Behandeling T3-T4aN0 hypofarynxcarcinoom
Uitgangsvraag
Wat is de beste behandeling van T3-T4aN0 hypofarynxcarcinomen?
Aanbeveling
De behandeling van T3-T4N0 hypofarynxcarcinoom kan plaatsvinden met primaire chemoradiatie en met primaire chirurgie, afhankelijk van de pathologie uitslag gevolgd door radiotherapie dan wel chemoradiatie. De werkgroep kan op basis van de literatuur geen aanbevelingen geven over een voorkeur voor primaire chemoradiatie of primaire chirurgie met postoperatieve (chemo-)radiatie omdat geen verschil is gevonden in oncologische en functionele uitkomsten.
Bespreek de behandelopties en ondersteun de patiënt bij het maken van een behandelkeuze waarbij de individuele patiëntkarakteristieken afgewogen dienen te worden.
Bespreek de volgende belangrijke voor- en nadelen van de interventies indien van toepassing op de patiënt:
• Behandelduur:
- De duur van de behandelingen zonder complicaties is bij chirurgie gemiddeld twee tot drie weken gevolgd door gemiddeld vijf tot zeven weken (chemo-)radiatie.
- Voor radiotherapie is de behandeling poliklinisch en de behandelduur vijf tot zeven weken.
• Overblijvende behandelopties:
- Na radiotherapie is doorgaans geen radiotherapie meer mogelijk voor een recidief of tweede primaire tumor in het bestraalde gebied.
- Na chirurgie is hernieuwde chirurgie zelden nog mogelijk.
• Procedures:
- Een dergelijke operatie wordt onder narcose verricht.
• Korte en lange termijn complicaties en toxiciteit:
- Bij chirurgie kunnen bloedingen, pijn en ontstekingen optreden. Als langetermijneffect kunnen slikklachten als gevolg van stenosering optreden. Door het verrichten van een laryngopharyngectomie wordt de larynxfunctie geheel opgeheven.
- Bij radiotherapie kunnen heesheid en slikklachten optreden. Zes weken na afronding van radiotherapie verbeteren deze klachten in het algemeen. Voor deze klachten kan logopedische sliktraining of een blijvende gastrostomie nodig zijn.
- De kans op een disfunctionele larynx met slikklachten, passageklachten en slechte stem is reëel, wat een indicatie kan zijn voor een permanente tracheotomie of zelfs een laryngopharyngectomie. De kans op radionecrose is reëel, de kans op een secundaire tumor door de radiotherapie is zeer klein.
• Kans op adjuvante behandeling:
- Er zal na een resectie vrijwel altijd reden zijn (chemo-)radiatie te adviseren, na een chemoradiatietraject kan er ook resectie aan de orde zijn indien er residu ziekte is, of een recidief optreedt.
• Kans op genezing:
- Er is geen verschil gevonden tussen beide behandelopties met betrekking tot genezing.
Overwegingen
Voor- en nadelen van de interventie en de kwaliteit van het bewijs
Om de vergelijking van chemoradiatie met chirurgie voor patiënten met T3-T4N0 hypofarynxcarcinomen te kunnen beantwoorden, werden 2 RCT’s en 7 observationele studies geïncludeerd. De bewijskracht van deze studies is zeer laag, door een inadequate blindering in de RCT’s, de observationele aard van de geïncludeerde studies, de variatie in gebruikte behandelingen tussen sommige studies, en wegens het lage aantal geïncludeerde patiënten.
De cruciale uitkomstmaten overall survival en disease free survival werden gerapporteerd. Door de zeer lage bewijskracht, zijn we onzeker of overall survival en disease free survival beter zijn na behandeling met chemoradiatie, of na behandeling met chirurgie. Daarnaast werd informatie gerapporteerd voor de belangrijke uitkomstmaat morbiditeit (met name larynxpreservatie). De bewijskracht is echter zeer laag waardoor geen uitspraak kan worden gedaan over het verschil tussen de groepen wat betreft de kans op behoud van een functionele larynx. Logischerwijs mag verwacht mag worden dat chemoradiotherapie in vergelijking met chirurgie resulteert in een hoger percentage larynxpreservatie, mogelijk bij T4a tumoren met een mindere locoregionale tumor controle. Larynxpreservatie betekent echter niet altijd dat ook de functies van de larynx behouden blijven.
Conform expert opinion is er een indicatie voor primaire TLE als er sprake is van een disfunctionele larynx, voorafgaande aan de therapie. Hierbij moet gedacht worden aan slikklachten waarbij logopedische behandeling onvoldoende resultaat heeft opgeleverd en ernstige dyspnoe. De reden hiervoor is dat de larynx na (chemo-)radiatie dysfunctioneel blijft bestaan en deze waarschijnlijk toeneemt. Ondanks een mogelijke locoregionale controle blijven patiënten dan afhankelijk van een tracheostoma en/of sondevoeding.
Op basis van een uitgebreide observationele analyse van de algehele overleving voor het hypofarynxcarcinoom in Nederland (n=2999 waarvan n=1881 voor T3-T4), lijkt er voor het T4 hypofarynxcarcinoom voorkeur uit te gaan voor een primaire TLE. Voor het T3 hypofarynxcarcinoom was de algehele overleving gelijk voor TLE en chemoradiatie, maar lager voor radiotherapie alleen. Met radiotherapie alleen voor een T3 tumor was er wel een duidelijk verbetering in de jaren 2001 tot 2010 ten opzichte van 1991 tot 2000. Er zijn echter wel duidelijke methodologische beperkingen gezien de observationele aard van de studie. Daarnaast werd er bij de specifieke analyse voor T4 carcinomen geen correctie voor confounding toegepast. In deze studie ontbraken details aangaande radiotherapie data en sommige tumor- en patiëntgerelateerde karakteristieken. De studie bericht niet over ziektevrije overleving, toxiciteit of kwaliteit van leven, terwijl die ook een rol spelen bij de therapiekeuze.
Waarden en voorkeuren van patiënten (en eventueel hun verzorgers)
Naast lokale controle en ziektevrije overleving is het aannemelijk dat kwaliteit van leven, behoud van zelfstandigheid (Festen, 2021) en functie van de larynx van belang zijn voor patiënten. Het doel van de behandeling van T3-T4 hypofarynxtumoren is naast oncologische controle dan ook om orgaansparend te werk te gaan. Er zijn geen studies gevonden waarin (chemo-)radiotherapie versus chirurgie met postoperatieve (chemo)radiatie wordt onderzocht met betrekking tot de kwaliteit van leven en larynxfunctie. Bij gelijke oncologische resultaten zou een voordeel van primaire (chemo-)radiotherapie kunnen zijn dat patiënten hun normale spreekfunctie behouden, wat de kwaliteit van leven voor patiënten vergroot. Echter in een onbekend percentage van deze patiënten zal de in opzet larynxsparende behandeling resulteren in een disfunctionele larynx. Wat uiteindelijk als gevolg heeft dat patiënt dan wel tracheotomie afhankelijk wordt, dan wel alsnog een laryngopharyngectomie moet ondergaan. In de studie van Petersen (2018) wordt een salvage surgery of functionele totale laryngectomie binnen 5 jaar verricht voor 7% van de patiënten behandeld met radiotherapie, en voor 4% van de patiënten behandeld met chemoradiatie.
Het is echter onduidelijk welke waarde patiënten hechten aan deze voor- en nadelen omdat dit nooit is onderzocht. Het is dus belangrijk alle risico’s en mogelijke complicaties mee te nemen, en alle voor- en nadelen met een patiënt te bespreken.
Het streven is om een patiënt met zo min mogelijk verschillende modaliteiten te hoeven behandelen, maar in een aanzienlijk deel van de patiënten zal salvage chirurgie nodig zijn. Bij primaire chirurgie zal in het geval van een T3-4 tumor er altijd een indicatie zijn voor adjuvante radiotherapie met of zonder chemotherapie. Bij primair (chemo-)radiatie zal dat beperkt kunnen worden tot één of twee modaliteiten.
Kosten (middelenbeslag)
De voorkeur voor primaire chirurgie met postoperatieve (chemo-)radiatie versus primaire (chemo-)radiatie met eventuele salvage chirurgie laten een kostenanalyse nauwelijks toe.
Aanvaardbaarheid, haalbaarheid en implementatie
Er wordt geen effect verwacht van de aanbeveling op de gezondheidsgelijkheid. Ook worden er geen belemmerende factoren verwacht op het gebied van implementatie van de interventies.
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies
De werkgroep is van mening dat er geen voorkeur is voor chemoradiatie of chirurgie als primaire behandeling van patiënten met T3-4N0 hypofarynxcarcinoom. Het gebrek aan studies waarin chemoradiotherapie direct met chirurgie wordt vergeleken geeft vooralsnog geen richting om chirurgie als standaardbehandeling boven chemoradiatie te verkiezen of vice versa. Primaire radiotherapie lijkt niet de behandeling van voorkeur te zijn, maar kan bij contra-indicatie voor chemotherapie, met name voor het T3N0 hypofarynxcarcinoom een optie zijn als larynxsparende therapie.
Op basis van beperkte data uit de momenteel beschikbare literatuur lijkt er een voorkeur te zijn voor primaire TLE bij het T4 hypofarynxcarcinoom. Bij een functionele larynx en wanneer een patiënt de voorkeur heeft voor larynxsparing, kan primaire chemoradiatie worden overwogen, waarbij een mogelijk lagere algehele overleving wordt geaccepteerd.
TLE heeft als voordeel een mogelijk betere overleving, alhoewel het verschil in overleg mogelijk te verklaren is door andere selectiecriteria. Nadelen van TLE zijn verlies van de normale spreekfunctie en het feit dat nagenoeg alle patiënten alsnog (chemo-)radiatie krijgen.
De werkgroep is van mening dat patiënten door de verschillende complicatie- en toxiciteitspatronen die ontstaan wegens de aard van beide interventies een voorkeur voor één van beide interventies kunnen hebben. De werkgroep acht het daarom belangrijk dat de voor- en nadelen van beide interventies besproken worden.
Onderbouwing
Achtergrond
Het hypofarynxcarcinoom is vaak bij initiële diagnose al vergevorderd wat betreft T-stadiëring. Op dit moment is niet duidelijk wat de beste behandeling voor operabele T3-T4a hypofarynxcarcinomen is. Zowel primaire chirurgie, afhankelijk van de pathologie uitslag gevolgd door radiotherapie dan wel chemoradiatie, als primaire chemoradiotherapie, eventueel gevolgd door salvage surgery, worden beschouwd al behandelopties. In de literatuur ligt de frequentie van salvage chirurgie tussen de 6 en 15%. De frequentie hiervan zal echter afhankelijk van het behandelcentrum waarschijnlijk zeer variëren naar gelang de culturele achtergrond, chirurgische ervaring en patiëntkenmerken. Voor de behandeling heeft de keuze tussen chirurgie, met eventuele postoperatieve (chemo-)radiatie en primaire radiotherapie (met eventuele chemotherapie) naast curatieve uitkomsten ook belangrijke consequenties voor de kwaliteit van leven.
Conclusies
Overall survival (3 to 5 years)
|
Very low GRADE |
The evidence is very uncertain about the effect of treatment with chemoradiation compared to surgery (optionally with postoperative radiotherapy or with postoperative chemoradiotherapy) on overall survival in patients with a T3-T4, N0 hypopharyngeal carcinoma.
Sources: (Beauvillain, 1997; Lefebvre, 1996; Chung, 2019; Harris, 2015; Hung, 2006; Jang, 2016; Kim, 2016; Kim, 2018; Petersen, 2018) |
Disease-free survival
|
Very low GRADE |
The evidence is very uncertain about the effect of treatment with chemoradiation compared to surgery (optionally with postoperative radiotherapy or with postoperative chemoradiotherapy) on disease-free survival in patients with a T3-T4, N0 hypopharyngeal carcinoma.
Sources: (Lefebvre, 1996; Chung, 2019; Harris, 2015; Hung, 2006; Kim, 2016) |
Morbidity
|
Very low GRADE |
The evidence is very uncertain about the effect of treatment with chemoradiation compared to surgery (optionally with postoperative radiotherapy or with postoperative chemoradiotherapy) on morbidity in patients with a T3-T4, N0 hypopharyngeal carcinoma.
Sources: (Chung, 2019; Jang, 2016; Kim, 2016; Lefebvre, 1996) |
Quality of life
|
- GRADE |
No conclusion can be drawn about the effect of treatment with chemoradiation versus surgery (optionally with postoperative radiotherapy or with postoperative chemoradiotherapy) on quality of life. |
Dry mouth
|
- GRADE |
No conclusion can be drawn about the effect of treatment with chemoradiation versus surgery (optionally with postoperative radiotherapy or with postoperative chemoradiotherapy) on dry mouth. |
Head-neck specific quality of life
|
- GRADE |
No conclusion can be drawn about the effect of treatment with chemoradiation versus surgery (optionally with postoperative radiotherapy or with postoperative chemoradiotherapy) on head-neck specific quality of life. |
Samenvatting literatuur
Description of studies
The systematic review of Cui (2020) included 17 studies in their analysis. The table AMSTAR (see risk of bias tables) contains a quality assessment for the systematic review. The AMSTAR tool shows that the systematic review does not meet the following criteria: description of all included and excluded studies, description of all relevant characteristics of included studies, appropriate adjustment for potential confounders in observational studies, enough similarity between studies to make combining reasonable, and reporting of potential conflicts of interest.
The 17 included studies in Cui (2020) contained 2 RCT’s, these will be described here. Next to that 15 retrospective cohort studies were included. Of these 15 observational studies, 6 fulfilled all selection criteria and were included in the analysis. Due to the study design of these six studies pooling was not possible. Table 13.1 (see Appendix) contains an overview per observational study on why the studies were either excluded, or not suitable for pooling. Study characteristics of the two RCTs and six eligible observational studies included in the review and the observational study by Petersen (2018) are described here.
Randomised controlled trials
The RCT performed by Beauvillain (1997) included patients with a locally advanced resectable hypopharyngeal carcinoma (T3-T4, N0-N3 resectable squamous cell hypopharyngeal carcinoma) and was performed in France. They compared neoadjuvant chemotherapy, followed by laryngopharyngectomy, plus postoperative radiotherapy, with neoadjuvant chemotherapy followed by radiotherapy, with or without salvage surgery. The outcome Overall survival (OS) was studied. They included 90 patients, with 45 patients in the chemoradiation group and 47 patients in the surgery group. In the chemoradiation group the mean age was 54.5 years and 100% was male, in the surgery group the mean age of the patients was 56 years and 100% was male. The mean follow up was not mentioned, but follow-up took place with 3 months intervals during the first and second year, thereafter 6-month intervals for 3 to 5th year, thereafter 12 months intervals.
The RCT performed by Lefebvre (1996) included patients with squamous cell carcinoma of the hypopharynx, T2-T4, N0-N2b, defined as: “histologically proven squamous cell carcinoma of the pyriform sinus or of the hypopharyngeal aspect of the aryepiglottic fold (which are hardly distinguishable from true pyriform sinus tumors when they are advanced).” Data was collected in multiple European countries. They compared larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation). The outcomes disease-free survival (DFS) and OS were studied. A total of 194 patients was included, 100 received chemoradiation and 94 received surgery. Originally a total number of patients of 99 in the surgery arm and 103 in the chemotherapy arm was enrolled. However six patients were found to be ineligible, and for two other patients no information was received after randomization, which lead to the total number of 194 included patients. All 94 eligible patients in the surgery arm were included in the analysis, however 89 (95%) of patients received the planned treatment, due to inoperability or not receiving postoperative radiotherapy. For the chemotherapy arm, all 100 eligible patients were included in analysis, but 93 (93%) of patients underwent the planned treatment. Three patients did not start chemotherapy, of the patients treated with chemotherapy three had no subsequent treatment, and one patient treated with surgery died after the procedure. The mean age for the total sample was 55 years, and 96% of all patients were male. The mean follow-up was 51 months for all patients. Different numbers are reported in Cui (2020) and the original study Lefebvre (1996), here we report the numbers originating from Lefebvre (1996).
Observational studies
The retrospective cohort study performed by Chung (2019) included patients with locally advanced stage III/IV hypopharyngeal carcinomas and was performed in Korea. They compared different forms of chemoradiation: induction chemotherapy followed by (chemo)radiotherapy (ICT) and definitive chemoradiotherapy (CRT) as intervention, with surgery-based therapy (SRT) as a control. The outcomes DFS and OS were studied. A total of 266 patients was included, of which 127 were treated with a form of chemoradiation, and 139 were treated with SRT. The mean age of the patients was 63.7 years, and 93.6% of all patients was male. The mean follow-up of the study was 32.9 months of all patients, age, gender, and follow-up were not described per specific treatment.
The retrospective cohort study performed by Harris (2015) included patients with advanced stage hypopharyngeal squamous cell carcinoma and was performed in the USA. They compare definitive chemoradiotherapy with or without salvage surgery as intervention, with primary surgery, with either adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) as control. The outcomes DFS and OS were studied. A total of 76 patients was included, where 48 received definitive chemoradiotherapy and 28 received primary surgery. Patients receiving chemoradiotherapy had a mean age of 62.9 and 78% was male, patients receiving primary surgery had a mean age of 65.3 and 76% was male. The mean follow-up of the study was 30 months.
The retrospective cohort study performed by Hung (2006) included patients with advanced hypopharyngeal cancer and was performed in Taiwan. They compared definitive concurrent chemoradiation (CCRT) followed by adjuvant systemic chemotherapy as intervention, with surgery plus postoperative CCRT followed by adjuvant systemic chemotherapy (SCCRT) as control. The outcomes DFS and OS were studied. A total of 60 patients was included, where 38 were treated with definitive CCRT followed by adjuvant systemic chemotherapy and 22 were treated with surgery plus postoperative CCRT followed by adjuvant SCCRT. Patients receiving the intervention had a mean age of 61 years and 100% was male, patients receiving the control had a mean age of 55 years and 100% was male. The mean follow-up of the study was 20 months.
The retrospective cohort study performed by Jang (2016) included patients with hypopharyngeal cancer. The study includes both T1-T2 and T3-T4 patients together and individually, numbers described here are specifically for T3-T4 patients. The study was performed in Korea. They compared initial concurrent chemoradiation treatment (iCRT) as treatment with surgery (OP) ± adjuvant concurrent chemoradiation treatment (aCRT) as control. The outcome OS was studied. A total of 177 T3-T4 patients was included, 107 were treated with iCRT and 70 were treated with OP ± aCRT. Patients receiving iCRT had a mean age of 63.7 years and 95.3% was male. Patients receiving OP ± aCRT had a mean age of 66.7 years and 95.7% was male. The mean follow-up was 19 months.
The retrospective cohort study performed by Kim (2016) included patients with resectable stage III/IV hypopharyngeal cancer and was performed in Korea. They compared organ preserving chemoradiotherapy (CRT) as intervention, with surgery followed by radiotherapy (SRT) as control. The outcomes DFS and OS were studied. A total of 91 patients was included, 34 were treated with CRT and 57 were treated with SRT. Patients receiving CRT had a mean age of 65.5 years and 88.2% was male, patients receiving SRT had a mean age of 64 years and 98.2% was male. The mean follow-up was 50 months.
The retrospective cohort study performed by Kim (2018) included patients with locally advanced hypopharyngeal cancer and was performed in Korea. They compared chemoradiotherapy as intervention, with surgery as control. The outcome OS was studied. In the article OS is described for both T2-T4a together as for T4a individually. Only for T4a individually correction for confounding was performed, as to match the PICO only T4a is described here. For T4a carcinomas, 126 patients received chemoradiotherapy and 111 patients received surgery. Age and gender were only described for all T2-T4a patients together. For patients receiving chemoradiotherapy 55.2% of patients was < 65 years and 44.8% of patients > 65 years, and 82.6% was male. For patients receiving surgery 47.8% was < 65 years and 52.2% was >65 years, and 81.8% was male. The mean follow up was not described.
The retrospective population-based cohort study Petersen (2018) included patients with T1-T4N0-N3M0 squamous cell carcinoma of the hypopharynx and was performed in the Netherlands. All available data from all patients diagnosed in the Netherlands between 1991 and 2010 was retrieved and the treatments total laryngectomy (with/without (partial) pharyngectomy) and chemoradiotherapy were studied. The outcome OS was studied, and separately described for T1-T2, T3 and T4 hypopharynx cancer. We specifically retrieved data for patients with T3 and T4 hypopharynx cancer treated with the interventions total laryngectomy and chemoradiotherapy. For T3 carcinomas, 222 patients were included that received chemoradiotherapy, and 155 patients that received total laryngectomy. For T4 carcinomas, 316 patients received chemoradiotherapy and 294 patients received total laryngectomy. Age and gender were described for all T1-T4 stage carcinoma patients together. Of patients receiving chemoradiotherapy 82% was male, and they had the following age: < 50 years: 119/752 (15.8%) patients, 50-59 years: 309/752 (41%) patients, 60 to 69 years: 245/752 (32.6%) patients, > 70 years: 79/752 (10.5%) patients. Of patients receiving total laryngectomy 82% was male, and they had the following age: < 50 years: 83/567 (14.6%) patients, 50 to -59 years: 175/567 (30.9%) patients, 60 to 69 years: 191/567 (33.7%) patients, > 70 years: 118/567 (20.8%) patients. The mean follow up was not described.
Results
Overall survival (3 to 5 years)
Overall survival was reported by two RCT’s, Beauvillain (1997) and Lefebvre (1996), and by seven observational studies: Chung (2019), Harris (2015), Hung (2006), Jang (2016), Kim (2016), Kim (2018) and Petersen (2018).
The studies Chung (2019), Harris (2015), Hung (2006), Jang (2016) and Kim (2016) reported risk ratios (RR) for overall survival. As these are observational studies, odds ratios (OR) were calculated and are reported here, as risk ratios do not take residual confounding into account for observational studies. The calculated odds ratios are:
- Chung (2019): OR = 1.12 (95%CI = 0.69 to 1.82), in favour of surgery.
- Harris (2015): OR = 2.52 (95%CI = 0.96 to 6.60), in favour of surgery.
- Hung (2006): OR = 1.19 (95%CI = 0.40 to 3.48), in favour of surgery.
- Jang (2016): OR = 0.90 (95%CI = 0.38 to 2.12), in favour of surgery.
- Kim (2016): OR = 0.98 (95%CI = 0.68 to 1.43), in favour of chemoradiation.
The studies Beauvillain (1997), Lefebvre (1996) and Kim (2018) reported the overall survival rate (%). In addition to the original data, for the RCTs Lefebvre (1996) and Beauvillain (1997) the RR is calculated. The reported and calculated overall survival rates are:
-
- Beauvillain (1997): the overall survival rate was 19% in the chemoradiation group with a median survival of 20 months, and 37% in the surgery group with a median survival of 40 months, p=0.04. The calculated RR is 1.25 (95%CI = 0.97 to 1.63), in favour of surgery.
- Lefebvre (1996): the overall survival rate at 3 years was 57% in the chemoradiation group and 43% in the surgery group, the overall survival rate at 5 years was 30% in the chemoradiation group and 35% in the surgery group. The calculated RR at 5 years is 2.06 (95%CI = 1.51 to 2.80), in favour of surgery.
- Kim (2018): only for the overall survival rate for T4a stage carcinomas correction for confounders was performed, these data will be reported here. No significant difference in OR was found between surgery and chemoradiotherapy groups, the reported HR of the chemoradiotherapy group = 0.880 (95%CI = 0.617 to 1.256, p = 0.481).
The study Petersen (2018) reported the hazard ratio (HR) for T3-T4 stage carcinomas, after multivariable analysis using Cox regression analysis. They report a HR of 1.10 (95%CI = 0.94 to 1.28), p = 0.22 in favour of chemoradiation. Petersen (2018) also describes 5 year OS separately for T3 and T4 carcinomas. When described separately, a significant better OS is found for T4 stage carcinomas when treated with surgery, however, it should be noted that no correction for confounding was performed for these separated data.
Disease-free survival
Disease-free survival was reported by one RCT, Lefebvre (1996), and 4 observational studies, Chung (2019), Harris (2015), Hung (2006) and Kim (2016).
The studies Chung (2019), Harris (2015), Hung (200 6) and Kim (2016) reported risk ratios for disease-free survival. As these are observational studies, odds ratios (OR) were calculated and are reported here, as risk ratios do not take residual confounding into account for observational studies. The calculated odds ratios are:
-
- Chung (2019): OR = 1.70 (95%CI = 1.04 to 2.78), in favour of surgery.
- Harris (2015): OR = 2.31 (95%CI = 0.89 to 6.00), in favour of surgery.
- Hung (2006): OR = 1.19 (95%CI = 0.40 to 3.48), in favour of surgery.
- Kim (2016): OR = 1.11 (95%CI = 0.47 to 2.60), in favour of surgery.
The study of Lefebvre (1996) reported the 3- and 5-years disease free survival rate (%). In addition to the original data, the RR is calculated for the 5-year DFS. The reported overall survival rates are:
-
- The disease-free survival rate at 3 years was 43% in the chemoradiation group and 32% in the surgery group. The disease-free survival rate at 5 years was 25% in the chemoradiation group and 27% in the surgery group. The calculated RR at 5 years is 2.71 (95%CI = 1.92 to 3.83) in favour of surgery.
Morbidity
Larynx preservation was reported by one RCT (Lefebvre, 1996) and three observational studies (Chung, 2019; Jang, 2016 and Kim, 2016). The studies by Chung (2019), Jang (2016) and Kim (2016) reported risk ratios for larynx preservation. As these are observational studies, odds ratios (OR) were calculated and are reported here, as risk ratios do not take residual confounding into account for observational studies. The calculated odds ratios are:
-
- Chung (2019): OR = 0.32 (95%CI 0.19 to 0.53), in favour of chemoradiation
- Jang (2016): OR = 0.10 (95%CI 0.05 to 0.23), in favour of initial concurrent chemoradiation treatment
- Kim (2016): OR = 0.06 (95%CI 0.02 to 0.19), in favour of chemoradiation
The study by Lefebvre (1996) reported that 43 out of 100 patients (43%) in the chemotherapy group underwent radical surgery.
(Head-neck specific) Quality of Life, dry mouth
None of the studies reported on these outcomes.
Level of evidence of the literature
Overall survival (3 to 5 years)
The level of evidence regarding the outcome measure overall survival started low, as the evidence originated from both observational studies and RCTs, and was downgraded by three levels because of study limitations: one level because of serious risk of bias (risk of bias in the observational studies due to inadequate adjustment for all important prognostic factors), one level because of indirectness (both the two RCTs and the observational study Harris (2015) deviate a bit from the PICO), one level because of imprecision (small number of patients in the studies), Publication bias could not be assessed. The certainty of the evidence was graded as very low.
Disease-free survival
The level of evidence regarding the outcome measure disease-free survival started low as the evidence originated from both observational studies and an RCT, and was downgraded by four levels because of study limitations: two levels because of serious risk of bias (risk of bias in the RCTs due to inadequate blinding of participants, care providers and outcome assessors, and risk of bias in the observational studies due to inadequate adjustment for all important prognostic factors), one level because of indirectness (both RCTs and the observational study Harris (2015) deviate a bit from the PICO), one level because of imprecision (small number of patients in the studies), Publication bias could not be assessed. The certainty of the evidence was graded as very low.
Morbidity
The level of evidence regarding the outcome measure morbidity (larynx preservation) started low as the evidence originated from both observational studies and an RCT, and was downgraded by three levels because of study limitations: one level because of risk of bias (risk of bias in the observational studies due to inadequate adjustment for all important prognostic factors), one level because of indirectness (the RCT deviates a bit from the PICO), one level because of imprecision (small number of patients in the studies), Publication bias could not be assessed. The certainty of the evidence was graded as very low.
(head-neck specific) Quality of life, Dry mouth
None of the studies reported on the outcome measures (head-neck specific) quality of life, or dry mouth and therefore GRADE could not be applied, and no conclusions could be drawn.
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question:
What is the best treatment of T3-T4a hypopharynx carcinomas? The focus is on the surgical versus nonsurgical approach.
P: (Patients)= Patients with a primary hypopharyngeal carcinoma (T3-T4a, N0).
I: (Intervention)= Chemoradiation.
C: (Comparison)= Surgery (optionally with postoperative radiotherapy or with postoperative chemoradiotherapy).
O: (Outcomes)= Overall survival (3 to 5 years), disease-free survival, morbidity, quality of life, dry mouth, head-neck specific quality of life.
Relevant outcome measures
The guideline development group considered overall survival and disease-free survival as critical outcome measures for decision making; and morbidity, dry mouth, head-neck specific quality of life and quality of life as measured with EORTC QLQ-C30, EORTC QLQ-H&N35, H&N43 as an important outcome measure for decision making.
The working group defined the outcome measures as follows:
Head-neck specific quality of life: measured using EORTC QLQ-C30, EORTC QLQ-H&N35, H&N43
Clinically relevant difference
The guideline development group defined a minimal clinically relevant difference at a minimum of a median follow-up period of three years) (in line with “NVMO-commissie ter Beoordeling van Oncologische Middelen (BOM)”) of:
- Overall survival: > 5% difference, or > 3% and HR <0.7.
- Relapse-free survival: HR< 0.7.
And, in case of absence of a clinically relevant difference in overall survival or relapse-free survival:
- Quality of life: A minimal clinically important difference of 10 points on the quality-of-life instrument EORTC QLQ-C30 or a difference of a similar magnitude on other quality of life instruments.
- Complications/adverse events: Statistically significant less complications/adverse events.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until August 11, 2020. The detailed search strategy is depicted under the tab Methods. The systematic literature search resulted in 745 hits.
Studies were selected based on the following criteria: included patients with a primary hypopharyngeal carcinoma (T3-T4, N0), compared chemoradiation with either surgery, surgery with postoperative radiotherapy, or surgery with postoperative chemoradiotherapy, reported at least one of the outcomes of interest, the study design was a systematic review (SR) or randomized controlled trial (RCT), and were written in English language.
After the systematic search was performed, the working group brought forward the retrospective population-based cohort study Petersen (2018). This study was judged to be relevant to include as the study specifically contains data from Dutch clinical settings, and includes a large number of patients. Although the study did not meet the criteria for study design due to its observational character, it was decided to include the study of Petersen (2018) after the systematic search was performed, because of the importance of the study.
All in all, 5 studies were initially selected based on title and abstract screening from the systematic search. After reading the full text, 4 studies were excluded (see the table with reasons for exclusion under the tab Methods), and 1 systematic review was included. Next to that, 1 retrospective cohort study was included.
Data-synthesis
The systematic review of Cui (2020) included 17 studies in their analysis, including two RCTs and 15 retrospective cohort studies. Results from RCTs and observational studies were described and synthesized (preferably by meta-analysis) separately. For all included observational studies, the following criteria were used: a priori, the guideline development group decided that observational studies should be of sufficient quality to allow a useful GRADE assessment and to allow conclusions that can guide the recommendations. The guideline development group used the following criteria for eligible observational studies of sufficient quality:
- Compared at least two interventions.
- Included at least 50 patients.
- Corrected for at least one plausible confounder, for example by matching cases and controls, stratification, or statistical correction by performing a multivariable analysis.
Results
One systematic review and one retrospective cohort study were included in the analysis of the literature. From the systematic review, for 2 RCTs and 6 observational studies the important study characteristics and results are summarized in the evidence tables, as not all included observational studies corrected for confounding. The assessment of the risk of bias is summarized in the risk of bias tables.
Referenties
- Beauvillain C, Mahé M, Bourdin S, Peuvrel P, Bergerot P, Rivière A, Vignoud J, Deraucourt D, Wesoluch M. Final results of a randomized trial comparing chemotherapy plus radiotherapy with chemotherapy plus surgery plus radiotherapy in locally advanced resectable hypopharyngeal carcinomas. Laryngoscope. 1997 May;107(5):648-53. doi: 10.1097/00005537-199705000-00017. PMID: 9149168.
- Chung, E. J., Jeong, W. J., Jung, Y. H., Kwon, S. K., Kwon, T. K., Ahn, S. H., ... & Rho, Y. S. (2019). Long-term oncological and functional outcomes of induction chemotherapy followed by (chemo) radiotherapy versus definitive chemoradiotherapy versus surgery-based therapy in locally advanced stage III/IV hypopharyngeal cancer: multicenter review of 266 cases. Oral oncology, 89, 84-94.
- Cui, J., Wang, L., Piao, J., Huang, H., Chen, W., Chen, Z., ... & Liu, G. (2020). Initial Surgical versus Non-Surgical treatments for advanced hypopharyngeal cancer: a meta-analysis with trial sequential analysis. International Journal of Surgery.
- Festen S, van Twisk YZ, van Munster BC, de Graeff P. 'What matters to you?' Health outcome prioritisation in treatment decision-making for older patients. Age Ageing. 2021 Nov 10;50(6):2264-2269. doi: 10.1093/ageing/afab160. PMID: 34343234; PMCID: PMC8581373.
- Harris, B. N., Biron, V. L., Donald, P., Farwell, D. G., Luu, Q. C., Bewley, A. F., ... & Daly, M. E. (2015). Primary surgery versus chemoradiation treatment of advanced-stage hypopharyngeal squamous cell carcinoma. JAMA OtolaryngologyHead & Neck Surgery, 141(7), 636-640.
- Harwood AR, Rawlinson E. The quality of life of patients following treatment for laryngeal cancer. Int J Radiat Oncol Biol Phys. 1983 Mar;9(3):335-8. doi: 10.1016/0360-3016(83)90292-4. PMID: 6841185.
- Holsinger FC, Funk E, Roberts DB, Diaz EM Jr. Conservation laryngeal surgery versus total laryngectomy for radiation failure in laryngeal cancer. Head Neck. 2006 Sep;28(9):779-84. doi: 10.1002/hed.20415. PMID: 16637055.
- Hung, S. K., Chen, H. L., Hsieh, C. H., Hsu, W. L., Chang, K. H., Liu, D. W., ... & Lee, M. S. (2006). Treatment of advanced hypopharyngeal cancer-comparison of two modalities. Tzu Chi Med J, 18, 15-21.
- Jang, J. Y., Kim, E. H., Cho, J., Jung, J. H., Oh, D., Ahn, Y. C., ... & Jeong, H. S. (2016). Comparison of oncological and functional outcomes between initial surgical versus non-surgical treatments for hypopharyngeal cancer. Annals of surgical oncology, 23(6), 2054-2061.
- Kim, J. W., Kim, M. S., Kim, S. H., Kim, J. H., Lee, C. G., Kim, G. E., & Keum, K. C. (2016). Definitive chemoradiotherapy versus surgery followed by adjuvant radiotherapy in resectable stage III/IV hypopharyngeal cancer. Cancer research and treatment: official journal of Korean Cancer Association, 48(1), 45.
- Kim, Y. J., & Lee, R. (2018). Surgery versus radiotherapy for locally advanced hypopharyngeal cancer in the contemporary era: A population?based study. Cancer medicine, 7(12), 5889-5900.
- Lefebvre JL, Chevalier D, Luboinski B, Kirkpatrick A, Collette L, Sahmoud T. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996 Jul 3;88(13):890-9. doi: 10.1093/jnci/88.13.890. PMID: 8656441.
- Petersen, J. F., Timmermans, A. J., van Dijk, B. A., Overbeek, L. I., Smit, L. A., Hilgers, F. J., ... & van den Brekel, M. W. (2018). Trends in treatment, incidence and survival of hypopharynx cancer: a 20-year population-based study in the Netherlands. European Archives of Oto-Rhino-Laryngology, 275(1), 181-189.
Evidence tabellen
Randomised controlled trials
|
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3 |
Follow-up |
Outcome measures and effect size 4 |
Comments |
|
|
Beauvillain, 1997 |
Type of study: RCT
Setting and country: Patients were treated with either chemotherapy or radiotherapy between 1985 and 1989, Nantes France
Funding and conflicts of interest: Unclear |
Inclusion criteria: - Patients less than 70 years of age - Patients with T3, T4 N0-N3 resectable squamous cell hypopharyngeal carcinoma - Performance status of 2 or less
Exclusion criteria: Nothing mentioned
N total at baseline: Total: 90 Intervention: 44 Control: 46
Important prognostic factors2: Age I: 54.5 years C: 56 years
Sex: I: 44/44 male, 100% C: 46/46 male, 100%
Groups comparable at baseline? Yes |
Three courses of neoadjuvant chemotherapy every 2 weeks, involving: on day 1: cisplatin 100 g/m2, Days 2 to 5: fluorouracil 1 g/m2.
Followed by radiotherapy, with or without salvage surgery |
Three courses of neoadjuvant chemotherapy every 2 weeks, involving: on day 1: cisplatin 100.g/m2, Days 2 to 5: fluorouracil 1 g/m2.
Thereafter: total laryngopharyngectomy, plus postoperative radiotherapy. |
Length of follow-up: 3 months intervals during the first and second year, thereafter 6-month intervals for 3 – 5th year, thereafter 12 months intervals.
Loss-to-follow-up: Intervention: 29 (65.9%) Reasons: dead from cancer
Control: 20 (43.5%) Reasons: dead from cancer
Incomplete outcome data: None
|
Outcome measures and effect size:
Overall survival, 5 years: I: 9/45, 19% Median survival: 20 months C: 17/47, 37% Median survival: 40 months P = 0.04
Disease-free survival Not reported
Morbidity Not reported
Quality of life Not reported
Dry mouth Not reported
Head neck specific quality of life Not reported
|
- Some patients in the intervention arm received salvage surgery, others did not
Authors conclusion: - Better results were obtained for the group with surgery with regard to overall survival |
|
Lefebvre, 1996 |
Type of study: RCT
Setting and country: Phase III trial by EORTC, Data collected in: France, Belgium, Italy, the Netherlands, Switzerland.
Funding and conflicts of interest: No conflicts of interest reported. Funding: Public Health Service grants CA11488-20 through CA11488-25 from the National Cancer Institute. |
Inclusion criteria: - Histologically proven squamous cell carcinoma of the pyriform sinus or of the hypopharyngeal aspect of the aryepiglottic fold, classified as T2, T3, or T4 with NO, N1, N2a, or N2b stages of neck involvement - Patients were previously untreated - Patients were free of other cancers - Age: between 18 and 75 years - Patients had to have had a medical condition that could be treated with surgery under general anaesthesia or with chemotherapy - Disease had to be measurable or evaluable, and documented as precise as possible - Informed consent obtained
Exclusion criteria: Not mentioned
N total at baseline: Intervention: 100 Control: 94
Important prognostic factors2: Age and gender are only mentioned for the total group of participants:
Age: 55 years (35-70 years)
Sex: Male: 186 (96%)
Groups comparable at baseline? Yes, article mentions no significant differences between the two arms |
I = Chemoradiation
Cisplatin: 100 mg/m2 IV on day 1, fluoracil 100 mg/m2 on day 1-5.
After 2 cycles: partial and complete responders received a 3rd cycle.
After 2nd or 3rd cycle, patients were either treated with: - After complete response: patients were treated with irradiation, 70 Gy - After incomplete response: patients underwent conventional surgery with postoperative radiation (50-70 Gy). |
C = surgery
Conventional treatment: Total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation |
Length of follow-up: Median follow-up: 51 months (range, 3-106 months)
Loss-to-follow-up: Intervention, N (%): 59 (59%) Reasons: Hypopharynx cancer (N=35), second primary cancers (N=7), treatment-related causes (N=2) non cancer related causes (N=8), unknown causes (N=7)
Control, N (%): 57 (61%) Reasons: Hypopharynx cancer (N=40), second primary cancers (N=8), non cancer related causes (N=6), unknown causes (N=3)
Incomplete outcome data: None
|
Outcome measures and effect size:
Overall survival, 3 years: I: 57/100, 57% C: 41/94, 43%
Overall survival, 5 years: I: 30/100, 30% C: 32/94, 35%
Disease-free survival, 3 years: I: 43/100, 43% C: 30/94, 32%
Disease-free survival, 5 years: I: 25/100, 25% C: 26/94, 27%
Morbidity Not reported
Quality of life Not reported
Dry mouth Not reported
Head neck specific quality of life Not reported
|
- The systematic review Cui (2020) and the original study Lefebvre (1996) report different data. Here, the original data from Lefebvre is reported. - Also, some T2 hypopharynx tumours were included - The trial does not solely study chemoradiation versus surgery. The chemotherapy group consists of 100 eligible patients, of which only 60 are treated with chemotherapy and concurrent radiotherapy, the other patients are either not treated or treated with surgery. - Patients in the chemoradiation group are treated with radiation therapy in patients who showed a complete response or surgery in those who did not respond |
Observational studies
|
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3 |
Follow-up |
Outcome measures and effect size 4 |
Comments |
|
Chung, 2019
|
Type of study: Retrospective cohort study
Setting and country: Korea
Funding and conflicts of interest: funding by the Korea Health Industry Development Institute (KHIDI), Korean Ministry of Health & Welfare, Korean Ministry of Education. No conflicts of interest reported. |
Inclusion criteria: Patients with resectable stage III/IV hypopharyngeal SCC who underwent curative treatment
Exclusion criteria: Patients with stage I/II (n=52) and those who underwent SRT at SNUH or induction chemotherapy followed by surgery were excluded.
N total at baseline: 266 Intervention: 127 Control: 139
Important prognostic factors2: Age and sex are not mentioned per intervention, only as total
Age (in years): 63.7 (41-86)
Sex: Number of males, %: 249, 93.6%
Groups comparable at baseline? Yes |
Intervention Different forms of chemoradiation: induction chemotherapy followed by (chemo)radiotherapy (ICT), definitive chemoradiotherapy (CRT)
|
Control Surgery-based therapy (SRT). |
Length of follow-up: 32.9 months (6–152 months)
Loss-to-follow-up: None
Incomplete outcome data: Not mentioned
|
Outcome measures and effect size:
OS: I: 54/127 (42.5%) C: 63/139 (45.3%) RR 1.07 (0.81, 1.40)
DFS: I: 67/127 (52.8%) C: 91/139 (65.5%)
Morbidity Not reported
Quality of life Not reported
Dry mouth Not reported
Head neck specific quality of life Not reported
|
- Different forms of chemoradiation are used |
|
Harris, 2015
|
Type of study: Retrospective cohort study
Setting and country: USA
Funding and conflicts of interest: no funding or conflicts of interest reported |
Inclusion criteria: - Patients undergoing surgery or CRT with curative intent for advanced stage HP SCC
Exclusion criteria: - Second primary lesion - Early-stage disease (stage I or II) - Metastases at presentation - Treatment with palliative intent - Loss to follow-up within 3 months
N total at baseline: 76 Intervention: 48 Control: 28
Important prognostic factors2: Age: I: 62.9 years (±8.9) C: 65.3 years (±8.3)
Sex: I: 37M, 78% C: 21M, 76%
Groups comparable at baseline? Yes |
Intervention Definitive chemoradiotherapy (CRT) with or without salvage surgery (SS)
|
Control Primary surgery, with adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) |
Length of follow-up: 30 months (6-120 months)
Loss-to-follow-up: Not described
Incomplete outcome data: Not described
|
Outcome measures and effect size:
OS: I: 20/48 (41.7%) C: 18/28 (64.3%) RR: 1.54 (1.00, 2.38)
DFS: I: 16/48 (33%) C: 15/28 (53.6%)
Morbidity Not reported
Quality of life Not reported
Dry mouth Not reported
Head neck specific quality of life Not reported
|
- Patients treated with surgery were also treated with either adjuvant RT or CRT. Patients with CRT were sometimes treated with salvage surgery as well - Small number of patients included |
|
Hung, 2006
|
Type of study: Retrospective cohort study
Setting and country: Taiwan
Funding and conflicts of interest: not mentioned |
Inclusion criteria: Patients with locally advanced stage III/IV hypopharyngeal cancer
Exclusion criteria: - patients were treated with surgery alone - lost to follow up - patients had a performance status >2 as assessed using ECOG performance status - patients had a synchronous second primary
N total at baseline: 60 Intervention: 38 Control: 22
Important prognostic factors2: Age: I: 61 years (43-76) C: 55 years (45-74)
Sex: I: 38, 100% M C: 22, 100% M
Groups comparable at baseline? Yes |
Intervention Definitive concurrent chemoradiation (CCRT) followed by adjuvant systemic chemotherapy
|
Control Surgery plus postoperative CCRT followed by adjuvant systemic chemotherapy (SCCRT) |
Length of follow-up: 20 months average (2-55 months)
Loss-to-follow-up: 4 patients, no reason or given treatment mentioned
Incomplete outcome data: Not mentioned
|
Outcome measures and effect size:
OS: I: 14/38 (36.8%) C: 9/22 (40.9%) RR: 1.11 (0.58, 2.13)
DFS: I: 14/38 (36.8%) C: 9/22 (40.9%)
Morbidity Not reported
Quality of life Not reported
Dry mouth Not reported
Head neck specific quality of life Not reported
|
- Only 60 patients in total are included - Patients treated with chemoradiation were also treated with adjuvant systemic chemotherapy - Patients treated with surgery were also treated with concurrent chemoradiation followed by adjuvant systemic chemotherapy |
|
Jang, 2016
|
Type of study: Retrospective cohort study
Setting and country: Korea
Funding and conflicts of interest: No conflicts of interest. Funding not reported. |
Inclusion criteria: - Patients diagnosed as having biopsy-proven squamous cell carcinoma of the hypopharynx.
Exclusion criteria: Only mentioned for subgroup analyses, not for the whole study protocol
N total at baseline: T3/T4 patients: 177 Intervention: 107 Control: 70
Important prognostic factors2: Age: I: 63.7 years (±9.2) C: 66.7 years (±9.7)
Sex: I: 102 (95.3% M) C: 67 (95.7% M)
Groups comparable at baseline? Yes |
Intervention Initial concurrent chemo-radiation treatment (iCRT) |
Control Surgery (OP) ± adjuvant concurrent chemo-radiation treatment (aCRT) |
Length of follow-up: Median of 19 months (1-179 months)
Loss-to-follow-up: Not described
Incomplete outcome data: None
|
Outcome measures and effect size:
OS: I: 48/107 (44.9%) C: 35/70 (50%) RR: 1.11 (0.81, 1.53)
DFS: Not reported
Morbidity Not reported
Quality of life Not reported
Dry mouth Not reported
Head neck specific quality of life Not reported
|
- Study includes both T1/T2 and T3/T4 patients: numbers described here are specifically for T3/T4 patients |
|
Kim, 2016
|
Type of study: Retrospective cohort study
Setting and country: Korea
Funding and conflicts of interest: No funding or conflicts of interest reported |
Inclusion criteria: - Patients who received definitive or adjuvant RT - Patients with stage III or IV SCC of the hypopharynx
Exclusion criteria: Patients with: - T1N1 disease - Distant metastasis - Double primary tumour - Unresectable disease or compromised speech or swallowing functions at presentation - Treated with RT alone - Incomplete RT - Re-irradiation - Treated with trans-oral robotic surgery
N total at baseline: 91 Intervention: 34 Control: 57
Important prognostic factors2: Age: I: 65.5 years (37-81) C: 64 years (39-81)
Sex: I: 30 (88.2% M) C: 56 (98.2% M)
Groups comparable at baseline? Yes |
Intervention Organ-preserving chemoradiotherapy (CRT)
|
Control Surgery followed by radiotherapy (SRT) |
Length of follow-up: Median 50 months (range 5-141 months)
Loss-to-follow-up: Not described
Incomplete outcome data: Not described
|
Outcome measures and effect size:
OS: I: 20/34 (58.8%) C: 32/57 (56.1%) RR: 0.95 (0.66, 1.37)
DFS: I: 17/34 (50%) C: 30/57 (52.6%)
Morbidity Not reported
Quality of life Not reported
Dry mouth Not reported
Head neck specific quality of life Not reported
|
- Only 91 patients are included |
|
Kim, 2018
|
Type of study: Retrospective cohort study
Setting and country: Korea
Funding and conflicts of interest: No funding or conflicts of interest reported |
Inclusion criteria: - Pathologically diagnosed hypopharynx squamous cell carcinoma between 2010 and 2015 - T2‐4aN0‐3M0 based on the 7th edition of the American Joint Committee on Cancer staging system - Having information of race, age, and tumour grade - Treated with total pharyngectomy (code 32‐52) with 10 or more lymph nodes dissection (surgery group) or definitive external beam radiotherapy and chemotherapy without surgery or lymph node dissection (chemoradiotherapy group)
Exclusion criteria: None mentioned
N total at baseline: T3 stage: Intervention: 240 Control: 62
T4a stage: Intervention: 126 Control: 111
Important prognostic factors2: Age, reported for all patients (T2-T4): I: <65 y: 358 (55.2%), >65y: 290 (44.8%) C: <65 y: 100 (47.8%), >65y: 109 (52.2%)
Sex, reported for all patients (T2-T4): I: 535/648, 82.6% M C: 171/209, 81.8% % M
Groups comparable at baseline? Yes |
Intervention Chemoradiotherapy
|
Control Surgery |
Length of follow-up: Not described
Loss-to-follow-up: Not described
Incomplete outcome data: Not described
|
Outcome measures and effect size:
OS, 3 years: T4a stage: Number of events not reported.
HR of chemoradiotherapy group: 0.880 (95% CI = 0.617 ‐ 1.256, P = 0.481
DFS: Not reported
Morbidity Not reported
Quality of life Not reported
Dry mouth Not reported
Head neck specific quality of life Not reported
|
- OS is reported both together for T2-T4 stages, as for individually for T2, T3 and T4 stages. T3 and T4 are separately reported here as these are included in PICO - Not described during which period patients are followed |
|
Petersen, 2018 |
Type of study: retrospective population-based cohort study
Setting and country: all patients diagnosed with T1-T4N0- N3M0 SCC of the hypopharynx in the Netherlands were included. Data was retrieved from the databases of the Netherlands Cancer Registry (NCR) and PALGA (the nationwide network and registry of histo- and cytopathology in the Netherlands)
Funding and conflicts of interest: The Department of Head and Neck Oncology and Surgery of the Netherlands Cancer Institute receives a research grant from ATOS Medical Sweden which contributes to the existing infrastructure for health-related quality of life research of the department of Head and Neck Oncology and Surgery. Some of the researchers work at this department. |
Inclusion criteria: Patients diagnosed with T1-T4N0- N3M0 SCC of the hypopharynx in the Netherlands, (1991 -2010)
Exclusion criteria: - Main tumour location outside of the hypopharynx - Questionable presence of malignancy in pathology report
N total at baseline: All patients: Intervention: 752 Control: 567
T3 stage: Intervention: 222 Control: 155
T4 stage: Intervention: 316 Control: 294
Important prognostic factors2: Age (reported for T1-T4 stage): I: <50: 119 50-59: 309 60-69: 245 >70: 79 C: <50: 83 50-59: 175 60-69: 191 >70: 118
Sex (reported for T1-T4 stage): I: 614, 82% M C: 465, 82% M
Groups comparable at baseline? Yes |
Intervention Chemoradiation (CRT)
|
Control Total laryngectomy (TL)
|
Length of follow-up: Not mentioned
Loss-to-follow-up: Not mentioned
Incomplete outcome data: Not mentioned
|
Outcome measures and effect size:
OS, 5 years: T3 hypopharynx I: 87/222, 39% C: 62/155, 40% P = 0.475
T4 hypopharynx I: 76/316, 24% C: 86/294, 29% P=0.039
DFS: Not reported
Morbidity: Not reported
Quality of life: Not reported
Dry mouth: Not reported
Head neck specific quality of life: Not reported
|
- The study shows no significant difference between TL and CRT for patients with T3 hypopharynx. Patients with T4 hypopharynx have a significantly better OS when treated with TL compared to CRT (p=0.039). - Study is a retrospective population-based cohort study, data is retrieved from the databases of the Netherlands. Cancer Registry (NCR) and PALGA (the nationwide network and registry of histo- and cytopathology in the Netherlands). - Prognostic factors are only available for the whole patient group, T1-T4. - Data on overall survival for patients with T3 and T4 tumours is reported. separately from patients T1-T2 tumours, however data from T3N+ and T4N+ is included. |
Risk of bias tables
Randomised controlled trials
|
Study reference
(first author, publication year) |
Describe method of randomisation1 |
Bias due to inadequate concealment of allocation?2
(unlikely/likely/unclear) |
Bias due to inadequate blinding of participants to treatment allocation?3
(unlikely/likely/unclear) |
Bias due to inadequate blinding of care providers to treatment allocation?3
(unlikely/likely/unclear) |
Bias due to inadequate blinding of outcome assessors to treatment allocation?3
(unlikely/likely/unclear) |
Bias due to selective outcome reporting on basis of the results?4
(unlikely/likely/unclear) |
Bias due to loss to follow-up?5
(unlikely/likely/unclear) |
Bias due to violation of intention to treat analysis?6
(unlikely/likely/unclear) |
|
Beauvillain 1997 |
“Randomization was always performed by the physician prior to chemotherapy, and particular treatment was then offered to the patients.
|
Unclear
Not clearly described whether randomization was blinded |
Likely
Blinding not possible due to used interventions used in different arms |
Likely
Blinding not possible due to used interventions used in different arms |
Likely
Blinding not possible due to used interventions used in different arms |
Unclear
Predefined outcome measures are not reported |
Unlikely
Reasons for loss to follow up are mentioned and do not differ between groups |
Unlikely
Intention to treat analysis is mentioned |
|
Lefebvre, 1996 |
“A random assignment of patients in different arms were carried out centrally at the EORTC Data Center using the minimization technique (i.e., tending to balance the marginal distribution of each prognostic factor in the different treatment arms).” |
Unlikely
Randomization performed at data centre |
Likely
Blinding not possible due to nature of treatment
|
Likely
Blinding not possible due to nature of treatment
|
Unlikely
Only ‘hard’ outcome measures (overall survival and disease-free survival) are taken along |
Unclear
Predefined outcome measures are not reported |
Unlikely
Reasons for loss to follow up are clearly specified |
Unclear
Patients in the chemoradiation group are treated with radiation therapy in patients who showed a complete response or surgery in those who did not respond |
Observational studies
|
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) |
|
Chung, 2019 |
Unlikely
Exclusion criteria are stated, and exposed and non-exposed are drawn from the same sample |
Unclear
Follow-up was not reported for the individual groups, but only for the whole sample |
Unlikely
Outcome measure is defined, and outcome is measured the same in treatment and control group. |
Unlikely
Multivariate analysis was applied |
|
Harris, 2015
|
Unlikely
The study applied specific eligibility criteria |
Unclear
Follow-up was not reported for the individual groups, but only for the whole sample |
Unlikely
Outcome measure is defined, and outcome is measured the same in treatment and control group. |
Unlikely
Multivariate analysis was applied |
|
Hung, 2006
|
Unlikely
The study applied specific eligibility criteria |
Unclear
Follow-up was not reported for the individual groups, but only for the whole sample |
Unlikely
Outcome measure is defined, and outcome is measured the same in treatment and control group. |
Unlikely
Multivariate analysis was applied |
|
Jang, 2016
|
Unlikely
The study applied specific eligibility criteria |
Unclear
Follow-up was not reported for the individual groups, but only for the whole sample |
Unlikely
Only a hard (objective) outcome measure is reported (5-year overall survival) |
Unlikely
Multivariate analysis was applied |
|
Kim, 2016 |
Unlikely
The study applied specific eligibility criteria |
Unclear
Follow-up was not reported for the individual groups, but only for the whole sample |
Unclear
Blinding is not mentioned, and outcome is not clearly described |
Likely
Univariate analysis was applied, which gives potential to residual confounding |
|
Kim, 2018 |
Unlikely
The study applied specific eligibility criteria |
Unclear
Follow-up was not described |
Unlikely
Only a hard (objective) outcome measure is reported (5-year overall survival) |
Likely
Authors state that variables which had prognostic potential as suggested by univariate analysis were selected for multivariate analysis. Therefore, there is a risk that confounders were not pre-defined, and results were not corrected by all plausible confounders, resulting is residual confounding. |
|
Petersen, 2018 |
Unlikely
Exclusion criteria are mentioned, and all patients are selected from the same population |
Unclear
Follow up period not mentioned |
Unlikely
Only the ‘hard’ outcome measure overall survival is reported, so bias is unlikely as blinding is irrelevant |
Unlikely
Multivariate statistical analysis is performed |
- 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.
AMSTAR tool -quality assessment for systematic review
Table of quality assessment for systematic reviews of RCTs and observational studies
Based on AMSTAR checklist (Shea, 2007; BMC Methodol 7: 10; doi:10.1186/1471-2288-7-10) and PRISMA checklist (Moher, 2009; PLoS Med 6: e1000097; doi:10.1371/journal.pmed1000097)
|
First author, year |
Appropriate and clearly focused question?1
Yes/no/unclear |
Comprehensive and systematic literature search?2
Yes/no/unclear |
Description of included and excluded studies?3
Yes/no/unclear |
Description of relevant characteristics of included studies?4
Yes/no/unclear |
Appropriate adjustment for potential confounders in observational studies?5
Yes/no/unclear/not applicable |
Assessment of scientific quality of included studies?6
Yes/no/unclear |
Enough similarities between studies to make combining them reasonable?7
Yes/no/unclear |
Potential risk of publication bias taken into account?8
Yes/no/unclear |
Potential conflicts of interest reported?9
Yes/no/unclear |
|
Cui, 2020 |
Yes
PICO and inclusion criteria are defined |
Yes
The following databases were searched: Medline (via the PUBMED interface), ISI Web of Knowledge, the Cochrane Library (via the Ovid interface), and EMBASE. The search terms are described and seem adequate. Search period was up until April 10, 2019 |
No
It is mentioned that 88 studies are read full text, and that 71 are excluded, with reasons for exclusion. However, no references are provided for these 71 studies |
No
Baseline characteristics are mentioned, but not all potential confounders are mentioned |
No
Some observational studies only perform univariate analysis, others don’t mention adjustment for confounding at all
|
Yes
Trials were assessed in risk of bias tables, the quality of observational studies was evaluated using the Newcastle-Ottawa scale |
No
Different patient populations are included in the different studies (differing T or N stages), interventions are not the same over studies (some include concomitant chemotherapy, other concomitant radiotherapy etc)
|
Yes
Funnel plot inspection and Harbord test were carried out |
No
The authors of the review declared that they have no conflicts of interest. No information is reported for the included studies.
|
Table of excluded studies
|
Author and year |
Reason for exclusion |
|
Fan, 2020 |
Article in Chinese |
|
Blanchard, 2011 |
Wrong treatments are used |
|
Che, 2019 |
Wrong patient population (hypopharyngeal and laryngeal patients are considered together), wrong tumour type is included (early-stage carcinomas, only subgroup analysis for T2-T4, not T3-T4) |
|
Habib, 2018 |
Wrong interventions used |
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.
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 |
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 |
|
|
Redelijk |
|
|
Laag |
|
|
Zeer laag |
|
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. |
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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. |
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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
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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.
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Zoekverantwoording
Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.