj C, von Buchwald C. Impact of surgical resection margins less than 5?mm in oral cavity squamous cell carcinoma: a systematic review (published online ahead of print, 2020 Jun 21). Acta Otolaryngol. 2020;1-7. doi:10.1080/00016489.2020.1773532.
Chiou WY, Lin HY, Hsu FC, Lee MS, Ho HC, Su YC, Lee CC, Hsieh CH, Wang YC, Hung SK. Buccal mucosa carcinoma: surgical margin less than 3 mm, not 5 mm, predicts locoregional recurrence. Radiat Oncol. 2010 Sep 15;5:79. doi: 10.1186/1748-717X-5-79. PMID: 20840791; PMCID: PMC2946296.
Heiduschka G, Virk SA, Palme CE, Ch'ng S, Elliot M, Gupta R, Clark J. Margin to tumor thickness ratio - A predictor of local recurrence and survival in oral squamous cell carcinoma. Oral Oncol. 2016 Apr;55:49-54. doi: 10.1016/j.oraloncology.2016.01.010. Epub 2016 Feb 6. PMID: 26861256.
Huang CY, Lin YS, Kang BH, Chang KP, Chi CC, Lin MY, Su HH, Chang TS, Lee HP, Lee CC. Log margin-to-thickness ratio improves disease-specific survival prediction in oral cancer: A single cancer centre database. Clin Otolaryngol. 2019 Jan;44(1):63-69. doi: 10.1111/coa.13237. Epub 2018 Oct 25. PMID: 30296003.
Nason RW, Binahmed A, Pathak KA, Abdoh AA, Sándor GK. What is the adequate margin of surgical resection in oral cancer? Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009 May;107(5):625-9. doi: 10.1016/j.tripleo.2008.11.013. Epub 2009 Jan 25. PMID: 19168372.
NVMO-commissie ter Beoordeling van Oncologische Middelen (BOM). PASKWIL criteria 2018.
Tsai WT, Lee MS, Hung SK, Chiou WY, Huang TT, Tseng CE, Chang SM, Hsu FC, Su YC, Li SC, Hsu WL. A very close margin of? 1 mm predicts a poor outcome in resected buccal cancer patients with a pathological margin of? 3 mm. Tzu Chi Medical Journal. 2011 Dec 1;23(4):123-30.
Wong LS, McMahon J, Devine J, McLellan D, Thompson E, Farrow A, Moos K, Ayoub A. Influence of close resection margins on local recurrence and disease-specific survival in oral and oropharyngeal carcinoma. Br J Oral Maxillofac Surg. 2012 Mar;50(2):102-8. doi: 10.1016/j.bjoms.2011.05.008. Epub 2011 Jul 13. PMID: 21742422.
Yamada S, Kurita H, Shimane T, Kamata T, Uehara S, Tanaka H, Yamamoto T. Estimation of the width of free margin with a significant impact on local recurrence in surgical resection of oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2016 Feb;45(2):147-52. doi: 10.1016/j.ijom.2015.09.024. Epub 2015 Oct 27. PMID: 26522780.
Yanamoto S, Yamada S, Takahashi H, Yoshitomi I, Kawasaki G, Ikeda H, Minamizato T, Shiraishi T, Fujita S, Ikeda T, Asahina I, Umeda M. Clinicopathological risk factors for local recurrence in oral squamous cell carcinoma. Int J Oral Maxillofac Surg. 2012 Oct;41(10):1195-200. doi: 10.1016/j.ijom.2012.07.011. Epub 2012 Aug 14. PMID: 22901502.
Zanoni DK, Migliacci JC, Xu B, Katabi N, Montero PH, Ganly I, Shah JP, Wong RJ, Ghossein RA, Patel SG. A Proposal to Redefine Close Surgical Margins in Squamous Cell Carcinoma of the Oral Tongue. JAMA Otolaryngol Head Neck Surg. 2017 Jun 1;143(6):555-560. doi: 10.1001/jamaoto.2016.4238. PMID: 28278337; PMCID: PMC5473778.

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

Brinkman 2020

Type of study:

Observational, database

Setting and country: Hospital, Ireland

Funding and conflicts of interest: Supported by the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital. The support consisted of the mayment of salary of a research assistant. Authors declare that there are no CoI.

Inclusion criteria:

Underwent primary surgery for oral cavity SCC between 2009-2018

Exclusion criteria:

Second primary tumor, previous history of head and neck cancer or radiotherapy, not undergoing resection with curative intent

N total at baseline:

N=244

Important prognostic factors²:

Only total sample characteristics described.

Median age (range) :

63 (27-93)

Sexe:

164M/80F

Tumor site:

Tongue: 105

FOM: 71

Buccal: 20

Alveolus/RMT/palate: 37

Lip: 11

Bone resection:

Yes: 149

No: 95

Neck dissection:

None: 48

Unilateral: 142

Bilateral: 54

T-stage:

T1: 59

T2: 91

T3: 38

T4: 56

N-stage:

N0: 103

N1: 30

N2a: 9

N2b: 13

N2c: 4

N3b: 37

cN0: 48

Extracapsular spread:

No: 201

Yes: 114

Postoperative radiotherapy:

No: 130

Yes: 114

Groups comparable at baseline?

Unclear, characteristics were not described at the 3mm cut-off

Describe intervention (treatment/procedure/test):

1: Resection margin <3mm

Describe control (treatment/procedure/test):

1: Resection margin ≥3mm

Length of follow-up:

Median follow-up: 29 months

Mean follow-up: 36 months

Loss-to-follow-up:

Unclear

Incomplete outcome data:

Unclear

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

Disease specific survival (Cox proportional hazard model), <3mm (close) versus ≥3mm (clear) , HR (95%CI):

HR = 1.86 (95%CI: 1.06-3.27)

Significant HR: p=0.03

Other variables in model: T-stage (T3-4 versus T1/2), N-stage (N+ versus N0), extracapsular spread, postoperative radiotherapy

Overall survival (Cox proportional hazard model), <3mm (close) versus ≥3mm (clear) , HR (95%CI):

HR = 1.78 (95%CI: 1.18-2.70)

Significant HR: p=0.006

Other variables in model: T-stage (T3-4 versus T1/2), N-stage (N+ versus N0), extracapsular spread, postoperative radiotherapy

Local recurrence (not reported in table 4) (Cox proportional hazard model), <3mm (close) versus ≥3mm (clear) , HR (95%CI):

HR = 1.63 (95%CI: 0.90-2.96)

Non-significant HR: p-value not reported

Other variables in model: Unclear

TNM 8 was used

Unclear group sizes at 3mm cut-off.

Chiou 2010

Type of study:

Setting and country:

Funding and conflicts of interest:

Inclusion criteria:

Patient with buccal mucosa carcinoma treated between august 2000-june 2008

Exclusion criteria:

CCRT treatment alone, RT treatment alone, neoadjuvant treatment therapy plus surgery, synchronous second primary.

N total at baseline:

Total: 110

(unclear at cut-off points)

Important prognostic factors²:

Tot total sample only

Age, n:

≤50: 44

>50: 66

Sex:

103M / 7F

pT-stage, n:

pT1-2: 70

pT3-4: 40

pN-stage, n:

pN0: 84

pN1-3: 26

Differentiation, n:

Well: 6

Moderately: 90

Poorly: 12

Not specified: 2

Treatment:

Surgery: 32

Surgery+RT: 38

Surgery+CCRT: 40

Smoking:

No: 16

Yes: 93

Unknown: 1

Betel nut chewing:

No: 15

Yes: 93

Unknown: 2

Groups comparable at baseline?

Unclear

Describe intervention (treatment/procedure/test):

1: ≤1 mm

2: ≤2 mm

3: ≤3 mm

4: ≤4 mm

5: ≤5 mm

Describe control (treatment/procedure/test):

1: >1 mm

2: >2 mm

3: >3 mm

4: >4 mm

5: >5 mm

Length of follow-up:

Unclear, for DFS at least 3 year

Loss-to-follow-up:

Unclear

Incomplete outcome data:

Unclear

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

Continuous:

Locoregional control*:

HR = 2.16 (95%CI: 1.14-4.11)

p-value not reported

Other variables in model: unclear

*Surgical margin was probably added as a continuous variable in a multivariable model to estimate local control.

1 mm (≤1mm versus >1mm)

3-year Disease-free survival (%):

≤1mm : 56%

>1mm: 77%

3-year Disease-free survival, multivariate HR (95%CI):

HR = 0.2 (95%CI: 0.06-0.72)

P=0.02

Other variables in model: unclear

Locoregional control (%):

≤1mm : 59%

>1mm: 81%

Locoregional control, multivariate HR (95%CI):

HR = 0.2 (95%CI: 0.05-0.67)

P=0.01

Other variables in model: unclear

2 mm (≤2mm versus >2mm)

3-year Disease-free survival (%):

≤1mm : 59%

>1mm: 93%

3-year Disease-free survival, multivariate HR (95%CI):

HR = 0.1 (95%CI: 0.01-0.60)

P=0.01

Other variables in model: unclear

Locoregional control (%):

≤1mm : 64%

>1mm: 97%

Locoregional control, multivariate HR (95%CI):

HR = 0.1 (95%CI: 0.01-0.72)

P=0.02

Other variables in model: unclear

3 mm (≤3mm versus >3mm)

3-year Disease-free survival (%):

≤1mm : 67%

>1mm: 91%

3-year Disease-free survival, multivariate HR (95%CI):

HR = 0.2 (95%CI: 0.03-1.86)

P=0.17

Other variables in model: unclear

Locoregional control (%):

≤1mm : 71%

>1mm: 95%

Locoregional control, multivariate HR (95%CI):

HR = 0.3 (95%CI: 0.03-2.12)

P=0.21

Other variables in model: unclear

4 mm (≤4mm versus >4mm)

3-year Disease-free survival (%):

≤1mm : 69%

>1mm: 89%

3-year Disease-free survival, multivariate HR (95%CI):

HR = 0.3 (95%CI: 0.04-2.16)

P=0.22

Other variables in model: unclear

Locoregional control (%):

≤1mm : 73%

>1mm: 94%

Locoregional control, multivariate HR (95%CI):

HR = 0.3 (95%CI: 0.04-2.52)

P=0.28

Other variables in model: unclear

5 mm (≤5mm versus >5mm)

3-year Disease-free survival (%):

≤1mm : 72%

>1mm: 86%

3-year Disease-free survival, multivariate HR (95%CI):

HR = 0.5 (95%CI: 0.07-4.22)

P=0.56

Other variables in model: unclear

Locoregional control (%):

≤1mm : 75%

>1mm: 92%

Locoregional control, multivariate HR (95%CI):

HR = 0.6 (95%CI: 0.08-4.80)

P=0.63

Other variables in model: unclear

Unclear group sizes at cut-off points

Heiduchka 2016

Type of study:

Observational, database

Setting and country: Hospital, Australia

Funding and conflicts of interest: Authors reported that there was no financial support and no CoI

Inclusion criteria:

Treated for oral SCC carcinoma between 1987 and 2014.

Exclusion criteria:

Insufficient data

N total at baseline:

N=501

Important prognostic factors²:

Total sample

Median age (IQR)

63.6 (IQR: 53.2-72.9)

Sex:

289M / 212F

Median Maximum tumor diameter (mm):

24.0 (IQR: 15-33)

Tumor differentiation (data available from n=465):

Well: 81

Moderate: 307

Poor: 77

Perineural invasion:

Yes: 151

No: 350

Lymphovascular invasion:

Yes: 69

No: 432

T-stage, n:

T1: 170

T2: 180

T3: 43

T4: 108

N-stage, n:

N0: 303

N1: 56

N2: 140

N3: 2

Extracapsular spread, n:

Yes: 83

No: 418

Radiation therapy, n:

Yes: 225

No: 276

Chemotherapy, n:

Yes: 29

No: 472

Groups comparable at baseline?

unclear

Describe intervention (treatment/procedure/test):

Margin to size ratio was calculated by: margin (mm) / tumor diameter (mm)

Margin to thickness ratio was calculated by: margin (mm) / tumor thickness (mm)

Describe control (treatment/procedure/test):

Length of follow-up:

Median: 2.3 years (range: 0.1-18.6)

Loss-to-follow-up:

Not described

Incomplete outcome data:

Not described (although n=38 were excluded due to insufficient data)

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

Continuous:

Local control, log(MSR):

HR = 0.74 (95%CI: 0.53-1.05)

P=0.089

Other variables in model: perineural invasion, lymphovascular invasion, tumor thickness, radiotherapy

Disease specific survival, log(MSR):

HR = 0.83 (95%CI: 0.63-1.10)

P=0.205

Other variables in model: perineural invasion, lymphovascular invasion, nodal status, extra capsular spread, radiotherapy

Local control, log(MTR):

HR = 0.71 (95%CI: 0.52-0.97)

P=0.033

Other variables in model: perineural invasion, lymphovascular invasion, tumor diameter, radiotherapy

Disease specific survival, log(MTR):

HR = 0.77 (95%CI: 0.60-0.99)

P=0.038

Other variables in model: perineural invasion, lymphovascular invasion, nodal status, extra capsular spread, radiotherapy

MTR >0.3 mm cut-off (MTR >0.3 clear)

Local control, close (MTR 0.06-0.3) versus clear (MTR >0.3):

HR= 1.22 (95%CI: 0.62-2.41)

P=0.559

Other variables in model: perineural invasion, lymphovascular invasion, nodal status

Local control, close (MTR <0.06) versus clear (MTR >0.3):

HR= 1.92 (95%CI: 1.02-3.61)

P=0.043

Other variables in model: perineural invasion, lymphovascular invasion, nodal status

Local control*, close (MTR <0.06) versus clear (MTR >0.3):

HR= 2.64 (95%CI: 1.05-6.63)

P=0.039

Other variables in model: perineural invasion, lymphovascular invasion, nodal status

*n=79 with involved margins were removed from analysis

Disease specific survival*, close (MTR <0.06) versus clear (MTR >0.3):

HR= 2.27 (95%CI: 1.07-4.81)

P=0.032

Other variables in model: perineural invasion, lymphovascular invasion, nodal status

*n=79 with involved margins were removed from analysis

MSR: Margin to tumor size ratio

MTR: Resection margin to tumor thickness ratio

Stained paraffin-embedded sections were measured with an ocular micrometer.

Huang 2019

Type of study:

Observational, database

Setting and country: Hospital, Taiwan

Funding and conflicts of interest: Funding not reported, authors declare that there were no CoI

Inclusion criteria:

Newly diagnosed oral SCC, underwent radical surgery, sufficient pathology data, with or without adjuvant treatment

Exclusion criteria:

Chemotherapy or radiotherapy as initial treatment, previous cancer history, distant metastasis upon diagnosis

N total at baseline:

N=302

MTR≤33%: 100

MTR>33%: 202

Important prognostic factors²:

Median age (range):

MTR≤33%: 51 (31-88)

MTR>33%: 54 (28-92)

Sex:

MTR≤33%: 93M / 7F

MTR>33%: 187M / 15F

Margin status:

MTR≤33%: 79 negative / 21 positive

MTR>33%: 202 negative / 0 positive

Tumor thickness:

MTR≤33%: 24 had ≤10mm / 76 had >10mm

MTR>33%: 132 had ≤10mm / 70 had >10 mm

Tumor site:

MTR≤33%: 41 at tongue / 59 at buccal

MTR>33%: 88 at tongue / 114 at buccal

Perineural invasion:

MTR≤33%: 48 yes / 52 no

MTR>33%: 6 yes / 196 no

Lymphovascular invasion:

MTR≤33%: 14 yes / 86 no

MTR>33%: 6 yes / 196 no

pT-stage:

MTR≤33%: T1: 8 / T2 : 43 / T3: 10 / T4: 39

MTR>33%: T1: 63 / T2: 91 / T3: 12 / T4: 36

pN-stage

MTR≤33%: N0: 44 / N1: 15 / N2: 41

MTR>33%: N0: 136 / N1: 22 / N2: 44

Differentiation:

MTR≤33%: Well: 7 / moderate: 79 / poor: 14

MTR>33%: well: 38 / moderate: 150 / poorly: 14

Alcohol use:

MTR≤33%: 70 yes / 30 no

MTR>33%: 150 yes / 32 no

Areca quid:

MTR≤33%: 85 yes / 15 no

MTR>33%: 170 yes / 32 no

Smoking:

MTR≤33%: 88 yes / 12 no

MTR>33%: 179 yes / 23 no

Adjuvant therapy:

MTR≤33%: 35 no therapy / 35 radiotherapy / 7 chemotherapy / 23 chemoradiotherapy

MTR>33%: 107 no therapy / 45 radtiotherapy / 22 chemotherapy / 28 chemoratiotherapy

Groups comparable at baseline?

No, differences in perineural invasion, lymphovascular invasion, t-stage, n-stage, differentiation, adjuvant therapy

Describe intervention (treatment/procedure/test):

Positive = malignant cells infiltrating at the cutting margin

Margin to size ratio was calculated by: log₁₀((margin (mm) +0.1) / (tumor diameter (mm)+0.1))

1: log(MTR) ≤ 33%

Describe control (treatment/procedure/test):

1: log(MTR) > 33%

Length of follow-up:

Unclear

Loss-to-follow-up:

Not reported

Incomplete outcome data:

Not reported

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

Log(MTR) >33% (log(MTR)> 33% clear)

5-year Disease specific survival in n=302, close (log(MTR) ≤ 33%) versus clear (log(MTR) > 33%):

HR= 1.73 (95%CI: 1.16-2.57)

P=0.006

Other variables in model: perineural invasion, lymphovascular invasion, pT-stage, pN-stage, tumor differentiation

5-year Disease specific survival in n=97 with T3-4, close (log(MTR) ≤ 33%) versus clear (log(MTR) > 33%):

HR= 2.67 (95%CI: 1.44-4.95)

P=0.002

Other variables in model: pN-stage, adjuvant therapy

TNM 7 was used

MTR: Resection margin to tumor thickness ratio

Nason 2009

Type of study:

Observational, database

Setting and country:Cancer registry, Canada

Funding and conflicts of interest: Funding and CoI not declared in the manuscript

Inclusion criteria:

SCC of the oral cavity

Exclusion criteria:

Incomplete records, seen in consultation only, treated with palliative intent, treated with RT only

N total at baseline:

277

Important prognostic factors²:

Total sample only

Mean age ± SD:

63.3 (12)

Smoking (%):

70% smoked

Alcohol use:

90% used alcohol

Groups comparable at baseline?

Unclear

Describe intervention (treatment/procedure/test):

1: Positive margin

2: >3 mm (clear)

Describe control (treatment/procedure/test):

1: >3mm (clear)

2: ≤3mm (close)

Length of follow-up:

Median 36 months (range 0-360)

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

Continuous:

5-year overall survival:

HR = 0.92 (95%CI: 0.86-0.99)

P=0.02

Other variables in model: gender, age, stage (IV versus I-III).

Positive margins versus >3mm (clear)(ref)

5-year overall survival:

HR= 2.5 (95%CI: 0.95-2.70)

P=0.000

Identified with the Cox model, Other variables in model: gender, age, stage, surgical margin

≤3mm (close) versus >3mm (clear) (ref)

5-year overall survival:

HR= 1.54 (95%CI: 0.95-2.70)

P=0.076)

Identified with the Cox model, Other variables in model: gender, age, stage, surgical margin

Unclear group sizes at cut-off points

Tsai 2011

Type of study:

Observational, database

Setting and country: Hospital, Taiwan

Funding and conflicts of interest: Funding and CoI not declared in the manuscript

Inclusion criteria:

Resectable buccal mucosa, M0, histologically proven

Exclusion criteria:

Margin >3mm, no postoperative therapy, RT dose <45 Gy, positive surgical margin.

N total at baseline:

Total: 30

Important prognostic factors²:

Median age (range):

51.5 (35-82)

Sex:

26M / 4F

ECOG, n:

0-1: 21

≥2: 9

Smoking, n:

No: 6

Yes: 24

Betel nut chewing, n:

No: 7

Yes: 23

Histology, n:

Well to moderate: 28

Poor differentiation: 2

Invasion depth, n:

<10mm: 12

≥10mm: 18

pT-stage, n:

pT1-3: 20

pT4: 10

pN-stage, n:

pN0: 25

pN1-2: 5

pathological margin, n:

>1 mm: 13

≤1mm: 17

RT dose, n:

≤66Gy: 16

>66Gy: 14

Groups comparable at baseline?

Unclear

Describe intervention (treatment/procedure/test):

≤1mm

Describe control (treatment/procedure/test):

>1mm (ref)

Length of follow-up:

Median 52.8 months (6.4-65.8)

Mean 56.8 months (SD: 11.5 months)

Loss-to-follow-up:

None lost

Incomplete outcome data:

N=2 died before analysis

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

1 mm (≤1mm versus >1mm(ref))

Locoregional control, multivariate HR (95%CI):

HR = 9.53 (95%CI: 1.33-18.48)

P=0.025

Other variables in model: age (>50 versus ≤50), Gender (male versus female), ECOG PS (≥2 versus 0-1), Smoking (Yes versus no), Betel nut chewing (yes versus no), Histology (poor differentiation versus good to moderate), invasion depth (≥10mm versus <10mm), PNI (yes versus no), LVERSUSI (yes versus no), ECS (yes versus no), pT-stage (pT4 versus pT1-3), pN-stage (pN1-2 versus pN0), Pathology stage (IVa/b versus I-III), RT dose (>66Gy versus ≤66Gy).

Local control, multivariate HR (95%CI):

HR = 14.02 (95%CI: 1.13-29.76)

P=0.043

Regional control, multivariate HR (95%CI):

HR = 3.90 (95%CI: 0.39-11.91)

P=0.672

Disease-free survival, multivariate HR (95%CI):

HR = 12.78 (95%CI: 1.93-25.22)

P=0.013

Other variables in model: age (>50 versus ≤50), Gender (male versus female), ECOG PS (≥2 versus 0-1), Smoking (Yes versus no), Betel nut chewing (yes versus no), Histology (poor differentiation versus good to moderate), invasion depth (≥10mm versus <10mm), PNI (yes versus no), LVSI (yes versus no), ECS (yes versus no), pT-stage (pT4 versus pT1-3), pN-stage (pN1-2 versus pN0), Pathology stage (IVa/b versus I-III), RT dose (>66Gy versus ≤66Gy).

Disease-specific survival, multivariate HR (95%CI):

HR = 16.52 (95%CI: 0.88-36.46)

P=0.198

Other variables in model: age (>50 versus ≤50), Gender (male versus female), ECOG PS (≥2 versus 0-1), Smoking (Yes versus no), Betel nut chewing (yes versus no), Histology (poor differentiation versus good to moderate), invasion depth (≥10mm versus <10mm), PNI (yes versus no), LVSI (yes versus no), ECS (yes versus no), pT-stage (pT4 versus pT1-3), pN-stage (pN1-2 versus pN0), Pathology stage (IVa/b versus I-III), RT dose (>66Gy versus ≤66Gy).

Overall survival, multivariate HR (95%CI):

HR = 15.88 (95%CI: 0.54-35.98)

P=0.879

Other variables in model: age (>50 versus ≤50), Gender (male versus female), ECOG PS (≥2 versus 0-1), Smoking (Yes versus no), Betel nut chewing (yes versus no), Histology (poor differentiation versus good to moderate), invasion depth (≥10mm versus <10mm), PNI (yes versus no), LVSI (yes versus no), ECS (yes versus no), pT-stage (pT4 versus pT1-3), pN-stage (pN1-2 versus pN0), Pathology stage (IVa/b versus I-III), RT dose (>66Gy versus ≤66Gy).

pathological margin, n:

>1 mm: 13

≤1mm: 17

Wong 2012

Type of study:

Observational, database

Setting and country: Hospital, UK

Funding and conflicts of interest:

Inclusion criteria:

Untreated oral or oropharyngeal SCC treated between 2001 and 2007

Exclusion criteria:

Not reported

N total at baseline:

192

Important prognostic factors²:

Total sample only

Mean age (SD):

61 (11)

Sex:

122M / 70F

cT-Stage, n:

T1: 72

T2: 48

T3: 16

T4: 56

cN-Stage, n:

N0: 119

N1: 28

N2: 44

N3: 1

Tumor differentiation:

Poor: 27

Moderate: 134

Well: 21

Perineural invasion:

Yes: 28

No: 164

Vascular invasion:

Yes: 36

No: 156

Lymphatic invasion:

Yes: 26

No: 166

Bony invasion:

Yes: 31

No: 161

Invasive front:

Cohesive: 56

Non-cohesive: 105

Distribution of close margins (n=107):

1.0-2.0mm: 31

2.1-3.0mm: 23

3.1-4.0mm: 20

4.1-5.0mm: 33

Site:

Oral: 160

Oropharyngeal: 32

Groups comparable at baseline?

Unclear.

Describe intervention (treatment/procedure/test):

1: >1.6mm

2: >1mm

Describe control (treatment/procedure/test):

1: ≤1.6mm

2: ≤1mm

Length of follow-up:

Mean follow-up: 34 months

Loss-to-follow-up:

All surviving patients had at least 24 months follow-up at the time of assessment.

Incomplete outcome data:

None described

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

>1.6mm versus ≤1.6mm

Disease-specific survival group size:

≤1.6mm: 13 cases survived

>1.6mm: 26 cases survived

Disease-specific survival, 1.6mm versus ≤1.6mm(ref):

HR= 2.43 (95%CI: 1.21-4.88)

P=0.01

Other variables in model: cT-stage, cN-stage, Lympharic invasion, vascular invasion, histopathological involved lymph nodes, extracapsular spread, tumor depth.

Area under the curve for disease-specific survival:

AUC = 0.58 (95%CI: 0.50-0.65)

Sensitivity: 0.33

Specificity: 0.82

>1mm versus ≤1mm

Local recurrence group size:

≤1mm: 8 cases with LR

>1mm: 16 cases with LR

Local recurrence, 1mm versus ≤1mm(ref):

HR= 2.86 (95%CI: 1.20-6.85)

P=0.02

Other variables in model: cN-stage, lymphatic invasion, histopathological involved nodes, extracapsular spread, depth of tumor.

Area under the curve for local recurrence:

AUC = 0.58 (95%CI: 0.51-0.65)

Sensitivity: 0.33

Specificity: 0.84

Paraffin-embeded tumor blocks were sectioned at 4 micrometre and stained. Margin measurement were made under a microscope.

Unclear group sizes at cut-off

Yamada 2016

Type of study:

Observational, database (consecutive)

Setting and country: Hospital, Japan

Funding and conflicts of interest: Authors state there is no funding and CoI.

Inclusion criteria:

Planned radical resection with or without adjuvant radiotherapy and/or chemotherapy, previously untreated oral squamous cell carcinoma,

Exclusion criteria:

T4b tumors, dysplastic epithelium at mucosal margin

N total at baseline:

N=127

Important prognostic factors²:

Total sample

Median age (range):

66 (27-84)

Sex:

73M / 54F

Tumor location:

Tongue: 59

Lower gum: 2

Upper gum: 16

Cheek mucosa: 16

Floor of mouth: 14

Hard palate: 1

T-stage:

T1: 20

T2: 39

T3: 22

T4a: 46

N-stage:

N0: 72

N1: 20

N2b: 26

N2c: 8

N3: 1

Differentiation:

Micro invasive: 4

Well-defined: 79

Moderate: 38

Poor: 6

Mode of invasion:

YK-2: 18

YK-3: 55

YK4C: 41

YK4D: 13

Preoperative therapy:

Yes: 82

No: 45

Postoperative radiotherapy >50Gy:

Yes: 35

No: 92

Margin distribution:

Involved: 10

0mm-≤1mm: 6

>1mm-≤2mm: 8

>2mm-≤3mm: 0

>3mm-≤4mm: 5

>4mm-≤5mm: 5

>5mm: 93

Groups comparable at baseline?

Unclear

Describe intervention (treatment/procedure/test):

Involved margin = carcinoma in situ

Margins were assessed with conventional microscope processing.

Involved / close

1: involved / 0mm-≤5mm

2: involved / 0mm-≤4mm

3: involved / 0mm-≤2mm

4: involved / 0mm-≤1mm

5: involved

Describe control (treatment/procedure/test):

Clear:

1: >5mm (ref)

2: >4mm (ref)

3: >2mm (ref)

4: >1mm (ref)

5: >0mm (ref)

Length of follow-up:

Median: 43 months (range: 2-180)

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

5 mm cut-off (>5mm clear)

Group-size:

>5mm: 93

Close: 24

Involved: 10

Local control (unadjusted):

>5mm: 91.7%

Close: 87.3%

Involved: 57.1%

2-year local control, close (0mm-≤5mm) versus clear (>5mm; ref):

HR= 3.32 (95%CI: 0.87-12.73)

P=0.08

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

2-year local control, involved (carcinoma in situ) versus clear (>5mm; ref):

HR= 14.42 (95%CI: 3.82-54.36)

P<0.001

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

4 mm cut-off (>4mm clear)

Group-size:

>4mm: 98

Close: 19

Involved: 10

Local control (unadjusted):

>4mm: 92.1%

Close: 83.9%

Involved: 57.1%

2-year local control, close (0mm-≤4mm) versus clear (>4mm; ref):

HR= 4.35 (95%CI: 1.09-17.32)

P=0.037

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

2-year local control, involved (carcinoma in situ) versus clear (>4mm; ref):

HR= 14.42 (95%CI: 3.95-53.73)

P<0.001

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

2 mm cut-off (>2mm clear)

Group-size:

>2mm: 103

Close: 14

Involved: 10

Local control (unadjusted):

>2mm: 92.5%

Close: 77.9%

Involved: 57.1%

2-year local control, close (0mm-≤2mm) versus clear (>2mm; ref):

HR= 4.37 (95%CI: 1.04-18.42)

P=0.045

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

2-year local control, involved (carcinoma in situ) versus clear (>2mm; ref):

HR= 13.22 (95%CI: 3.73-46.85)

P<0.001

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

1 mm cut-off (>1mm clear)

Group-size:

>1mm: 111

Close: 6

Involved: 10

Local control (unadjusted):

>1mm: 92.1%

Close: 66.7%

Involved: 57.1%

2-year local control, close (0mm-≤1mm) versus clear (>1mm; ref):

HR= 23.69 (95%CI: 3.38-166.15)

P=0.001

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

2-year local control, involved (carcinoma in situ) versus clear (>1mm; ref):

HR= 17.00 (95%CI: 4.49-64.42))

P<0.001

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

0 mm cut-off (>0mm clear)

Group-size:

>0mm: 117

Involved: 10

Local control (unadjusted):

>0mm: 90.8%

Involved: 57.1%

2-year local control, involved (carcinoma in situ) versus clear (>0mm; ref):

HR= 10.74 (95%CI: 3.07-37.54)

P<0.001

Other variables in model: T-stage, degree of differentiation, mode of invasion, preoperative therapy, postoperative therapy over 50 Gy

Pathology reports on margins were reviewed.

Yanamoto 2012

Type of study:

Retrospective

Setting and country:

Hospital, Japan

Funding and conflicts of interest: Authors declared that there was no funding and competing interests

Inclusion criteria:

Histologically confirmed oral squamous cell carcinoma, minimal follow-up of 12 months.

Exclusion criteria:

Not reported

N total at baseline:

Total: 187

N total (superficial margin):

≤4mm: 31

>4mm: 156

N total (deep margin):

≤4mm: 25

>4mm: 162

Important prognostic factors²:

Age, n:

≥68 years: 111

≤67 years: 76

Mean age, total:

67.3 (range: 28-95)

Sex (M/F):

Total: 102M/85F

Tumor site, total n:

Tongue: 73

Oral floor: 26

Upper gingiva: 36

Lower gingiva: 44

Buccal mucosa: 8

T-stage, total n:

T1: 52

T2: 92

T3: 14

T4: 29

N-stage, total n:

N0: 141

N1: 26

N2a: 2

N2b: 12

N2c: 6

Tumor differentiation, total n:

Well: 166

Moderate: 20

Poor: 1

Preoperative treatment, total n:

Surgery alone: 124

Neoadjuvant chemotherapy: 63

Postoperative adjuvant radiotherapy, total n:

Yes: 15

No: 172

Groups comparable at baseline?

Describe intervention (treatment/procedure/test):

≤ 4 mm in superficial or deep margin

Describe control (treatment/procedure/test):

>4mm in superficial or deep margin as clear

Length of follow-up:

At least 12 months; mean follow-up 36.7 months (range: 10-125 months).

Loss-to-follow-up:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

Incomplete outcome data:

Intervention:

N (%)

Reasons (describe)

Control:

N (%)

Reasons (describe)

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

4 mm cut-off margin (>4mm clear)

Superficial margin

Group-size (superficial):

>4mm: 156

≤4mm: 31

Local control superficial margin (unadjusted):

>4mm: 10.3%

≤4mm: 45.2%

Local recurrence for superficial margin, close (≤4mm) versus clear (>4mm; ref):

OR= 7.12 (95%CI: 2.28-22.35)

P<0.001

Other variables in model: pattern of invasion, preoperative treatment, deep surgical margin, postoperative adjuvant radiotherapy

Deep margin

Group-size (deep):

>4mm: 162

≤4mm: 25

Local control superficial margin (unadjusted):

>4mm: 8.6%

≤4mm: 64.0%

Local recurrence for superficial margin, close (≤4mm) versus clear (>4mm; ref):

OR= 4.90 (95%CI: 1.44-16.70)

P=0.011

Other variables in model: pattern of invasion, preoperative treatment, superficial surgical margin, postoperative adjuvant radiotherapy

TNM staging by IUCC, 6^th ed.

Zanoni 2017

Type of study:

Observational, database

Setting and country: Hospital, USA

Funding and conflicts of interest: partially funded through a cancer center support grant from the national cancer institute (national institute of health). Authors declared that there were no CoI.

Inclusion criteria:

Patients underwent primary surgery for SCC of the tongue from January 2000-December 2012, histopathologic slides available for review.

Exclusion criteria:

Not reported

N total at baseline:

N=381

Important prognostic factors²:

Total sample

Mean Age (SD):

58 (14.7)

Sex:

222M / 159F

Tobacco use:

Never: 121

Ever: 260

cT-stage, n:

cT1: 193

cT2: 135

cT3: 34

cT4: 15

cTX: 4

cN-stage, n:

cN0: 275

cN1: 40

cN2: 64

cN3: 2

Groups comparable at baseline?

unclear

Describe intervention (treatment/procedure/test):

Positive = invasive carcinoma at margin of the resected specimen

1: 0.01mm-2.2mm

2: 2.3mm-5.0mm

3: positive

4: 0.01mm-2.2mm

5: positive

Describe control (treatment/procedure/test):

1: >5mm (reference)

2: >5mm (ref)

3: >5mm (ref)

4: >2.2mm (ref)

5: >2,2mm (ref)

Length of follow-up:

Median: 40 months (range: 0-150)

Loss-to-follow-up:

Not described

Incomplete outcome data:

Not described

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

5 mm cut-off (>5mm clear)

Local recurrence-free survival, close (0.01mm-2.2mm) versus clear (>5mm; ref):

HR= 2.25 (95%CI:1.03-4.92)

P-value not reported

Other variables in model: Tumor size, adjuvant therapy

Local recurrence-free survival, close (2.3mm-5.0mm) versus clear (>5mm; ref):

HR= 1.17 (95%CI: 0.51-2.66)

P-value not reported

Other variables in model: Tumor size, adjuvant therapy

Local recurrence-free survival, close (positive) versus clear (>5mm; ref):

HR= 5.71 (95%CI: 2.08-15.65)

P-value not reported

Other variables in model: Tumor size, adjuvant therapy

2.2 mm cut-off (>2.2mm clear)

Group-size:

>2.2mm: 243

0.01-2.2: 115

Positive: 23

Local recurrence-free survival, close (0.01mm-2.2mm) versus clear (>2.2mm; ref):

HR= 2.00 (95%CI: 1.13-3.55)

P-value not reported

Other variables in model: Tumor size, perineural invasion, pN-stage

Local recurrence-free survival, close (positive) versus clear (>2.2mm; ref):

HR= 5.73 (95%CI: 2.45-13.41)

P-value not reported

Other variables in model: Tumor size, perineural invasion, pN-stage

Specimens were reviews by a pathologist for margin status

Group size at cut-offs unclear with 5mm as a cutoff

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)

Research question:

Study reference

(first author, year of publication)

Bias due to a non-representative or ill-defined sample of patients?¹

(unlikely/likely/unclear)

Bias due to insufficiently long, or incomplete follow-up, or differences in follow-up between treatment groups?²

(unlikely/likely/unclear)

Bias due to ill-defined or inadequately measured outcome ?³

(unlikely/likely/unclear)

Bias due to inadequate adjustment for all important prognostic factors?⁴

(unlikely/likely/unclear)

Brinkman 2020

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. In- and exclusion criteria were stated and seemed to be adhered.

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Unclear

Reason: unclear whether confounders were selected a priori and whether all important confounders were used.

Chiou 2010

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. In- and exclusion criteria were stated and seemed to be adhered.

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Unclear

Reason: unclear which variables were in the model.

Heiduchka 2016

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. In- and exclusion criteria were stated and seemed to be adhered.

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Unlikely

Reason: Multiple plausible confounders seem to be defined a priori and remained in the model, even though significance was not reached.

Huang 2019

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. In- and exclusion criteria were stated and seemed to be adhered.

Unclear

Reason: follow-up time is not described

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Likely

Reason: confounders were not selected a priori. Only significant predictors remained in the model instead of predefined confounders.

Nason 2009

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. In- and exclusion criteria were stated and seemed to be adhered.

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Likely

Reason: confounders were not selected a priori. Only significant predictors remained in the model instead of predefined confounders.

Tsai 2011

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. In- and exclusion criteria were stated and seemed to be adhered.

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Unlikely

Reason: model was built with various probable confounders, which stayed in the model even though not significant

Wong 2012

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. Note that there were no exclusion criteria reported.

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Likely

Reason: confounders were not selected a priori. Only significant predictors in univariable analyses were entered in the multivariable model instead of predefined confounders.

Yamada 2016

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. In- and exclusion criteria were stated and seemed to be adhered.

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Unlikely

Reason: Multiple plausible confounders were defined a priori and remained in the model, even though significance was not reached.

Yanamoto 2012

Unclear

Reason: Selection of patients does not seem to be sampled from different populations, however no exclusion criteria were reported/

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: procedures regarding the blinding of outcome assessment were not reported

Likely

Reason: confounders were not selected a priori. Only significant predictors in univariable analyses were entered in the multivariable model instead of predefined confounders.

Zanoni 2017

Unlikely

Reason: Selection of patients does not seem to be sampled from different populations. Note that there were no exclusion criteria reported.

Unclear

Reason: follow-up time is described for the total sample, not for the groups at the cut-off

Unclear

Reason: Pathologists reviewed archived slides for margin status and histologic outcomes. Pathologists were blinded for the outcome of the patients. However no procedure were described for the blinden of the outcome assessors who assessed local recurrence and local recurrence-free survival.

Likely

Reason: confounders were not selected a priori. Only significant predictors in univariable analyses were entered in the multivariable model instead of predefined confounders.

Failure to develop and apply appropriate eligibility criteria: a) case-control study: under- or over-matching in case-control studies; b) cohort study: selection of exposed and unexposed from different populations.
2 Bias is likely if: the percentage of patients lost to follow-up is large; or differs between treatment groups; or the reasons for loss to follow-up differ between treatment groups; or length of follow-up differs between treatment groups or is too short. The risk of bias is unclear if: the number of patients lost to follow-up; or the reasons why, are not reported.
Flawed measurement, or differences in measurement of outcome in treatment and control group; bias may also result from a lack of blinding of those assessing outcomes (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary.
Failure to adequately measure all known prognostic factors and/or failure to adequately adjust for these factors in multivariate statistical analysis.

Table of excluded studies

Author and year	Reason for exclusion
Akheel 2019	No stratification of resection margins on outcomes or alternative classification used in analyses
Anderson 2015	No stratification of resection margins on outcomes or alternative classification used in analyses
Barry 2015	No stratification of resection margins on outcomes or alternative classification used in analyses
Binahmed 2007	No multivariable analysis for the question of interest
Brandwein-Gensler 2005	No stratification of resection margins on outcomes or alternative classification used in analyses
Buchakjian 2018	Uses standard classification of <1mm, 1-5mm, and >5mm in a prediction model
Buchakjian 2016	involved: positive CIS and <1mm / uninvolved: mild to moderate dysplasia and >1mm, let op: groepen gaan ook over intraoperative assessment
Ch'Ng 2013	No multivariable analysis for the question of interest
Dik 2014	No multivariable analysis for the question of interest
Iseli 2012	Uses standard classification of <1mm, 1-5mm, and >5mm for the effect of radiotherapy
Jain 2020	No multivariable analysis for the question of interest
Loree 1990	Uses standard cutoff at 5mm
Luryi 2014	Uses standard cutoff at 5mm
McMahon 2003	No stratification of resection margins on outcomes or alternative classification used in analyses
Miller 2019	Margins were not defined
Mitchell 2018	No multivariable analysis for the question of interest
Pandey 2009	No stratification of resection margins on outcomes or alternative classification used in analyses
Pu 2016	Margin status not defined in millimeters (dysplasia at margin)
Safi 2017	Only cases with a negative margin were selected
Sieczka 2001	No stratification of resection margins on outcomes or alternative classification used in analyses
Sopka 2013	Margin status not defined in millimeters (dysplasia at margin)
Stathopoulos 2018	No stratification of resection margins on outcomes or alternative classification used in analyses
Subramaniam 2018	Cases with margins <5mm were excluded
Tasche 2017	No multivariable analysis for the question of interest
Tomoika 2013	Margins were not defined, besides positive margin (0mm)
Torantini 2019	No stratification of resection margins on outcomes or alternative classification used in analyses
Van Es 1996	No stratification of resection margins on outcomes or alternative classification used in analyses
Varvares 2015	No stratification of resection margins on outcomes or alternative classification used in analyses
Vedemeyer 2014	Margin status not defined in millimeters (R0 versus R1)
Welinder 2018	Uses standard classification of <1mm, 1-5mm, and >5mm for the effect of radiotherapy
Welfensberger 1989	Article in German.
Wooglar 2005	No stratification of resection margins on outcomes or alternative classification used in analyses
Yahalom 2008	Margins were not defined
Zaman 2018	Article in Spanish
Zelefski 1993	Margins do not seem to be clearly defined (possibly standard margins)
Ball 1997	No stratification of resection margins on outcomes or alternative classification used in analyses
Cariati 2019	No multivariable analysis for the question of interest
Chakrabarti 2018	narrative review
Dillon 2015	Uses standard definition
Dourado 2020	No stratification of resection margins on outcomes or alternative classification used in analyses
Fridman 2018	Uses standard definition
Jang 2017	No stratification of resection margins on outcomes or alternative classification used in analyses
Joseph 2019	No stratification of resection margins on outcomes or alternative classification used in analyses
Kar 2020	Margins were not defined
Kurita 2010	No multivariable analysis for the question of interest
Lee 2018	Margins were assessed in 5 directions. Margin status was not stratified by mm.
Lee 2019	No multivariable analysis for the question of interest
Liao 2008	Margins were not defined, only margin negative cases were used in this study, no stratification per margin mm
Lin 2020	No stratification of resection margins on outcomes or alternative classification used in analyses

Verantwoording

Autorisatiedatum en geldigheid

Laatst beoordeeld : 20-09-2023

Laatst geautoriseerd : 20-09-2023

Geplande herbeoordeling :

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

Initiatief en autorisatie

Initiatief:

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

Geautoriseerd door:

Nederlandse Internisten Vereniging
Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied
Nederlandse Vereniging voor Nucleaire geneeskunde
Nederlandse Vereniging voor Pathologie
Nederlandse Vereniging voor Plastische Chirurgie
Nederlandse Vereniging voor Radiologie
Nederlandse Vereniging voor Radiotherapie en Oncologie
Verpleegkundigen en Verzorgenden Nederland
Nederlandse Vereniging voor Mond- Kaak- en Aangezichtschirurgie
Patiëntenvereniging HOOFD HALS
Nederlandse Federatie van Kankerpatiëntenorganisaties

Algemene gegevens

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

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodule is in 2019 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) 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
Prof. 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/Bewegingswetenschapper/Epidemioloog, 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 (tot november 2021), EN
A.C.P. Kauerz-de Rooij, Ergotherapeut, UMC Utrecht, Utrecht (vanaf januari 2022), EN
J. Poelstra, Medisch maatschappelijk werkster, op persoonlijke titel
Dr. K.S. Versteeg, Internist, Amsterdam UMC, Amsterdam, NIV ouderengeneeskunde

Met dank aan

Drs. Maarten Donswijk, Nucleair geneeskundige, AVL
Dr. José Hardillo, KNO-arts/hoofd-halschirurg, Erasmus MC, Rotterdam
Drs. Dominique Monserez, KNO-arts/hoofd-halschirurg, Erasmus MC, Rotterdam

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
Dr. N. Elbert, 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 (zie aanverwante producten) 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.

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 inventariseerde 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 aanverwante producten voor het verslag van de Invitational conference). 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.

Waar relevant is er specifieke aandacht voor de (oudere) kwetsbare patiëntengroep in de overwegingen en wordt er ingegaan op de begeleiding en behandeling van deze patiënten.

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 richtlijnmodules 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.

Herziening 2023

De werkgroep besloot na het bestuderen van alle aanbevelingen van de richtlijn Hoofd-halstumoren om in de periode 2019-2023 te werken aan de volgende updates:

De indeling van de richtlijn is aangepast en per tumortype zijn alle relevante modules te vinden. Sommige modules (zoals Systemische therapie bij radiotherapie lokaal gevorderde tumoren) zijn daarom bij zowel Orofarynxcarcinoom, Hypofarynxcarcinoom, als Larynxcarcinoom in de richtlijn te vinden.
In de meest recente UICC/AJCC classificatie is lipcarcinoom niet langer ondergebracht bij mondholte (TNM7) maar bij huid (TNM8). Dit brengt een verandering in stadiëring (volgens TNM8) met zich mee, maar niet in behandeling (volgens TNM7).
Nieuwe modules zijn ontwikkeld over het bepalen van botinvasie, bepalen HPV-status, indicaties voor onderzoek naar afstandsmetastasen en het diagnostisch onderzoek naar afstandsmetastasen, de behandeling van HPV-positieve orofarynxtumoren, dosering cisplatin en systemische therapie bij radiotherapie voor lokaal gevorderde tumoren, en Tis/T1 supgraglottisch larynxcarcinoom.
Een groot aantal modules zijn herzien. Literatuuronderbouwingen, overwegingen en aanbevelingen zijn geupdate.
Een aantal modules zijn herbevestigd en waar nodig tekstueel verbeterd, waaronder de modules Diagnostiek hypofarynxcarcinoom en Premaligne afwijkingen larynx.
Een aantal modules zijn vervallen: Indicaties FDG PET-CT-scan, Behandeling per lokalisatie en T-classificatie, Reconstructieve chirurgie mondholtecarcinoom, Invasieve chirurgie bij orofarynxcarcinoom, Reconstructieve chirurgie orofarynxcarcinoom, T1-T4N+ hypofarynxcarcinoom, Stemkwaliteit als uitkomstmaat na behandeling, T2- en kleine T3 larynxcarcinomen, Niet gemetastaseerde speekselklier tumoren. Deze modules bleken moeilijk te vatten in richtlijn, of zijn samengevoegd in een (nieuwe) module.

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. http://richtlijnendatabase.nl/over_deze_site/over_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.

Hoofd-halstumoren

Hoofd-halstumoren

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

Werkwijze

Zoekverantwoording

Bijlagen

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