Alternatief voor cisplatin bij chemoradiatie
Uitgangsvraag
Wat is de rol van systemische therapie in aanvulling op definitieve radiotherapie bij patiënten met een lokaal gevorderd plaveiselcelcarcinoom in het hoofd-halsgebied bij wie cisplatin is gecontra-indiceerd?
Aanbeveling
Bespreek met patiënten met een lokaal gevorderd plaveiselcelcarcinoom in het hoofd-halsgebied bij wie cisplatin gecontra-indiceerd is de alternatieven voor cisplatin in aanvulling op definitieve radiotherapie, te weten cetuximab, carboplatin of carboplatin in combinatie met 5-FU, en wijs daarbij op de voor- en nadelen van deze alternatieven.
Op basis van prospectief onderzoek kan geen aanbeveling worden gedaan voor patiënten boven de 70 jaar.
Overwegingen
Voor- en nadelen van de interventie en de kwaliteit van het bewijs
Onze systematische zoekactie in diverse databases resulteerde in 13 relevante studies die resultaten rapporteren van 9 verschillende RCT’s.
1. RT + cetuximab
In totaal hadden 3 van de 13 studies betrekking op de vergelijking tussen radiotherapie en cetuximab enerzijds en alleen radiotherapie anderzijds (Bonner, 2006; Curran, 2007 en Bonner, 2010). Deze studies rapporteerden resultaten van een en dezelfde trial. Er werden klinisch relevante verschillen gevonden voor totale overleving (cruciale uitkomstmaat) op 3 en 5 jaar en progressievrije overleving (belangrijke uitkomstmaat) op 2 en 3 jaar, ten faveure van bioradiotherapie. Er werd geen klinisch relevant verschil gevonden voor kwaliteit van leven (belangrijke uitkomstmaat). Van de acute bijwerkingen van graad 3 of hoger (belangrijke uitkomstmaat) traden een acné-achtige huiduitslag, infusiereacties en anemie statistisch significant vaker op bij patiënten die behandeld werden met radiotherapie en cetuximab, vergeleken met patiënten die alleen radiotherapie kregen. Het percentage patiënten met een late bijwerking van graad 3 of hoger verschilde niet tussen de behandelgroepen. Een subgroepanalyse liet zien dat voor totale overleving patiënten met een orofarynxtumor mogelijk het meeste baat hebben bij de toevoeging van cetuximab aan radiotherapie. Het percentage patiënten met een lokaal recidief (cruciale uitkomstmaat) werd niet gerapporteerd in de studies. De bewijskracht voor de cruciale en belangrijke uitkomstmaten was zeer laag. Er werd afgewaardeerd voor studiebeperkingen (vanwege de actieve rol van de studiesponsor bij het verzamelen en analyseren van de data), indirectheid (vanwege het feit dat de studiepopulatie niet bestond uit patiënten bij wie cisplatin gecontra-indiceerd was) en imprecisie (vanwege het geringe aantal deelnemers en het feit dat de 3 studies betrekking hadden op slechts 1 RCT). Inconsistentie en publicatiebias konden niet beoordeeld worden.
2. RT + carboplatin
Eveneens 3 van de 13 studies hadden betrekking op de vergelijking tussen radiotherapie en carboplatin enerzijds en alleen radiotherapie anderzijds (Fountzilas, 2004; Jeremic, 1997 en Ruo Redda, 2010). Deze studies rapporteerden resultaten van 3 verschillende trials. Er werd een klinisch relevant verschil gevonden voor totale overleving (cruciale uitkomstmaat) op 1, 2, 3 en 4 jaar, ten faveure van chemoradiotherapie, maar niet voor totale overleving op 10 jaar. De studies toonden conflicterende resultaten voor totale overleving op 5 jaar: 2 studies (n = 79 en n = 106) lieten wel een klinisch relevant verschil zien, terwijl in 1 studie (n = 164) geen klinisch relevant verschil werd gevonden. Voor ziektevrije overleving (belangrijke uitkomstmaat) werd een klinisch relevant verschil gevonden op 3 jaar, ten faveure van chemoradiotherapie, maar niet op 5 en 10 jaar. Voor geen van de acute en late bijwerkingen van graad 3 of hoger (belangrijke uitkomstmaat) werd een eenduidig klinisch relevant verschil gevonden. Het percentage patiënten met een lokaal recidief (cruciale uitkomstmaat), progressievrije overleving en kwaliteit van leven werden niet gerapporteerd in de studies. De bewijskracht voor de cruciale en belangrijke uitkomstmaten was zeer laag. Er werd afgewaardeerd voor studiebeperkingen (vanwege onvolledige rapportage, verschillen in patiëntkenmerken tussen de behandelarmen in een studie en het vroegtijdig stoppen van een trial), inconsistentie (vanwege conflicterende resultaten), indirectheid (vanwege het feit dat de studiepopulatie niet bestond uit patiënten bij wie cisplatin gecontra-indiceerd was) en imprecisie (vanwege het geringe aantal deelnemers per studie). Inconsistentie kon niet beoordeeld worden voor ziektevrije overleving, en publicatiebias kon in het geheel niet beoordeeld worden.
3. RT + carboplatin and 5-FU
De resterende 7 studies hadden betrekking op de vergelijking tussen radiotherapie gecombineerd met carboplatin en 5-FU enerzijds en alleen radiotherapie anderzijds (Bourhis, 2012; Calais, 1997; Denis, 2004; Chitapanarux, 2013; Olmi, 2003; Staar, 2001 en Semrau, 2006). Deze studies rapporteerden resultaten van 5 verschillende trials. Er werd een klinisch relevant verschil gevonden voor totale overleving (cruciale uitkomstmaat) op 1, 2, 3 en 5 jaar, ten faveure van chemoradiotherapie. Voor het percentage patiënten met een lokaal recidief (cruciale uitkomstaat) en ziektevrije overleving (belangrijke uitkomstmaat) op 2, 3 en 5 jaar werd eveneens een klinisch relevant verschil gevonden, ten faveure van chemoradiotherapie, maar niet voor progressievrije overleving (belangrijke uitkomstmaat). Voor geen van de acute bijwerkingen van graad 3 of hoger (belangrijke uitkomstmaat) werd een eenduidig klinisch relevant verschil gevonden. Voor de late bijwerkingen van graad 3 of hoger (belangrijke uitkomstmaat) gold dat late slikproblemen en permanente sondevoeding vaker werden gezien bij patiënten die behandeld waren met hypergefractioneerde, geaccelereerde radiotherapie in combinatie met 5-FU, vergeleken met alleen radiotherapie; dit verschil was klinisch relevant. Kwaliteit van leven werd niet gerapporteerd in de studies. De bewijskracht voor de cruciale en belangrijke uitkomstmaten was laag tot zeer laag. Er werd afgewaardeerd voor studiebeperkingen (vanwege onvolledige rapportage, verschillen in patiëntkenmerken tussen de behandelarmen in een studie en het vroegtijdig stoppen van 2 trials), inconsistentie (vanwege conflicterende resultaten), indirectheid (vanwege het feit dat de studiepopulatie niet bestond uit patiënten bij wie cisplatin gecontra-indiceerd was en het gebruik van verschillende radiotherapeutische regimes) en imprecisie (vanwege het geringe aantal deelnemers per studie). Inconsistentie kon niet beoordeeld worden voor het percentage patiënten met een lokaal recidief en ziekte- en progressievrije overleving, en publicatiebias kon in het geheel niet beoordeeld worden.
Op basis van de resultaten van de studie van Mehanna (2019) lijkt het toevoegen van cetuximab aan definitieve radiotherapie niet van waarde te zijn voor patiënten met een gevorderd HPV-positief orofarynxcarcinoom. De studie van Mehanna (2019) is in deze module overigens geëxcludeerd omdat er alleen patiënten met een gevorderd HPV-positief orofarynxcarcinoom zijn geïncludeerd. Voor deze patiëntenpopulatie is een aparte module beschikbaar (RLDB: link invoegen naar module ‘Behandeling HPV-positieve orofarynx tumoren’). Daarnaast wordt in de studie van Mehanna (2019) en ook de studie van Gillison (2019) geen vergelijking gemaakt tussen radiotherapie en cetuximab met alleen radiotherapie, maar wordt radiotherapie en cetuximab vergeleken met radiotherapie met cisplatin. Op basis van de huidige literatuur kan geen uitspraak gedaan worden over de rol van carboplatin met of zonder 5-FU als alternatief voor cetuximab.
Waarden en voorkeuren van patiënten (en eventueel hun verzorgers)
Curran (2007) vonden geen statistisch significant, maar wel een beperkt klinisch relevant verschil in kwaliteit van leven tussen patiënten die behandeld werden met radiotherapie en cetuximab en patiënten die alleen radiotherapie kregen, ten nadele van de patiënten die met cetuximab werden behandeld. Er is geen onderzoek gedaan naar kwaliteit van leven bij de andere schema’s. Vanwege de beperkte literatuur op dit gebied kan de werkgroep geen uitspraak doen over de waarden en voorkeuren van patiënten.
Het doel van het toevoegen van cetuximab of carboplatin met of zonder 5-FU aan definitieve radiotherapie is het verbeteren van de locoregionale controle, zonder duidelijke toename van de toxiciteit. Dit laatste is met name ook voor de patiënt van belang, omdat het hier een kwetsbare groep patiënten betreft. Uit een meta-analyse van 107 RCT’s naar de effecten van chemotherapie bij hoofd-halstumoren (Lacas, 2021) bleek dat met het toenemen van de leeftijd het effect van het toevoegen van cisplatin aan radiotherapie afneemt, waarbij er in de leeftijdsgroep boven de 70 jaar geen positief effect is op overleving en dit positieve effect in de leeftijdsgroep 60-69 al weer aanzienlijk lager is dan in de groep jonger dan 50 jaar. Het is goed om te realiseren dat in de studies ook selectie heeft plaatsgevonden, bijvoorbeeld op basis van leeftijd en de aan- of afwezigheid van ernstige comorbiditeit. Met de patiënt moet duidelijk gecommuniceerd worden wat met de huidige behandelopties bereikt kan worden, en tegen welke prijs. Op basis hiervan en de eigen doelen van de patiënt kan een gewogen beslissing worden genomen.
Kosten (middelenbeslag)
Extra kosten voor de patiënt zijn het regelmatig bezoeken van het ziekenhuis voor de behandelingen. Ook de bijwerkingen kunnen leiden tot extra kosten, zoals de kosten van medicatie vanwege huiduitslag, de kosten die gepaard gaan met een eventuele infectie of bloeding en de kosten van mogelijke extra ziekenhuisopnames. De meeste van deze kosten zijn verzekerd, maar dit betekent kosten voor de samenleving en voor familie en relaties. Gezien de onzekerheid die bestaat over de gunstige effecten is het moeilijk aan te geven of dit de (extra) middelen waard is? Een kosten-batenanalyse ontbreekt in de literatuur.
Gezien de langere overleving bij HPV-positieve patiënten met een orofarynxcarcinoom zou bij deze groep adjuvante therapie meer van waarde kunnen zijn. Anderzijds zal bij oudere patiënten (> 75 jaar) met een ‘WHO performance status’ > 2 gezien de bijwerkingen meer terughoudendheid moeten worden betracht.
De werkgroep heeft geen informatie gevonden over de kosteneffectiviteit van de-escalatiestrategieën. De werkgroep heeft dit aspect daarom niet meegewogen bij het formuleren van de aanbeveling. De werkgroep verwacht dat de aanbeveling geen relevante impact heeft op de zorgkosten.
Aanvaardbaarheid, haalbaarheid en implementatie
In Nederland is de hoofd-halsoncologie gecentreerd in 8 werkgroepen, waardoor een hoge mate van expertise is gewaarborgd. Voor sommige patiënten betekent dit langere reistijden wat een belasting kan zijn. Er zijn geen aanwijzingen dat dit de therapietrouw ten nadele beïnvloedt. In het algemeen is in de centra sprake van voldoende capaciteit, hoewel er binnen financiële kaders er spanningen op kunnen treden. Gezien de zeer goede onderlinge samenwerking binnen een groot team, waarvan de samenstelling en benodigde expertise is vastgesteld in de SONCOS-normen, is de kwaliteit gewaarborgd. De centra worden regelmatig gevisiteerd. Alle patiënten worden besproken binnen het multidisciplinaire overleg (MDO), waarbij ook de behandelaar aanwezig is. Hierna vindt uitgebreid verleg plaats met de patiënt, waarbij op basis van de adviezen uit het MDO en de eigen voorkeur van de patiënt een beleid wordt uitgestippeld.
De werkgroep is van mening dat de aanbeveling aanvaardbaar is voor zowel zorgverleners als patiënten. De werkgroep verwacht dat het uitvoeren van de aanbeveling haalbaar en implementeerbaar is. De aanbeveling sluit aan bij de huidige werkwijze in de praktijk.
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies
Op basis van de huidige literatuur kan geen zekere uitspraak gedaan worden over een goed alternatief voor cisplatin bij patiënten bij wie cisplatin gecontra-indiceerd is. In de voorgaande richtlijn werd cetuximab genoemd als alternatief voor patiënten bij wie cisplatin gecontra-indiceerd is. Op basis van recente studies (Gillison (2019) en Mehanna (2019) is twijfel gerezen over de toegevoegde waarde van cetuximab aan radiotherapie in de behandeling van patiënten met een gevorderd plaveiselcelcarcinoom in het hoofd-halsgebied, hoewel in deze studies met name patiënten met een HPV-positief orofarynxcarcinoom waren geïncludeerd. Voor patiënten met een gevorderd HPV-positief orofarynxcarcinoom lijkt het toevoegen van cetuximab aan definitieve radiotherapie niet van waarde te zijn, zie ook de module ‘Behandeling HPV-positieve orofarynx tumoren’).
Deze onzekerheid wat betreft het beste alternatief voor cisplatin dient besproken te worden met deze patiënten. Er kan gekozen worden voor een van de in deze richtlijnmodule besproken alternatieven, maar dan moet het risico op toegenomen toxiciteit worden afgewogen tegen de onzekere voordelen.
Onderbouwing
Achtergrond
Patiënten met een lokaal gevorderd plaveiselcelcarcinoom in het hoofd-halsgebied kunnen in opzet curatief behandeld worden met radiotherapie. Het toevoegen van cisplatin aan deze behandeling leidt bij patiënten van 70 jaar of jonger en een ‘WHO performance status’ van 0 of 1 tot een betere lokale controle en overleving, maar gaat ook gepaard met meer toxiciteit. Met het toenemen van de leeftijd neemt het effect van het toevoegen van chemotherapie aan radiotherapie af, waarbij er bij patiënten boven de 70 jaar geen positief effect op overleving is gerapporteerd. Bij een deel van de patiënten is behandeling met cisplatin gecontra-indiceerd vanwege bijvoorbeeld cardiovasculaire problemen of nierinsufficiëntie. Mogelijke behandelalternatieven voor deze patiënten zijn cetuximab, carboplatin of carboplatin én 5-fluoro-uracil (5-FU). Het toxiciteitsprofiel van deze geneesmiddelen is weliswaar anders dan dat van cisplatin, maar het is onduidelijk hoe effectief deze middelen zijn en welk middel de voorkeur heeft.
Conclusies
1. RT + cetuximab
Overall survival
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with cetuximab on overall survival when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Bonner, 2006; Bonner, 2010) |
Local recurrence
- GRADE |
No evidence was found regarding the effect of radiotherapy combined with cetuximab on local recurrence in patients with a locally advanced squamous cell carcinoma in the head and neck region. |
Disease-free survival
- GRADE |
No evidence was found regarding the effect of radiotherapy combined with cetuximab on disease-free survival in patients with a locally advanced squamous cell carcinoma in the head and neck region. |
Progression-free survival
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with cetuximab on progression-free survival when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Bonner, 2006) |
Quality of life
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with cetuximab on quality of life when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Curran, 2007) |
Adverse events
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with cetuximab on adverse events when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Bonner, 2006) |
2. RT + carboplatin
Overall survival
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with carboplatin on overall survival when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Fountzilas, 2004; Jeremic, 1997; Ruo Redda, 2010) |
Local recurrence
- GRADE |
No evidence was found regarding the effect of radiotherapy combined with carboplatin on local recurrence in patients with a locally advanced squamous cell carcinoma in the head and neck region. |
Disease-free survival
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with carboplatin on disease-free survival when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Ruo Redda, 2010) |
Progression-free survival
- GRADE |
No evidence was found regarding the effect of radiotherapy combined with carboplatin on progression-free survival in patients with a locally advanced squamous cell carcinoma in the head and neck region. |
Quality of life
- GRADE |
No evidence was found regarding the effect of radiotherapy combined with carboplatin on quality of life in patients with a locally advanced squamous cell carcinoma in the head and neck region. |
Adverse events
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with carboplatin on adverse events when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Fountzilas, 2004; Jeremic, 1997; Ruo Redda, 2010) |
3. RT + carboplatin and 5-FU
Overall survival
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with carboplatin and 5-FU on overall survival when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Bourhis, 2012; Calais, 1999; Denis, 2004; Chitapanarux, 2013; Olmi, 2003; Staar, 2001; Semrau, 2006) |
Local recurrence
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with carboplatin and 5-FU on local recurrence when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: Calais, 1999; Denis, 2004) |
Disease-free survival
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with carboplatin and 5-FU on disease-free survival when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Calais, 1999; Denis, 2004; Olmi, 2003) |
Progression-free survival
Low GRADE |
The evidence suggests that radiotherapy combined with carboplatin and 5-FU results in little to no difference in progression-free survival when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Bourhis, 2012) |
Quality of life
- GRADE |
No evidence was found regarding the effect of radiotherapy combined with carboplatin and 5-FU on quality of life in patients with a locally advanced squamous cell carcinoma in the head and neck region. |
Adverse events
Very low GRADE |
The evidence is very uncertain about the effect of radiotherapy combined with carboplatin and 5-FU on adverse events when compared with radiotherapy alone in patients with a locally advanced squamous cell carcinoma in the head and neck region.
Sources: (Bourhis, 2012; Calais, 1999; Denis, 2004; Chitapanarux, 2013; Olmi, 2003; Staar, 2001; Semrau, 2006) |
Samenvatting literatuur
Description of studies
1. Radiotherapy + cetuximab
Bonner (2006), Curran (2007) and Bonner (2010) report on a multicenter, randomized controlled phase 3 trial that was conducted at 73 academic centers in the US and 14 other countries, including the Netherlands. Patients with previously untreated, non-metastatic, stage III or IV, measurable squamous cell carcinoma of the oropharynx, hypopharynx, or larynx were eligible. Criteria for eligibility also included a Karnofsky performance score ≥ 60, and normal bone marrow, hepatic and renal function. Patients were randomly assigned (1:1) to receive high-dose radiotherapy and cetuximab (n = 211), or high-dose radiotherapy alone (n = 213). Investigators were required to select 1 of 3 radiotherapy-fractionation regimens (concomitant boost, once daily, or twice daily) before randomization. The final review of radiotherapy revealed that the mean and median doses for the 3 regimens did not differ between the 2 treatment groups. Administration of cetuximab was initiated 1 week before radiotherapy at a loading dose of 400 mg/m2 over a period of 120 minutes, followed by weekly 60-minute infusions of 250 mg/m2 for the duration of radiotherapy. The primary outcome measure was the duration of locoregional control, which was not of our interest. Secondary outcome measures of our interest included overall survival, progression-free survival, quality of life and safety. Quality of life was assessed using two validated, multidimensional instruments, namely the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (H&N35). Acute toxic effects were assessed through the eighth week after treatment using the criteria of the Radiation Therapy Oncology Group (RTOG). Late toxic effects of radiotherapy were assessed thereafter using the criteria of the RTOG/EORTC.
2. Radiotherapy + carboplatin
Fountzilas (2004) conducted a multicenter, randomized controlled phase 3 trial at 5 hospitals in Greece, Romania and Germany. Patients aged ≥ 18 years with biopsy-proven, previously untreated, non-metastatic, stage III or IV, measurable squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were eligible. Criteria for eligibility also included an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, adequate bone marrow, hepatic and renal function, and adequate cardiovascular, pulmonary, nutritional and mental status. Patients were randomly assigned (1:1:1) to receive standard fractionated radiotherapy and carboplatin (n = 38), standard fractionated radiotherapy and cisplatin (n = 45) or standard fractionated radiotherapy alone (n = 41). The treatment group of patients who received standard fractionated radiotherapy and cisplatin is not relevant for the current clinical question and is, therefore, disregarded in the summary of the literature. Radiotherapy was given in a total dose of 70 Gy at 1.8 Gy per fraction per day, 5 days per week. Carboplatin was administered at an AUC of 7 on days 2, 22 and 42. The primary outcome measure was the overall survival at 3 years. The authors also report the overall survival at 5 years, the median overall survival, and safety. Acute toxic effects were assessed using the criteria of the RTOG.
Jeremic (1997) conducted a single-center, randomized controlled trial in Yugoslavia. Patients aged > 18 years with histologically confirmed, previously untreated, unresectable, non-metastatic, stage III or IV, measurable squamous cell carcinoma of the head and neck were eligible. Criteria for eligibility also included a Karnofsky performance score ≥ 50, adequate bone marrow, hepatic and renal function, and no serious concomitant disease. Patients were randomly assigned (1:1:1) to receive standard fractionated radiotherapy and carboplatin (n = 53), standard fractionated radiotherapy and cisplatin (n = 53) or standard fractionated radiotherapy alone (n = 53). The treatment group of patients who received standard fractionated radiotherapy and cisplatin is not relevant for the current clinical question and is, therefore, disregarded in the summary of the literature. Radiotherapy was given in a total dose of 70 Gy at 1.8 Gy per fraction per day, 5 days per week. Carboplatin was intravenously administered 45-60 minutes before the irradiation as a bolus at a daily dose of 25 mg/m2. The primary outcome measure was the overall survival at 3 years. The authors also report the overall survival at 1 year, 2 years, 4 years and 5 years, and safety. Acute and late toxic effects of radiotherapy were assessed using the criteria of the RTOG and RTOG/EORTC, respectively. Toxic effects of chemotherapy were assessed using the criteria of the ECOG. The trial was prematurely stopped before the planned accrual of 85 patients per treatment group was reached, because the chief investigator had to leave the department.
Ruo Redda (2010) conducted a multicenter, randomized controlled phase 3 trial at 6 centers in Italy. Patients aged 18-70 with biopsy-proven, previously untreated, stage III or IV, non-metastatic, measurable, unresectable squamous cell carcinoma of the head and neck were eligible. Criteria for eligibility also included an ECOG performance status ≤ 2, adequate bone marrow, hepatic and renal function, adequate nutritional and liquid intake, and no serious concomitant disease. Patients were randomly assigned (1:1) to receive standard fractionated radiotherapy and carboplatin (n = 82), or standard fractionated radiotherapy alone (n = 82). Radiotherapy was given in a total dose of 70 Gy at 2 Gy per fraction per day, 5 days per week. Carboplatin was intravenously administered 45-60 minutes before the irradiation as a bolus at a daily dose of 45 mg/m2 on day 1-5 of the 1st, 3rd, 5th and 7th week of the combined treatment (total dose: 900 mg/m2). The primary outcome measure was the locoregional recurrence-free survival, which was not of our interest. Secondary outcome measures of our interest included overall survival, disease-free survival, and safety. Acute toxic effects were assessed using the criteria of the World Health Organization (WHO). Late toxic effects were assessed using the criteria of the RTOG/EORTC.
3. Radiotherapy + carboplatin and 5-FU
Bourhis (2012) conducted a multicenter, randomized controlled phase 3 trial at 22 centers in France and Belgium (GORTEC 99-02 trial). Patients with histologically confirmed, previously untreated, stage III or IV, non-metastatic, squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were eligible. Criteria for eligibility also included an ECOG performance status ≤ 2, adequate bone marrow, hepatic and renal function, no history of other cancer in the previous 5 years, and no clinically significant cardiac disease. Patients were randomly assigned (1:1:1) to receive standard fractionated radiotherapy plus carboplatin and 5-FU (n = 279), accelerated radiotherapy plus carboplatin and 5-FU (n = 280) or very accelerated radiotherapy alone (n = 281). Patients allocated to receive standard fractionated radiotherapy received a total dose of 70 Gy in 7 weeks: 5 fractions of 2 Gy per week, with spinal cord exclusion at 40 Gy. These patients also received 3 cycles of 4 days of carboplatin 70 mg/m² per day plus 5-FU 600 mg/m² per day on day 1 to 4, day 22-25, and day 43-46. Patients allocated to receive accelerated radiotherapy received a total dose of 70 Gy in 6 weeks: 5 fractions of 2 Gy per week until 40 Gy, with spinal cord exclusion at 40 Gy, followed by 1.5 Gy per fraction twice daily for 5 days per week for the remaining 30 Gy. These patients also received 2 cycles of 5 days of carboplatin 70 mg/m² per day and 5-FU 600 mg/m² per day on day 1 to 5 and day 29 to 33. Patients allocated to receive very accelerated radiotherapy alone received a total dose of 64.8 Gy in 3.5 weeks: 1.8 Gy per fraction twice daily for 5 days per week, with spinal cord exclusion at 34.2 Gy. The primary outcome measure was progression-free survival, defined as the time between randomisation and the first of the following events: locoregional progression or relapse, distant relapse, or death from any cause (or the last follow-up contact for patients who did not have any of these events). Secondary outcome measures of our interest included overall survival and safety. Acute toxic effects of radiotherapy and chemotherapy occurring during treatment or within 3 months after the end of treatment were assessed using the criteria of the RTOG and WHO. Late toxic effects occurring more than 3 months after the end of treatment were assessed using the criteria of the RTOG/EORTC.
Calais (1999) and Denis (2004) report on a multicenter, randomized controlled phase 3 trial that was conducted at university hospitals, cancer centers, and private hospitals in France (GORTEC 94-01 trial). Patients aged < 75 years with previously untreated, non-metastatic, stage III or IV, squamous cell carcinoma of the oropharynx were eligible. Criteria for eligibility also included a Karnofsky performance score ≥ 60, and normal bone marrow and renal function. Patients were excluded if they had lost more than 20% of their body weight, if they had previously undergone treatment for this disease or any other cancer, except basal cell carcinoma of the skin, or if they had synchronous primary lesions. Patients were randomly assigned (1:1) to receive standard fractionated radiotherapy plus carboplatin and 5-FU (n = 113), or standard fractionated radiotherapy alone (n = 109). Radiotherapy was given in a total dose of 70 Gy in 35 fractions at 2 Gy per fraction per day, 5 days per week. In the intervention group, patients received 3 cycles of chemotherapy during the 1st, 4th, and 7th week of radiotherapy. Chemotherapy consisted of carboplatin (i.v. bolus of 70 mg/m2 per day for 4 days) and 5-FU (600 mg/m2 per day infused continuously in 24 hours for 4 days). The primary outcome measure was the overall survival at 3 years. The authors also report the median overall survival, overall survival at 5 years, disease-free survival at 3 and 5 years, local recurrence rate, and safety. Acute toxic effects were assessed using the criteria of the EORTC. Late toxic effects were assessed using the criteria of the National Cancer Institute (NCI) and RTOG/EORTC.
Chitapanarux (2013) conducted a single-center, randomized controlled phase 3 trial at a university hospital in Thailand. Patients aged 18-75 years with previously untreated, stage III or IV, non-metastatic, squamous cell carcinoma of the head and neck, excluding the nasopharynx, nasal cavity, paranasal sinuses and salivary glands, were eligible. Criteria for eligibility also included an ECOG performance status ≤ 1 and adequate organ system function. Patients were randomly assigned (1:1) to receive standard fractionated radiotherapy plus carboplatin and 5-FU (n = 48) or hybrid accelerated radiotherapy alone (n = 37). Patients allocated to receive standard fractionated radiotherapy received a total dose of 66 Gy in 6.5 weeks: 5 fractions of 2 Gy per week, with spinal cord exclusion at 40 Gy. These patients also received 3 cycles of 4 days of carboplatin 70 mg/m² per day plus 5-FU 600 mg/m² per day on day 1 to 4, day 22-25, and day 43-46. Patients allocated to receive hybrid accelerated radiotherapy received a total dose of 70 Gy in 6 weeks: 5 fractions of 2 Gy per week until 40 Gy, with spinal cord exclusion at 40 Gy, followed by a first daily fraction of 1.8 Gy and a second daily fraction of 1.2 Gy for 5 days per week for the remaining 30 Gy. The primary outcome measure was the locoregional control rate, which was not of our interest. Secondary end points of our interest included overall survival and safety. Acute toxic effects of radiotherapy and chemotherapy were assessed using the criteria of the NCI. Late toxic effects were assessed using the criteria of the RTOG/EORTC. Due to slow inclusion, the trial was prematurely stopped before reaching the planned accrual of 106 patients.
Olmi (2003) conducted a multicenter, randomized controlled phase 3 trial at 18 centers in Italy (ORO 93-01 trial). Patients aged < 70 years with histologically confirmed, previously untreated, stage III or IV, non-metastatic, epidermoid tumors of the oropharynx were eligible. Criteria for eligibility also included a Karnofsky performance score ≥ 70 or an ECOG performance status ≤ 1, adequate bone marrow, hepatic, renal, cardiac and pulmonary function, no previous tumors, except adequately treated in situ carcinoma of the cervix and basal cell carcinoma of the skin, and no psychosis or active infectious disease. Patients were excluded if they had a T1N1 or T2N1 lesion. Patients were randomly assigned (1:1:1) to receive standard fractionated radiotherapy plus carboplatin and 5-FU (n = 64), split-course hyperfractionated accelerated radiotherapy alone (n = 65) or standard fractionated radiotherapy alone (n = 63). The treatment group of patients who received split-course hyperfractionated accelerated radiotherapy alone is not relevant for the current clinical question and is, therefore, disregarded in the summary of the literature. Radiotherapy was given in a total dose of 66-70 Gy in 33-35 fractions in 6.5-7 weeks at 2 Gy per fraction per day, 5 days per week. In the intervention group, patients received 3 cycles of chemotherapy. The first 2 cycles were given in the 1st and 5th week of radiotherapy, whereas the last cycle was given in the 9th week, therefore, after the radiotherapy was finished. Chemotherapy consisted of carboplatin (bolus of 75 mg/m2 per day infused in 30 minutes for 4 days) and 5-FU (1000 mg/m2 infused continuously in 96 hours for 4 days). The authors report the overall and disease-free survival at 2 year, and safety. Acute toxic effects of radiotherapy occurring within 90 days from the start of treatment were assessed using the criteria of the RTOG. Acute toxic effects of chemotherapy were assessed using the criteria of the WHO. Late toxic effects of radiotherapy occurring after 90 days from the start of treatment were assessed using the criteria of the RTOG. Due to slow inclusion, the trial was prematurely stopped before reaching the planned accrual of 260 patients.
Staar (2001) and Semrau (2006) report on a multicenter, randomized controlled phase 3 trial that was conducted at 5 centers in Germany. Patients with histologically confirmed, previously untreated, unresectable, non-metastatic, stage III or IV, squamous cell carcinoma of the oro- or hypopharynx were eligible. Criteria for eligibility also included an ECOG performance status ≥ 60, adequate bone marrow and renal function, and no history of a prior malignancy. Patients were randomly assigned (1:1) to receive hyperfractionated accelerated radiotherapy plus carboplatin and 5-FU (n = 113), or hyperfractionated accelerated radiotherapy alone (n = 127). Radiotherapy was given in a total dose of 69.9 Gy in 38 days, using a concomitant boost regimen: 5 fractions of 1.8 Gy per week in week 1-3, followed by a first daily fraction of 1.8 Gy and a second daily fraction of 1.5 Gy for 5 days per week in week 4-5.5. In the intervention group, patients received 2 cycles of chemotherapy during the 1st and 5th week of radiotherapy. Chemotherapy consisted of carboplatin (i.v. bolus of 70 mg/m2 per day for 4 days) and 5-FU (600 mg/m2 per day infused continuously for 4 days). The primary outcome measure was survival with local control at 1 year, which was not of our interest. The authors also report overall survival at 1, 2 and 5 years, and safety. Acute toxic effects were assessed using the criteria of the RTOG. Late toxic effects were assessed using the criteria of the RTOG/EORTC.
Results
1. Radiotherapy + cetuximab
Overall survival
Bonner (2006) found that the median duration of overall survival was 49.0 months (95%CI: 32.8-69.5) among patients treated with high-dose radiotherapy and cetuximab and 29.3 months (95%CI: 20.6-41.4) among those treated with high-dose radiotherapy alone (HR 0.74; 95%CI: 0.57 to 0.97). The overall survival rate at 3 years was 55% in the intervention group versus 45% in the control group. In the same study population, Bonner (2010) found that the overall survival rate at 5 years was 46% among patients treated with high-dose radiotherapy and cetuximab and 36% among those treated with high-dose radiotherapy alone (HR 0.73; 95%CI: 0.56 to 0.95). Based on a subgroup analysis, cetuximab seemed to provide the most benefit for patients with an oropharyngeal tumor (n = 253). Although effect estimates and corresponding 95%-confidence intervals are not reported, the forest plot shows a statistically significant HR < 0.60, favoring the addition of cetuximab. For patients with a laryngeal or hypopharyngeal tumor, the HR did not reach the threshold for a minimal clinically important difference (i.e. HR < 0.7).
Progression-free survival
Bonner (2006) found that the median duration of progression-free survival was 17.1 months among patients treated with high-dose radiotherapy and cetuximab and 12.4 months among those treated with high-dose radiotherapy alone (HR 0.70; 95%CI: 0.54 to 0.90). The progression-free survival rates 2 and 3 years were 46% and 42%, respectively, in the intervention group versus 37% and 31%, respectively, in the control group (p-value for log-rank test = 0.04 for the comparison at 3 years, whereas no p-value is reported for the comparison at 2 years).
Quality of life
Curran (2007) found a small, albeit statistically non-significant, absolute difference of less than 10 points in the mean global health status score (EORTC QLQ-C30) at baseline between patients treated with high-dose radiotherapy and cetuximab and patients treated with high-dose radiotherapy alone. At all visits up to and including month 12, the mean score of patients treated with high-dose radiotherapy and cetuximab was a few points higher compared with patients treated with radiotherapy alone (with higher scores representing better quality of life). The line graph shows that patients in both treatment groups had a global health score of approximately 60 at baseline. Scores decreased during treatment and had returned to baseline levels by month 12. For functional and symptom scale scores, also no statistically significant differences were found between treatment groups.
Adverse events
Bonner (2006) reported adverse events that occurred in at least 10% of patients in either treatment, regardless of the cause. The prevalence of grade ≥ 3 acute toxic effects did not differ significantly between patients treated with high-dose radiotherapy and cetuximab and patients treated with high-dose radiotherapy alone, except for acneiform rash (17% versus 1%; p < 0.001) and infusion reactions (3% versus 0%; p = 0.01) and anemia (1% versus 6%; p = 0.006). Severe late toxic effects related to radiotherapy were reported in about 20% of the patients in each treatment group. The sites most commonly affected were the esophagus, salivary glands, larynx, mucous membranes, subcutaneous tissues, bone, and skin. For late toxic effects, no absolute numbers or percentages per treatment group are reported.
Local recurrence and disease-free survival
No data were reported for these outcome measures.
2. RT + carboplatin
Overall survival
Fountzilas (2004) found that the median duration of overall survival was 24.5 months (range: 0.2 to 79.9) among patients treated with standard fractionated radiotherapy and carboplatin and 12.2 months (range: 1.2 to 81.7) among those treated standard fractionated radiotherapy alone (p-value for log-rank test = 0.0064). Patients treated with standard fractionated radiotherapy and carboplatin had a non-statistically significant higher overall survival than patients treated with standard fractionated radiotherapy alone (adjusted HR 0.57; 95%CI: 0.31 to 1.04). The overall survival rates at 3 and 5 years were 42% and 38%, respectively, in the intervention group versus 17.5% and 9%, respectively, in the control group.
Jeremic (1997) found that the median duration of overall survival was 30 months among patients treated with standard fractionated radiotherapy and carboplatin and 16 months (range: 1.2 to 81.7) among those treated standard fractionated radiotherapy alone (p = 0.0064). Patients in the intervention group had higher overall survival rates at 1, 2, 3, 4 and 5 years, compared with the control group: 76%, 55%, 47%, 31% and 29% versus 57%, 35%, 27%, 17% and 15%, respectively (p-value for log-rank test = 0.019).
Ruo Redda (2010) found that patients treated with standard fractionated radiotherapy and carboplatin had higher overall survival rates at 3, 5 and 10 years, compared with those treated with standard fractionated radiotherapy alone: 28.9%, 9% and 5.5% versus 11.1%, 6.9% and 6.9%, respectively (p-value for log-rank test = 0.02).
Disease-free survival
Ruo Redda (2010) found that patients treated with standard fractionated radiotherapy and carboplatin had higher disease-free survival rates at 3, 5 and 10 years, compared with those treated with standard fractionated radiotherapy alone: 28.9%, 9% and 5.5% versus 11.1%, 6.9% and 6.9%, respectively (p-value for log-rank test = 0.09).
Adverse events
Fountzilas (2004) found that the prevalence of grade ≥ 3 acute toxic effects did not differ significantly between patients treated with standard fractionated radiotherapy and carboplatin and patients treated with standard fractionated radiotherapy alone, except for thrombocytopenia (26% versus 0%; p = 0.0004), and nausea and vomiting (16% versus 0%; p = 0.0107).
Jeremic (1997) found that the prevalence of grade ≥ 3 acute non-hematological toxic effects, including mucositis, xerostomia, esophagitis, nausea and vomiting, and nephrotoxicity, did not differ significantly between patients treated with standard fractionated radiotherapy and carboplatin and patients treated with standard fractionated radiotherapy alone. Grade ≥ 3 acute hematological toxic effects, including leukopenia (11% versus 0%; p = 0.012) and thrombocytopenia (8% versus 0%; p = 0.041), occurred more frequently in patients treated with standard fractionated radiotherapy and carboplatin. The prevalence of grade ≥ 3 late toxic effects, including bone toxicity, skin toxicity and subcutaneous tissue fibrosis, was similar between treatment groups.
Ruo Redda (2010) found that the prevalence of grade ≥ 3 acute toxic effects, including mucositis, anemia, leukopenia and thrombocytopenia, did not differ significantly between patients treated with standard fractionated radiotherapy and carboplatin and patients treated with standard fractionated radiotherapy alone. The prevalence of grade ≥ 3 late toxic effects was similar between treatment groups, except for severe neck fibrosis, which occurred more frequently in patients treated with radiotherapy and carboplatin (7 versus 3 cases). One patient treated with radiotherapy and carboplatin developed mandibular bone necrosis. No radiation myelitis or toxic-related death was observed in either treatment group.
Local recurrence, progression-free survival and quality of life
No data were reported for these outcome measures.
3. RT + carboplatin and 5-FU
Overall survival
Bourhis (2012) found that the overall survival rate at 3 years was 42.6% (95%CI: 37.0 to 48.5) among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU (arm A), 39.4% (95%CI: 33.8 to 45.3) among patients treated with accelerated radiotherapy combined with carboplatin and 5-FU (arm B), and 36.5% (95%CI: 31.1 to 42.3) among patients treated with very accelerated radiotherapy alone (arm C). Resultantly, the HRs and corresponding 95%-confidence intervals are as follows: arm A versus C: HR 0.81; 95%CI: 0.67 to 0.99; arm B versus C: HR 0.87; 95%CI: 0.72 to 1.06; and arm B versus A: HR 1.05; 95%CI: 0.86 to 1.29).
Calais (1999) found that after a median follow-up of 35 months (range: 12 to 56) the median duration of overall survival was 29.2 months among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU, and 15.4 months among those treated with standard fractionated radiotherapy alone. The overall survival rate at 3 years was 51% (95%CI: 39 to 68) in the intervention group versus 31% in the control group (p-value for log-rank test = 0.02). In the same study population, Denis (2004) found that after a median follow-up of 5.5 years (range: 4 to 7.2) the median duration of overall survival was 20 months among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU, and 13 months among those treated with standard fractionated radiotherapy alone. The overall survival rate at 5 years was 22.4% in the intervention group versus 15.8% in the control group (p-value for log-rank test = 0.05).
Chitapanarux (2013) found that the overall survival rate at 5 years was 76.1% (95%CI: 57.8 to 7.3) among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU, and 63.5% (95%CI: 42.0 to 78.8) among patients treated with hybrid accelerated radiotherapy alone (p-value for log-rank test = 0.05).
Olmi (2003) found that the overall survival rate at 2 years was 51% among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU, and 40% among patients treated with standard fractionated radiotherapy alone (p-value for log-rank test = 0.129).
Staar (2001) found that the overall survival rates at 1 and 2 years for all tumor types was 66% (95%CI: 57 to 75) and 48% (95%CI: 38 to 58), respectively, among patients treated with hyperfractionated accelerated radiotherapy combined with carboplatin and 5-FU, and 60% (95%CI: 51 to 69) and 39% (95%CI: 30 to 48), respectively, among patients treated with hyperfractionated accelerated radiotherapy alone (p-value for log-rank test = 0.1139). For patients with an oropharyngeal tumor (n = 178), the overall survival rate at 1 year was 68% in the intervention group versus 57% in the control group (95%CI: ± 10; p-value for log-rank test = 0.0091). For patients with a hypopharyngeal tumor (n = 62), the overall survival curves did not differ significantly between treatment groups. In the same study population, Semrau (2006) found that the overall survival rate at 5 years for all tumor types was 25.6% (95%CI: 15.8 to 35.4) among patients treated with hyperfractionated accelerated radiotherapy combined with carboplatin and 5-FU, and 15.8% (95%CI: 9.1 to 22.4) among patients treated with hyperfractionated accelerated radiotherapy alone (p-value for log-rank test = 0.016). For patients with an oropharyngeal tumor (n = 178), the overall survival rate at 5 years was 26.1% (95%CI: 14.3 to 37.8) in the intervention group versus 13.0% (95%CI: 5.3 to 20.6) in the control group (p-value for log-rank test = 0.008). For patients with a hypopharyngeal tumor (n = 62), the overall survival curves did not differ significantly between treatment groups (22.2% versus 22.2%; p-value for log-rank test = 0.722).
Local recurrence
Calais (1999) found that after a median follow-up of 35 months (range: 12 to 56) the local recurrence rate was lower among patients treated with standard fractionated combined with carboplatin and 5-FU, compared with patients treated with standard fractionated radiotherapy alone (33% versus 51%; risk ratio (RR) 0.64; 95%CI: 0.47 to 0.89). In the same study population, Denis (2004) found that after a median follow-up of 5.5 years (range: 4 to 7.2) the local recurrence rate remained lower among patients treated with standard fractionated combined with carboplatin and 5-FU (41% versus 58%; RR 0.71; 95%CI: 0.54 to 0.93).
Disease-free survival
Calais (1999) found that the disease-free survival rate at 3 years was 42% (95%CI: 30 to 57) among patients treated with standard fractionated combined with carboplatin and 5-FU, and 20% among those treated with standard fractionated radiotherapy alone (p-value for log-rank test = 0.04). In the same study population, Denis (2004) found that the disease-free survival rate at 5 years was 26.6% among patients treated with standard fractionated combined with carboplatin and 5-FU, and 14.6% among those treated with standard fractionated radiotherapy alone (p-value for log-rank test = 0.01).
Olmi (2003) found that the disease-free survival rate at 2 years was 42% among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU, and 23% among patients treated with standard fractionated radiotherapy alone (p-value for log-rank test = 0.022).
Progression-free survival
Bourhis (2012) found that the progression-free survival rate at 3 years was 37.6% (95%CI: 32.1 to 43.4) among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU (arm A), 34.1% (95%CI: 28.7 to 39.8) among patients treated with accelerated radiotherapy combined with carboplatin and 5-FU (arm B), and 32.2% (95%CI: 27.0 to 37.9) among patients treated with very accelerated radiotherapy alone (arm C) (arm A versus C: HR 0.82; 95%CI: 0.67 to 0.99; arm B versus C: HR 0.83; 95%CI: 0.69 to 1.01); arm B versus A: HR 1.02; 95%CI: 0.84 to 1.23).
Adverse events
Bourhis (2012) found that mucositis was the main grade ≥ 3 acute toxic effect. The prevalence of grade ≥ 3 mucositis was lower among patients treated with standard fractionated or accelerated radiotherapy combined with carboplatin and 5-FU (arm A and arm B, respectively), compared with patients treated with very accelerated radiotherapy alone (arm C). According to criteria of the RTOG, grade ≥ 3 mucositis occurred in 69% of patients in treatment arm A, in 76% of patients in treatment arm B, and in 84% of patients in treatment arm C (p = 0.0001). According to the criteria of the WHO, grade ≥ 3 mucositis occurred in 78% of patients in treatment arm A, in 84% of patients in treatment arm B, and in 89% of patients in treatment arm C (p = 0.0016). The prevalence of grade ≥ 3 skin toxicity and grade ≥ 3 hematological toxic effects, including anemia, leukopenia and thrombocytopenia, did not differ significantly between treatment groups. The rate of patients in need of a feeding tube differed significantly between treatment arm A and treatment arm C, both during treatment (60% versus 70%; p = 0.013) and during 5-year follow-up (36% versus 43% at 1 year, 16% versus 23% at 2 years, 11% versus 18% at 3 years, 8% versus 14% at 4 years, and 13% versus 25% at 5 years; p = 0.027), but not between other treatment groups. The prevalence of late toxic effects, including xerostomia, neck fibrosis, mucositis, laryngeal toxicity and bone toxicity, 1 to 5 years after randomization did not differ significantly between treatment groups, but the severity (i.e. grade) of these late toxic effects is not reported.
Calais (1999) found that skin toxicity was the main grade ≥ 3 acute toxic effect. The prevalence of grade ≥ 3 mucositis (71% versus 39%; p = 0.005) and grade ≥ 3 skin toxicity (67% versus 59%; p = 0.02) was higher among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU, compared with patients treated with standard fractionated radiotherapy alone. The prevalence of grade ≥ 3 hematological toxic effects, including neutropenia (4% versus 0%; p = 0.04), thrombocytopenia (6% versus 1%; p = 0.04) and anemia (3% versus 0%; p = 0.05), was also higher in the intervention group, but for anemia the result was not statistically significant. The rate of patients in need of a feeding tube during treatment differed significantly between treatment groups (36% versus 15%; p = 0.02). In the same study population, Denis (2004) found that the prevalence of late toxic effects during 5-year follow-up, including xerostomia, mucositis, skin toxicity and subcutaneous tissue fibrosis, neurological toxicity, mandibular bone necrosis, and taste-, hearing- and teeth-related toxicity, did not differ significantly between treatment groups.
Chitapanarux (2013) found that mucositis was the main grade ≥ 3 acute toxic effect. The prevalence of grade ≥ 3 mucositis was lower among patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU, compared with patients treated with hybrid accelerated radiotherapy alone (42% versus 68%; p = 0.01). The prevalence of grade ≥ 3 skin toxicity, grade ≥ 3 renal toxicity and grade ≥ 3 hematological toxic effects, including anemia, leukopenia and thrombocytopenia, did not differ significantly between treatment groups. The prevalence of grade ≥ 3 late toxic effects related to radiotherapy, including xerostomia, subcutaneous tissue fibrosis, mucositis and skin toxicity, did not differ significantly between treatment groups.
Olmi (2003) found that the prevalence of grade ≥ 3 acute toxic effects related to radiotherapy did not differ significantly between patients treated with standard fractionated radiotherapy combined with carboplatin and 5-FU, and patients treated with standard fractionated radiotherapy alone, except for mucositis (48% versus 15%; p = 0.0003) and skin toxicity (16% versus 4%; p = 0.0461). Grade ≥ 3 acute toxic effects related to chemotherapy included leukopenia (23% of patients), thrombocytopenia (5%), anemia (2%), anorexia (2%), and 1 fatal case of renal toxicity (1%). The prevalence of grade ≥ 3 late toxic effects related to radiotherapy during 2 year follow-up, including mucositis, skin toxicity, subcutaneous tissue fibrosis, xerostomia, spinal cord toxicity and laryngeal toxicity, did not differ significantly between treatment groups.
Staar (2001) found that mucositis was the main grade ≥ 3 acute toxic effect. The prevalence of grade ≥ 3 mucositis during treatment was higher among patients treated with hyperfractionated accelerated radiotherapy combined with carboplatin and 5-FU, compared with patients treated with hyperfractionated accelerated radiotherapy alone (68% versus 52%; p = 0.01). The prevalence of grade ≥ 3 skin toxicity (30% versus 28%) and grade ≥ 3 hematological toxic effects, including leukopenia (18% versus 0%) and thrombocytopenia (5% versus 0%), was also higher in the intervention group, but p-values are not reported and could not be calculated based on the data provided. Grade ≥ 3 anemia occurred less frequently in patients treated with hyperfractionated accelerated radiotherapy combined with carboplatin and 5-FU (1% versus 0%), but it is unclear whether this result was statistically significant. Late toxic effects were reported for the total study population (Staar, 2001) or for all grades together (Semrau, 2006), except for swallowing problems and continuous use of a feeding tube, which occurred more frequently in patients treated with hyperfractionated accelerated radiotherapy combined with carboplatin and 5-FU (51% versus 25%; p = 0.02).
Quality of life
No data were reported for this outcome measure.
Level of evidence of the literature
The evidence was derived from 13 studies reporting on 9 different randomized trials. Therefore, the level of evidence for all reported outcome measures started at ‘high quality’.
1. RT + cetuximab
The level of evidence regarding the outcome measure overall survival was downgraded by 3 levels because of study limitations (-1; risk of bias due to active role of sponsor in collecting and analyzing the data); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to reporting of results from a single RCT and upper boundary of confidence interval exceeding the threshold of minimal clinically important difference). Inconsistency and publication bias could not be assessed.
The level of evidence regarding the outcome measure progression-free survival was downgraded by 3 levels because of study limitations (-1; risk of bias due to active role of sponsor in collecting and analyzing the data); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to reporting of results from a single RCT). Inconsistency and publication bias could not be assessed.
The level of evidence regarding the outcome measure quality of life was downgraded by 3 levels because of study limitations (-1; risk of bias due to active role of sponsor in collecting and analyzing the data); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to reporting of results from a single RCT). The level of evidence was not downgraded because of study limitations (i.e., active role of sponsor in collecting and analyzing the data), because no minimal clinically important difference in quality of life was observed between treatment groups. Inconsistency and publication bias could not be assessed.
The level of evidence regarding the outcome measure adverse events was downgraded by 3 levels because of study limitations (-1; risk of bias due to active role of sponsor in collecting and analyzing the data); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to reporting of results from a single RCT). Inconsistency and publication bias could not be assessed.
The level of evidence regarding the outcome measures local recurrence and disease-free survival could not be assessed, because the included studies did not report these outcome measures.
2. RT + carboplatin
The level of evidence regarding the outcome measure overall survival was downgraded by 4 levels because of study limitations (-2; risk of bias due to incomplete reporting, imbalanced study population in Ruo Redda (2010), and premature termination of Jeremic (1997)); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to low number of included patients per individual study). Publication bias could not be assessed.
The level of evidence regarding the outcome measure disease-free survival was downgraded by 4 levels because of risk of bias (-2; due to incomplete reporting and imbalanced study population); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to low number of included patients in a single RCT). Inconsistency and publication bias could not be assessed.
The level of evidence regarding the outcome measure adverse events was downgraded by 5 levels because of study limitations (-2; risk of bias due to incomplete reporting, imbalanced study population in Ruo Redda (2010), and premature termination of Jeremic (1997)); inconsistency (-1; due to conflicting results); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to low number of included patients per individual study). Publication bias could not be assessed.
The level of evidence regarding the outcome measures local recurrence, progression-free survival and quality of life could not be assessed, because the included studies did not report these outcome measures.
3. RT + carboplatin and 5-FU
The level of evidence regarding the outcome measure overall survival was downgraded by 4 levels because of study limitations (-2; risk of bias due to incomplete reporting, imbalanced study population in Chitapanarux (2013), and premature termination of Chitapanarux (2013) and Olmi (2003)); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin and use of different radiotherapy regimens); and imprecision (-1; due to low number of included patients in most studies). Publication bias could not be assessed.
The level of evidence regarding the outcome measure local recurrence was downgraded by 3 levels because of study limitations (-1; risk of bias due to incomplete reporting); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to low number of included patients in a single RCT). Inconsistency and publication bias could not be assessed.
The level of evidence regarding the outcome measure disease-free survival was downgraded by 3 levels because of study limitations (-1; risk of bias due to incomplete reporting); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin); and imprecision (-1; due to low number of included patients per individual study). Inconsistency and publication bias could not be assessed.
The level of evidence regarding the outcome measure progression-free survival was downgraded by 2 levels because of indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin and use of different radiotherapy regimens); and imprecision (-1; due to reporting of results from a single RCT). Inconsistency and publication bias could not be assessed.
The level of evidence regarding the outcome measure adverse events was downgraded by 5 levels because of study limitations (-2; risk of bias due to incomplete reporting, imbalanced study population in Chitapanarux (2013), and premature termination of Chitapanarux (2013) and Olmi (2003)); inconsistency (-1; due to conflicting results); indirectness (-1; due to study population not involving patients who are ineligible to receive cisplatin and use of different radiotherapy regimens); and imprecision (-1; due to low number of included patients in most studies). Publication bias could not be assessed.
The level of evidence regarding the outcome measure quality of life could not be assessed, because the included studies did not report this outcome measure .
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question:
What are the (un)beneficial effects of definitive radiotherapy combined with cetuximab, carboplatin or carboplatin and fluorouracil (5-FU), compared with definitive radiotherapy alone, in patients with a locally advanced squamous cell carcinoma in the head and neck region who are ineligible to receive cisplatin?
P: Patients with a locally advanced squamous cell carcinoma in the head and neck region who are ineligible to receive cisplatin.
I: Definitive radiotherapy combined with cetuximab, carboplatin or carboplatin and 5-FU.
C: Definitive radiotherapy alone.
O: Overall survival, local recurrence, disease-free survival, progression-free survival, quality of life, adverse events.
Relevant outcome measures
The guideline development group considered overall survival and local recurrence as critical outcome measures for decision making; and disease-free survival, progression-free survival, quality of life, and adverse events as important outcome measures for decision making.
A priori, the working group did not define the outcome measures listed above but, instead, used the definitions used in the studies.
The working group defined a minimal clinically important difference as follows:
- Overall survival: absolute difference > 5%, or absolute difference > 3% and hazard ratio (HR) < 0.7.
- Local recurrence: 0.8 or 1.25 as borders for risk or odds ratios.
- Disease-free survival: absolute difference > 5%, or absolute difference > 3% and HR < 0.7.
- Progression-free survival: absolute difference > 5%, or absolute difference > 3% and HR < 0.7.
- Quality of life: absolute difference ≥ 10 points on the EORTC QLQ-C30 or a difference of a similar magnitude on other disease-specific quality of life questionnaires.
- Adverse events: statistically significant difference in grade ≥ 3 adverse event rate.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms for systematic reviews published until November 12, 2020. The detailed search strategy is depicted under the tab Methods. Studies were selected if they fulfilled the following criteria: (a) patients with a locally advanced squamous cell carcinoma in the head and neck region; (b) comparison between definitive radiotherapy combined with cetuximab, carboplatin or carboplatin and 5-FU, and definitive radiotherapy alone. Studies were excluded if they only included patients with HPV-positive oropharyngeal cancer, because treatment options for this group of patients are described in a separate module. This search resulted in unique 296 hits. Based on title and abstract screening, 40 studies were initially selected. After reading the full text, all 40 studies were excluded. A table with reasons for exclusion is presented under the tab Methods. One of the excluded reviews (Iocca (2018)) compared several interventions based on a network meta-analysis of 57 RCTs, of which 7 RCTs were relevant for the current clinical question. Similarly, another 5 RCTs were identified via other excluded reviews.
To update the search performed by Iocca (2018) up to 1 September 2017, we searched for relevant RCTs published from 2017 until 18 October 2021. This search resulted in 452 hits. Based on title and abstract screening, 40 studies were initially selected. After reading the full text, all 40 studies were excluded (see table with reasons for exclusion).
Results
Via an excluded systematic review and network meta-analysis (Locca, 2018), 7 relevant studies (Bourhis, 2012; Bonner, 2010; Chitapanarux, 2013; Denis, 2004; Fountzilas, 2004; Ruo Redda, 2010 and Semrau, 2006) were included in the analysis of the literature. In addition, 6 relevant studies (Bonner, 2006; Curran, 2007; Calais, 1999; Jeremic, 1997; Olmi, 2003 and Staar, 2001) were identified via other excluded systematic reviews. Together, these 13 studies report the results of 9 different randomized trials. Studies that focused on the effects of definitive radiotherapy combined with either cetuximab (Bonner, 2006; Bonner, 2010 and Curran, 2007), carboplatin (Fountzilas, 2004; Jeremic, 1997 and Ruo Redda, 2010) or carboplatin and 5-FU (Bourhis, 2012; Calais, 1999; Chitapanarux, 2013; Denis, 2004; Olmi, 2003; Semrau, 2006 and Staar, 2001), compared with definitive radiotherapy alone, are analyzed separately. 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
- Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006 Feb 9;354(6):567-78. doi: 10.1056/NEJMoa053422. PMID: 16467544.
- Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010 Jan;11(1):21-8. doi: 10.1016/S1470-2045(09)70311-0. PMID: 19897418.
- Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012 Feb;13(2):145-53. doi: 10.1016/S1470-2045(11)70346-1. PMID: 22261362.
- Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999 Dec 15;91(24):2081-6. doi: 10.1093/jnci/91.24.2081. PMID: 10601378.
- Curran D, Giralt J, Harari PM, Ang KK, Cohen RB, Kies MS, Jassem J, Baselga J, Rowinsky EK, Amellal N, Comte S, Bonner JA. Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol. 2007 Jun 1;25(16):2191-7. doi: 10.1200/JCO.2006.08.8005. Erratum in: J Clin Oncol. 2007 Aug 20;25(24):3790. PMID: 17538164.
- Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol. 2004 Jan 1;22(1):69-76. doi: 10.1200/JCO.2004.08.021. PMID: 14657228.
- Fountzilas G, Ciuleanu E, Dafni U, et al. Concomitant radiochemotherapy versus radiotherapy alone in patients with head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study. Med Oncol. 2004;21(2):95-107. doi: 10.1385/MO:21:2:095. PMID: 15299181.
- Gillison ML, Trotti AM, Harris J, Eisbruch A, Harari PM, Adelstein DJ, Jordan RCK, Zhao W, Sturgis EM, Burtness B, Ridge JA, Ringash J, Galvin J, Yao M, Koyfman SA, Blakaj DM, Razaq MA, Colevas AD, Beitler JJ, Jones CU, Dunlap NE, Seaward SA, Spencer S, Galloway TJ, Phan J, Dignam JJ, Le QT. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019 Jan 5;393(10166):40-50. doi: 10.1016/S0140-6736(18)32779-X. Epub 2018 Nov 15. PMID: 30449625.
- Iocca O, Farcomeni A, Di Rocco A, et al. Locally advanced squamous cell carcinoma of the head and neck: a systematic review and Bayesian network meta-analysis of the currently available treatment options. Oral Oncol. 2018 May;80:40-51. doi: 10.1016/j.oraloncology.2018.03.001. PMID: 29706187.
- Jeremic B, Shibamoto Y, Stanisavljevic B, Milojevic L, Milicic B, Nikolic N. Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. Radiother Oncol. 1997 Apr;43(1):29-37. doi: 10.1016/s0167-8140(97)00048-0. PMID: 9165134.
- Lacas B, Carmel A, Landais C, Wong SJ, Licitra L, Tobias JS, Burtness B, Ghi MG, Cohen EEW, Grau C, Wolf G, Hitt R, Corvò R, Budach V, Kumar S, Laskar SG, Mazeron JJ, Zhong LP, Dobrowsky W, Ghadjar P, Fallai C, Zakotnik B, Sharma A, Bensadoun RJ, Ruo Redda MG, Racadot S, Fountzilas G, Brizel D, Rovea P, Argiris A, Nagy ZT, Lee JW, Fortpied C, Harris J, Bourhis J, Aupérin A, Blanchard P, Pignon JP; MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 107 randomized trials and 19,805 patients, on behalf of MACH-NC Group. Radiother Oncol. 2021 Mar;156:281-293. doi: 10.1016/j.radonc.2021.01.013. Epub 2021 Jan 27. PMID: 33515668; PMCID: PMC8386522.
- Mehanna H, Robinson M, Hartley A, Kong A, Foran B, Fulton-Lieuw T, Dalby M, Mistry P, Sen M, O'Toole L, Al Booz H, Dyker K, Moleron R, Whitaker S, Brennan S, Cook A, Griffin M, Aynsley E, Rolles M, De Winton E, Chan A, Srinivasan D, Nixon I, Grumett J, Leemans CR, Buter J, Henderson J, Harrington K, McConkey C, Gray A, Dunn J; De-ESCALaTE HPV Trial Group. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019 Jan 5;393(10166):51-60. doi: 10.1016/S0140-6736(18)32752-1. Epub 2018 Nov 15. PMID: 30449623.
- Olmi P, Crispino S, Fallai C, et al. Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and chemotherapy--a multicenter randomized trial. Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):78-92. doi: 10.1016/s0360-3016(02)03792-6. PMID: 12504039.
- Ruo Redda MG, Ragona R, Ricardi U, et al. Radiotherapy alone or with concomitant daily low-dose carboplatin in locally advanced, unresectable head and neck cancer: definitive results of a phase III study with a follow-up period of up to ten years. Tumori. Mar-Apr 2010;96(2):246-53. PMID: 20572581.
- Semrau R, Mueller RP, Stuetzer H, et al. Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: updated results of a randomized multicentric trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2006 Apr 1;64(5):1308-16. doi: 10.1016/j.ijrobp.2005.10.039. PMID: 16464538.
- Staar S, Rudat V, Stuetzer H, et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1161-71. doi: 10.1016/s0360-3016(01)01544-9. PMID: 11483325.
Evidence tabellen
Evidence table for intervention studies
Study reference |
Study characteristics |
Patient characteristics |
Intervention (I) |
Comparison/control (C) |
Follow-up |
Outcome measures and effect size |
Comments |
1. Radiotherapy + cetuximab |
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Bonner (2006, 2010), Curran (2007) |
Type of study: Multicenter, randomized phase III trial
Setting and country: 73 centers in the US and 14 other countries (Spain, UK, South Africa, Poland, Belgium, France, Switzerland, Australia, Italy, Israel, New Zealand, Sweden, Germany, Netherlands)
Source of funding: This study was funded by ImClone Systems, Bristol-Myers Squibb, and Merck KGaA.
Conflicts of interest: Several authors report having been employed by and owning equity or stock options in the sponsors of this study (ImClone Systems). Another author is employed by a sponsor of this study (Merck). Several authors report having received consulting fees, having served on paid advisory boards, or having received lecture fees from ImClone Systems, Merck, or Bristol-Myers Squibb. One author has laboratory research support from ImClone Systems. The study was designed by ImClone Systems and the study chairman in collaboration with the lead investigators and was managed by ImClone Systems and Merck. ImClone Systems collected and analyzed the data. The article was written by the study chairman with assistance from the other authors. |
Patients with locoregionally advanced squamous-cell carcinoma of the head and neck
Inclusion criteria:
Exclusion criteria:
N total at baseline: Randomized: N = 424 I: N = 211 C: N = 213 Safety population: N = 420 I: N = 208 C: N = 212
Important characteristics: Age, median (range) I: 56 y (34-81) C: 58 y (35-83)
Sex, n/N (%) male I: 171/211 (81%) C: 169/213 (79%)
Karnofsky performance score 60 I: 6/211 (3%) C: 6/213 (3%)
70 I: 15/211 (7%) C: 16/213 (8%)
80 I: 42/211 (20%) C: 49/213 (23%)
90 I: 113/211 (54%) C: 103/213 (49%)
100 I: 34/211 (16%) C: 38/213 (18%)
Primary tumor site Oropharynx I: 118/211 (56%) C: 135/213 (63%)
Larynx I: 57/211 (27%) C: 51/213 (24%)
Hypopharynx I: 36/211 (17%) C: 27/213 (13%)
Groups were comparable at baseline. |
High-dose radiotherapy* + cetuximab (120-min infusion at an initial dose of 400 mg/m2, followed by weekly 60-min infusions of 250 mg/m2 for the duration of radiotherapy) |
High-dose radiotherapy* |
Length of follow-up: Bonner (2006): median 54 months
Curran (2007): 12 months
Bonner (2010): median 60 months
Loss to follow-up or missing outcome data: Bonner (2006): not reported
Curran (2007): I: 4/211 (2%) Reasons:
C: 1/213 (< 1%) Reason:
Bonner (2010): I: 4/211 (2%) C: 4/213 (2%)
Reasons for loss to follow-up are not reported. |
Based on subgroup analyses, cetuximab seemed to provide the most benefit for patients with oropharyngeal tumours.
Clinical outcomes Overall survival Months, median I: 49.0 (95%CI: 32.8-69.5) C: 29.3 (95%CI: 20.6-41.4) HR 0.74 (95%CI: 0.57-0.97)
Overall survival at 3 years I: 55% C: 45%
Overall survival at 5 years I: 46% C: 36% HR 0.73 (95%CI: 0.56-0.95)
Progression-free survival Months, median (range) I: 17.1 C: 12.4 HR 0.70 (95%CI: 0.54-0.90)
Progression-free survival at 2 years I: 46% C: 37%
Progression-free survival at 3 years I: 42% C: 31% p = 0.04
Quality of life† There were no significant differences in QoL scores between the treatment arms. This was particularly notable for global health status/QoL, social functioning, social eating, and social contact.
Safety Acute toxic effects grade ≥ 3 Mucositis I: 116/208 (56%) C: 110/212 (52%) p = 0.44
Acneiform rash I: 35/208 (17%) C: 3/212 (1%) p < 0.001
Skin reaction I: 73/208 (35%) C: 45/212 (21%) p < 0.05
Radiation dermatitis I: 23% C: 18% p = 0.27
Weight loss I I: 11% C: 7% p = 0.12
Xerostomia I: 10/208 (5%) C: 6/212 (3%) p = 0.32
Dysphagia I: 54/208 (26%) C: 63/212 (30%) p = 0.45
Asthenia I: 4% C: 5% p = 0.64
Nausea I: 2% C: 2% p = 1.00
Constipation I: 5% C: 5% p = 1.00
Taste perversion I: 0% C: 0% p = 1.00
Vomiting I: 2% C: 4% p = 0.42
Pain I: 6% C: 7% p = 0.84
Anorexia I: 2% C: 2% p = 1.00
Fever I: 1% C: 1% p = 1.00
Pharyngitis I: 3% C: 4% p = 0.80
Dehydration I: 6% C: 8% p = 0.57
Oral candidiasis I: 0% C: 0% p = 1.00
Coughing I: < 1% C: 0% p = 0.50
Voice alteration I: 2% C: 0% p = 0.06
Diarrhea I: 2% C: 1% p = 0.50
Headache I: < 1% C: < 1% p = 1.00
Pruritus I: 0% C: 0% p = 1.00
Infusion reaction I: 6/208 (3%) C: 0/212 (0%) p = 0.01
Insomnia I: 0% C: 0% p = 1.00
Dyspepsia I: 0% C: 1% p = 0.50
Increased sputum I: < 1 % C: 1% p = 0.62
Infection I: 1% C: 1% p = 1.00
Anxiety I: < 1% C: 1% p = 1.00
Chills I: 0% C: 0% p = 1.00
Anemia I: 1% C: 6% p = 0.006
Late toxic effects grade ≥ 3 Severe late effects related to radiation were reported in about 20% of the patients in each group. The sites most commonly affected were the esophagus, salivary glands, larynx, mucous membranes, subcutaneous tissues, bone, and skin. |
Definitions: * Radiotherapy regimens included:
Uninvolved nodal areas of the neck were treated with 50 to 54 Gy, depending on the fractionation regimen used. Gross nodal disease received the same dose as the primary tumor. If, at registration, an investigator stipulated the need for neck dissection in patients with N2 or N3 disease of the neck (with such dissection formally recommended to take place 4 to 8 weeks after the completion of radiotherapy), the dose administered to the involved lymph nodes was 60 Gy. In the case of uncontrollable pain, a maximum of 2 five-day treatment breaks were allowed.
† The EORTC QLQ-C30 (version 3.0) and the QLQ-H&N35 instruments were used to assess QoL. For the QLQ-C30, 15 scales were derived from the initial 30 items: 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea and vomiting, pain), 6 single-item symptom scales (dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties), and 1 global health status/QoL scale. For the QLQ-H&N35, 18 scales were derived from the initial 35 items: 7 multi-item symptom scales (pain, swallowing, sensation, speech, eating from a social perspective, social interactions, and sexuality) and 11 single-item symptom scales (teeth, opening mouth, dry mouth, sticky saliva, coughing, felt ill, pain medication use, nutritional supplementation, feeding tube requirement, weight loss, and weight gain).
Remarks: For patients with locoregionally advanced squamous-cell carcinoma of the head and neck, cetuximab plus radiotherapy significantly improves overall survival at 5 years compared with radiotherapy alone, confirming cetuximab plus radiotherapy as an important treatment option in this group of patients. Cetuximab-treated patients with prominent cetuximab-induced rash (grade 2 or above) have better survival than patients with no or grade 1 rash.
Authors conclusion: Bonner (2006): Cetuximab plus radiotherapy is superior to radiotherapy alone in increasing both the duration of locoregional disease control and survival in locoregionally advanced head and neck cancer.
Curran (2007): The addition of cetuximab to radiotherapy significantly improved locoregional control and increased overall survival without adversely affecting quality of life.
Bonner (2010): Cetuximab plus radiotherapy is superior to radiotherapy alone in increasing both the duration of locoregional disease control and survival in locoregionally advanced head and neck cancer. |
2. Radiotherapy + carboplatin |
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Fountzilas (2004) |
Type of study: Multicenter, randomized phase III trial
Setting and country: 2 hospitals in Greece, 1 hospital in Romania, 1 hospital in Germany
Source of funding: Supported in part by Hellenic Cooperative Oncology Group research grant.
Conflicts of interest: Not reported. |
Patients with locally advanced non-nasopharyngeal head and neck cancer
Inclusion criteria:
Exclusion criteria: Not reported.
N total at baseline: Randomized: N = 79 I: N = 38 C: N = 41
Important characteristics: Age, median (range) I: 53 y (31-71) C: 58 y (40-78)
Sex, n/N (%) male I: 29/38 (76%) C: 36/41 (88%)
Performance status 0 I: 24/38 (63%) C: 22/41 (54%)
1 I: 13/38 (34%) C: 15/41 (37%)
2 I: 1/38 (3%) C: 2/41 (5%)
Primary tumor site Larynx I: 15/38 (39%) C: 18/41 (44%)
Oropharynx I: 12/38 (32%) C: 14/41 (34%)
Hypopharynx I: 4/38 (10%) C: 5/41 (12%)
Oral cavity I: 7/38 (18%) C: 4/41 (10%)
There were no significant differences in major patient or tumor characteristics between the treatment groups. |
Standard fractionated radiotherapy* (total dose of 70 Gy at 1.8 Gy/fraction per day, 5 days/wk) + carboplatin (AUC of 7 on days 2, 22 and 42) |
Standard fractionated radiotherapy* (total dose of 70 Gy at 1.8 Gy/fraction per day, 5 days/wk) |
Length of follow-up: Median 5 years (range: 0.02-7.2+)
Loss to follow-up or missing outcome data: I: 2/38 (5%) C: 1/41 (2%)
Reasons for loss to follow-up are not reported. |
Clinical outcomes Overall survival Months, median (range) I: 24.5 (0.2-79.9) C: 12.2 (1.2-81.7)
Median overall survival curves were compared using the log-rank test: p = 0.0064
Overall survival at 3 years I: 42% C: 17.5%
Overall survival at 5 years I: 38% C: 9%
Overall survival curves were compared using the log-rank test: p < 0.001
Safety Adverse events grade ≥ 3 Anemia I: 3/38 (8%) C: 0/40 (0%) p ≥ 0.05
Leukopenia I: 7/38 (18%) C: 1/40 (3%) p ≥ 0.05
Neutropenia I: 1/38 (3%) C: 1/40 (3%) p ≥ 0.05
Thrombocytopenia I: 10/38 (26%) C: 0/40 (0%) p = 0.0004
Nausea/vomiting I: 6/38 (16%) C: 0/40 (0%) p = 0.0107
Stomatitis I: 7/38 (18%) C: 13/40 (33%) p ≥ 0.05
Diarrhea I: 0/40 (0%) C: 1/40 (3%) p ≥ 0.05
Mouth dryness I: 1/38 (3%) C: 0/40 (0%) p ≥ 0.05
Dermatitis I: 0/40 (0%) C: 1/40 (3%) p ≥ 0.05
Hoarseness I: 1/38 (3%) C: 1/40 (3%) p ≥ 0.05
Dysphagia I: 3/38 (8%) C: 2/40 (5%) p ≥ 0.05
Neurotoxicity I: 1/38 (3%) C: 0/40 (0%) p ≥ 0.05
Weight loss I: 2/38 (5%) C: 3/40 (8%) p ≥ 0.05
Infection I: 1/38 (3%) C: 0/40 (0%) p ≥ 0.05 |
Definitions: * RT was delivered using linear accelerator or cobalt-60 unit with a source-to-surface or source-to-isocenter distance ≥ 80 cm. A total dose of 70 Gy was given using standard fractionatron at 1.8 Gy/fraction/d, 5 d/week. In lateral opposing fields, dose was specified at midplane, while in the anterior field, dose was calculated at 3 cm depth. The clinically uninvolved areas received 50 Gy, while enlarged lymph nodes were irradiated with an additional boost of 20 Gy. The primary treatment fields were reduced off the spinal cord at 50 Gy.
Remarks: -
Authors conclusion: The present study clearly demonstrated that concomitant conventional radiotherapy and carboplatin, given in a 3-wk schedule, significantly improved 3-yr survival and locoregional control as compared to that achieved by conventional radiotherapy alone. This survival benefit was accompanied by considerable incidence of severe toxicity, mainly myelotoxicity and nausea/vomiting. |
Jeremic (1997) |
Type of study: Single-center, randomized trial
Setting and country: Yugoslavia
Source of funding: Not reported.
Conflicts of interest: Not reported. |
Patients with locally advanced, unresectable head and neck cancer
Inclusion criteria:
Exclusion criteria: Not reported.
N total at baseline: Randomized: N = 106 I: N = 53 C: N = 53
Important characteristics: Age, median (range) I: 58 y (34-68) C: 59 y (35-70)
Sex, n/N (%) male I: 45/53 (85%) C: 43/53 (81%)
Performance status 80-100 I: 40/53 (75%) C: 37/53 (70%)
50-70 I: 13/53 (25%) C: 16/53 (25%)
Primary tumor site Oral cavity I: 8/53 (15%) C: 9/53 (17%)
Oropharynx I: 20/53 (38%) C: 21/53 (40%)
Larynx I: 9/53 (17%) C: 8/53 (15%)
Hypopharynx I: 10/53 (19%) C: 10/53 (19%) Nasopharynx I: 6/53 (11%) C: 5/53 (9%)
Groups were comparable at baseline. |
Standard fractionated radiotherapy* (total dose of 70 Gy at 1.8-2.0 Gy/fraction per day, 5 days/wk) + carboplatin (bolus of 25 mg/m2 infused daily 45-60 min before irradition) |
Standard fractionated radiotherapy* (total dose of 70 Gy at 1.8-2.0 Gy/fraction per day, 5 days/wk) |
Length of follow-up: Not reported.
Loss to follow-up or missing outcome data: 3 patients were lost to follow-up immediately after the treatment completion, but were included in the final analysis, excluding that of the late treatment-related toxicity. However, it is unclear to what treatment group these patients were allocated. |
Clinical outcomes Overall survival Months, median I: 30 C: 16
Overall survival at 1 year I: 76% C: 57%
Overall survival at 2 years I: 55% C: 35%
Overall survival at 3 years I: 47% C: 27%
Overall survival at 4 years I: 31% C: 17%
Overall survival at 5 years I: 29% C: 15%
Overall survival curves were compared using the log-rank test: p = 0.019
Safety Acute toxic effects grade ≥ 3 Stomatitis I: 7/53 (13%) C: 5/53 (9%) p ≥ 0.05
Xerostomia I: 1/53 (2%) C: 3/53 (6%) p ≥ 0.05
Esophagitis I: 2/53 (4%) C: 2/53 (4%) p ≥ 0.05
Nausea/vomiting I: 1/53 (2%) C: 0/53 (0%) p ≥ 0.05
Nephrotoxicity I: 0/53 (0%) C: 0/53 (0%) p = 1.00
Leukopenia I: 6/53 (11%) C: 0/53 (0%) p = 0.012
Thrombocytopenia I: 4/53 (8%) C: 0/53 (0%) p = 0.041
Late toxic effects grade ≥ 3 Subcutaneous tissue I: 1/51 (2%) C: 1/51 (2%) p = 1.00
Bone I: 1/51 (2%) C: 1/51 (2%) p = 1.00
Skin I: 1/51 (2%) C: 1/51 (2%) p = 1.00 |
Definitions: * RT was employed with 6-10 MV photons from linear accelerators. The target volume included the primary tumor, the lymph nodes of the neck and supraclavicular fossa. The tumor bearing area received 70 Gy and uninvolved neck and supraclavicular nodes received 45 Gy. Daily fractions of 1.8-2.0 Gy were used five times a week. The primary tumor and upper neck nodes were treated with two lateral opposed fields with 45 Gy in 5 weeks after which reduced lateral fields were used to boost the primary and the involved nodes to 70 Gy in 7-7.5 weeks. The dose to the spinal cord was kept at 45 Gy. The uninvolved lower neck and supraclavicular nodes were treated with a single anterior field, starting 0.5 cm below the lateral fields and with a total dose of 45 Gy at 3-3.5 cm depth in 5 weeks with apical lung shield. All fields were treated every day.
Remarks: Initially, 85 patients were thought to be required per arm to detect a difference in the 3-year survival rate of 20% with a significance level of P < 0.05 and a power of 0.8 assuming a baseline survival rate of 25%. However, the study ended in December 1990 before the patient accrual had reached this number, because the chief investigator had to leave the department at this time.
Authors conclusion: This rather small, single-institutional study showed promising results and acceptable toxicity in patients with heterogenous head and neck subsites treated with standard fraction radiotherapy and concurrent low-dose daily carboplatin over that obtained with the same radiotherapy given alone. Improvement in survival was due to the improvement in local tumor control that was significantly superior for the intervention group attributed to the effect of carboplatin when given daily during radiotherapy, as in this schedule. |
Ruo Redda (2010) |
Type of study: Multicenter, randomized phase III trial
Setting and country: 6 centers in Italy
Source of funding: Not reported.
Conflicts of interest: Not reported. |
Patients with locally advanced, unresectable head and neck cancer
Inclusion criteria:
Exclusion criteria: Not reported.
N total at baseline: Randomized: N = 164 I: N = 82 C: N = 82
Important characteristics: Age, median (range) I: 58 y (39-70) C: 61 y (40-70)
Sex, n/N (%) male I: 66/73 (90%) C: 63/72 (88%)
Performance status 0 I: 47/73 (64%) C: 30/72 (42%)
1 I: 18/73 (25%) C: 33/72 (46%)
2 I: 8/73 (11%) C: 9/72 (13%)
Primary tumor site Oral cavity I: 14/73 (19%) C: 14/72 (19%)
Oropharynx I: 42/73 (58%) C: 39/72 (54%)
Larynx I: 9/73 (12%) C: 12/72 (14%)
Hypopharynx I: 8/73 (11%) C: 7/72 (10%)
Groups were comparable at baseline, except for ECOG performance status. The percentage of patients with an ECOG performance status of 1 was higher in the control group, whereas the percentage of patients with an ECOG performance status of 0 was higher in the intervention group. |
Standard fractionated radiotherapy* (total dose of 70 Gy at 2 Gy/fraction, 5 days/wk) + carboplatin (bolus of 45 mg/m2 infused 45-60 min before irraditation, on days 1-5 of weeks 1, 3, 5 and 7; total dose of 900 mg/m2) |
Standard fractionated radiotherapy* (total dose of 70 Gy at 2 Gy/fraction, 5 days/wk) |
Length of follow-up: Median 26.2 months (range: 6.2-169.5)
Loss to follow-up or missing outcome data: None. |
Clinical outcomes Overall survival at 3 years I: 28.9% C: 11.1%
Overall survival at 5 years I: 9% C: 6.9%
Overall survival at 10 years I: 5.5% C: 6.9%
Overall survival curves were compared using the log-rank test: p = 0.02
Disease-free survival at 3 years I: 16% C: 9%
Disease-free survival at 5 years I: 6.8% C: 5.5%
Disease-free survival at 10 years I: 6.8% C: 5.5%
Disease-free survival curves were compared using the log-rank test: p = 0.09
Safety Acute toxic effects grade ≥ 3 Anemia I: 3/73 (4%) C: 0/72 (0%) p ≥ 0.05
Leukopenia I: 7/73 (10%) C: 0/72 (0%) p ≥ 0.05
Thrombocytopenia I: 0/73 (0%) C: 0/72 (0%) p = 1.00
Mucositis I: 10/73 (14%) C: 9/72 (13%) p ≥ 0.05
Late toxic effects grade ≥ 3 The prevalence of late toxic effects was similar between treatment groups, except for severe neck fibrosis, which occurred more frequently in patients treated with radiotherapy and carboplatin (7 versus 3 cases). One patient treated with radiotherapy and carboplatin developed necrosis of the mandibular bone. No radiation myelitis or toxic-related death was observed in either treatment group. |
Definitions: * Radiotherapy was delivered by the use of cobalt-60 gamma rays or 6 MV photons and with electron beams to give a boost to the posterior cervical lymph nodes. The planned total radiation dose was 70 Gy to the involved areas given with a conventional fractionated schedule of 2 Gy/die, 5 fractions/week. Each patient was simulated before treatment, and field sizes were individualized using custom blocking to spare normal tissues. The primary tumor and upper neck nodes were treated with two opposed lateral fields; at the dose of 42 Gy, the lateral fields were reduced for spinal cord protection. Dose variation across the tumor target volume in the central plane was limited to 10% of the prescribed dose, from minimum to maximum, whenever possible. The uninvolved lower neck and supraclavicular nodal regions were treated with a single anterior field with a total dose of 54 Gy, using apical lung shields. A central block was used, when required.
Remarks: -
Authors conclusion: Long-term results in both treatment arms of the trial appear less positive than most published series. However, our findings do not exclude that carboplatin may be beneficial, but the benefit in local control must be lower than the 15% assumed to dimension the trial. |
3. Radiotherapy + carboplatin and 5-FU |
|||||||
Bourhis (2012)
(GORTEC 99-02 trial) |
Type of study: Multicenter, open-label, randomized phase III trial
Setting and country: 22 university hospitals, cancer centers, and private hospitals in France and Belgium
Source of funding: French Ministry of Health. The sponsor of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Conflicts of interest: The authors declare that they have no conflicts of interest. |
Patients with locally advanced head and neck squamous-cell carcinoma
Inclusion criteria:
Exclusion criteria: Not reported.
N total at baseline: Randomized: N = 840 I1: N = 279 I2: N = 280 C: N = 281
Important characteristics: Age, mean (SD, range) I1: 56.1 y (7.7, 39-77) I2: 56.9 (8.2, 37-75) C: 56.5 y (8.6, 34-74)
Sex, n/N (%) male I1: 244/279 (87%) I2: 245/280 (88%) C: 242/281 (86%)
Primary tumor site No primary I1: 244/279 (87%) I2: 245/280 (88%) C: 242/281 (86%)
Oropharynx I1: 244/279 (87%) I2: 245/280 (88%) C: 242/281 (86%)
Oral cavity I1: 244/279 (87%) I2: 245/280 (88%) C: 242/281 (86%)
Hypopharynx I1: 244/279 (87%) I2: 245/280 (88%) C: 242/281 (86%)
Larynx I1: 244/279 (87%) I2: 245/280 (88%) C: 242/281 (86%)
Groups were comparable at baseline, except for ECOG performance status. The percentage of patients with an ECOG performance status of 1 was higher in the control group, whereas the percentage of patients with an ECOG performance status of 0 was higher in the intervention group. |
Intervention 1: Standard fractionated radiotherapy* (total dose of 70 Gy in 7 wk at 5 fractions of 2 Gy per wk, with spinal cord exclusion at 40 Gy) + carboplatin (70 mg/m² per day on day 1-4, day 22-25 and day 43-46) and fluorouracil (600 mg/m² per day on day 1-4, day 22-25 and day 43-46)
Intervention 2: Accelerated radiotherapy* (total dose of 70 Gy in 6 wk at 5 fractions of 2 Gy per wk until 40 Gy, with spinal cord exclusion at 40 Gy, followed by 1.5 Gy per fraction twice daily for 5 days/wk for the remaining 30 Gy) + carboplatin (70 mg/m² per day on day 1-5 and day 29-33) and fluorouracil (600 mg/m² per day on day 1-5 and day 29-33) |
Very accelerated radiotherapy* (total dose of 64.8 Gy in 3.5 wk at 1.8 Gy per fraction twice daily for 5 days/wk, with spinal cord exclusion at 34.2 Gy) |
Length of follow-up: Median 5.2 years (range: 0.4-9.5; IQR: 4.9-6.2)
Loss to follow-up or missing outcome data: I1: 1 patient had ≤ 3 years follow-up, 278 patients had > 3 years follow-up I2: 4 patients had ≤ 3 years follow-up, 276 patients had > 3 years follow-up C: 1 patient had ≤ 3 years follow-up, 280 patients had > 3 years follow-up
It is not reported why 6 patients were followed up for less than 3 years. |
Clinical outcomes Overall survival at 3 years I1: 42.6% (95%CI: 37.0-48.5) I2: 39.4% (95%CI: 33.8-45.3) C: 36.5% (95%CI: 31.1-42.3) I1 versus C: HR 0.81 (95%CI: 0.67-0.99) I2 versus C: HR 0.87 (95%CI: 0.72-1.06) I2 versus I1: HR 1.05 (95%CI: 0.86-1.29)
Progression-free survival at 3 years† I1: 37.6% (95%CI: 32.1-43.4) I2: 34.1% (95%CI: 28.7-39.8) C: 32.2% (95%CI: 27.0-37.9) I1 versus C: HR 0.82 (95%CI: 0.67-0.99) I2 versus C: HR 0.83 (95%CI: 0.69-1.01) I2 versus I1: HR 1.02 (95%CI: 0.84-1.23)
Safety Acute toxic effects grade ≥ 3 (during treatment) At least one acute toxic effect I1: 222/266 (83%) I2: 243/276 (88%) C: 243/274 (89%) p = 0.07
Mucositis (RTOG grading) I1: 180/262 (69%) I2: 205/271 (76%) C: 226/268 (84%) p = 0.0001
Mucositis (WHO grading) I1: 206/264 (78%) I2: 228/271 (84%) C: 237/267 (89%) p = 0.016
Skin toxicity (RTOG grading) I1: 108/260 (42%) I2: 118/268 (44%) C: 104/265 (37%) p = 0.24
Feeding tube I1: 158/265 (60%) I2: 176/276 (64%) C: 190/272 (70%) I1 versus C: p = 0.013 I2 versus C: p = 0.13 I2 versus I1: p = 0.32
All hematological toxicity (during chemotherapy) I1: 36/264 (14%) I2: 45/275 (16%) p = 0.57
Anemia (during chemotherapy) I1: 11/264 (4%) I2: 7/275 (3%) p = 0.48
Leukopenia (during chemotherapy) I1: 28/264 (11%) I2: 38/275 (14%) p = 0.55
Thrombocytopenia (during chemotherapy) I1: 10/264 (4%) I2: 13/275 (5%) p = 0.90
Late toxic effects grade ≥ 3 (during follow-up; 1-5 years) Feeding tube I1: 36% at 1 y, 16% at 2 y, 11% at 3 y, 8% at 4 y, and 13% at 5 y I2: 39% at 1 y, 17% at 2 y, 11% at 3 y, 7% at 4 y, and 6% at 5 y C: 43% at 1 y, 23% at 2 y, 18% at 3 y, 14% at 4 y, and 25% at 5 y I1 versus C: p = 0.027 I2 versus C: p = 0.092 I2 versus I1: p = 0.59
Xerostomia I1: 8% at 1 y, 10% at 2 y, 7% at 3 y, 8% at 4 y, and 4% at 5 y I2: 11% at 1 y, 6% at 2 y, 4% at 3 y, 3% at 4 y, and 7% at 5 y C: 9% at 1 y, 8% at 2 y, 8% at 3 y, 5% at 4 y, and 6% at 5 y p ≥ 0.05
Subcutaneous fibrosis I1: 5% at 1 y, 8% at 2 y, 13% at 3 y, 7% at 4 y, and 5% at 5 y I2: 5% at 1 y, 5% at 2 y, 3% at 3 y, 9% at 4 y, and 9% at 5 y C: 7% at 1 y, 7% at 2 y, 5% at 3 y, 7% at 4 y, and 6% at 5 y p ≥ 0.05
Mucosal toxicity I1: 5% at 1 y, 8% at 2 y, 5% at 3 y, 3% at 4 y, and 1% at 5 y I2: 5% at 1 y, 2% at 2 y, 0% at 3 y, 1% at 4 y, and 0% at 5 y C: 5% at 1 y, 3% at 2 y, 1% at 3 y, 1% at 4 y, and 2% at 5 y p ≥ 0.05
Laryngeal toxicity I1: 6% at 1 y, 5% at 2 y, 4% at 3 y, 3% at 4 y, and 3% at 5 y I2: 3% at 1 y, 2% at 2 y, 1% at 3 y, 0% at 4 y, and 1% at 5 y C: 5% at 1 y, 3% at 2 y, 3% at 3 y, 2% at 4 y, and 0% at 5 y p ≥ 0.05
Bone toxicity Rate of late bone toxicity did not differ between treatment groups (data not shown). |
Definitions: * We used a 4-6 MV linac and a conventional three-dimensional treatment planning system (no intensity modulated radiation therapy was done at the same time). When appropriate, cervical posterior nodes were treated with electron beams (8-12 MeV) or with oblique posterior photon beams. The prophylactic nodal irradiation dose was 45 Gy in the uninvolved neck in the very accelerated radiotherapy group and 50 Gy for the two other groups.
† Progression-free survival was defined as time between randomisation and the first of the following events: locoregional progression or relapse, distant relapse, or death from any cause (or the last follow-up contact for patients who did not have any of these events). d Remarks: -
Authors conclusion: Chemotherapy has a substantial treatment effect given concomitantly with radiotherapy and acceleration of radiotherapy cannot compensate for the absence of chemotherapy. We noted the most favourable outcomes for conventional chemoradiotherapy, suggesting that acceleration of radiotherapy is probably not beneficial in concomitant chemoradiotherapy schedules. |
Calais (1999), Denis (2004)
(GORTEC 94-01 trial) |
Type of study: Multicenter, randomized phase III trial
Setting and country: university hospitals, cancer centers, and private hospitals in France
Source of funding: French Ministry of Health.
Conflicts of interest: The authors indicated no potential conflicts of interest. |
Patients with advanced oropharynx carcinoma
Inclusion criteria:
Exclusion criteria:
N total at baseline: Randomized: N = 222 I: N = 113 C: N = 109
Important characteristics: Age, mean (range) I: 55.7 y (32-73) C: 54.4 y (34-74)
Sex, n/N (%) male I: 99/109 (91%) C: 101/113 (89%)
Karnofsky performance score 70 I: 15/109 (14%) C: 16/113 (14%)
80 I: 36/109 (33%) C: 25/113 (22%)
90-100 I: 58/109 (53%) C: 72/113 (64%)
Primary tumor site Tonsillar region I: 43/109 (39%) C: 42/113 (37%)
Base of tongue I: 40/109 (37%) C: 39/113 (34%)
Soft palate-uvula I: 12/109 (11%) C: 11/113 (10%)
Posterior wall I: 8/109 (7%) C: 7/113 (6%)
Non-classified I: 5/109 (5%) C: 4/113 (4%)
Groups were comparable at baseline, except for a slightly higher proportion of patients with N3 lymph nodes in the intervention. Also, the intervention group comprised more patients with a Karnofsky performance score of 80 and less patients with a Karnofsky performance score of 90-100 than the control group. |
Standard fractionated radiotherapy* (total dose of 70 Gy in 35 fractions at 2 Gy/fraction per day, 5 days/wk) + carboplatin (i.v. bolus of 70 mg/m² per day for 4 days) and fluorouracil (600 mg/m² per day infused continously in 24 hr for 4 days) |
Standard fractionated radiotherapy* (total dose of 70 Gy in 35 fractions at 2 Gy/fraction per day, 5 days/wk) |
Length of follow-up: Calais (1999): median 35 months (range: 12-56)
Denis (2004): median 5.5 years (range: 4-7.2)
Loss to follow-up or missing outcome data: No patient was lost to follow-up for assessment of survival. Three were lost to follow-up for the late toxicity assessment, but were free of local or distant recurrence (2 patients in intervention group and 1 patient in the control group). |
Clinical outcomes Overall survival Months, median Calais (1999): I: 29.2 C: 15.4
Denis (2004): I: 20 C: 13
Overall survival at 3 years I: 51% (95%CI: 39-68) C: 31% (95%CI: 18-49)
Overall survival curves were compared using the log-rank test: p = 0.02
Disease-free survival at 3 years I: 42% (95%CI: 30-57) C: 20% (95%CI: 10-33)
Disease-free survival curves were compared using the log-rank test: p = 0.04
Overall survival at 5 years I: 22.4% C: 15.8%
Overall survival curves were compared using the log-rank test: p = 0.05
Disease-free survival at 5 years I: 26.6% C: 14.6%
Disease-free survival curves were compared using the log-rank test: p = 0.01
Local recurrence Calais (1999): I: 36/109 (33%) C: 58/113 (51%) p = 0.0067
Denis (2004): I: 45/109 (41%) C: 66/113 (58%) p = 0.0155
Safety Acute toxic effects grade ≥ 3 Mucositis I: 71% (95%CI: 54-85) C: 39% (95%CI: 29-56) p = 0.005
Radiation dermatitis I: 67% C: 59% p = 0.02
Weight loss I: 50% C: 21% p < 0.05
Hematology Neutropenia I: 4% C: 0% p = 0.04
Thrombocytopenia I: 6% C: 1% p = 0.04
Anemia I: 3% C: 0% p = 0.05
Toxic death I: 1/109 (1%) C: 0/113 (0%)
Late toxic effects grade ≥ 3 Calais (1999): Xerostomia I: 10/109 (9%) C: 6/113 (5g%) p = 0.1
Cervical fibrosis I: 12% C: 3% p = 0.08
Bone necrosis I: 0% C: 0% p = 1.00
Radiation myelitis I: 0% C: 0% p = 1.00
Denis (2004): ≥ 1 late toxic effects I: 56% C: 30% p = 0.12
Neurological toxicity I: 0/27 (0%) C: 0/17 (0%) p = 1.00
Taste I: 5/27 (19%) C: 1/17 (6%) p > 0.05
Hearing I: 0/27 (0%) C: 1/17 (6%) p > 0.05
Mandibula I: 2/27 (6%) C: 0/17 (0%) p > 0.05
Teeth I: 1/27 (4%) C: 2/17 (12%) p > 0.05
Xerostomia I: 4/27 (15%) C: 3/17 (18%) p > 0.05
Skin and subcutaneous tissue I: 2/27 (7%) C: 1/17 (6%) p > 0.05
Mucosa I: 4/27 (15%) C: 3/17 (18%) p > 0.05 |
Definitions: * Lateral field doses were prescribed at midplane. A supraclavicular field dose was prescribed at a 3-cm depth. If there were no palpable lymph nodes, 44 Gy was delivered in the lower part of the neck and in the spinal lymph nodes, and 56 Gy was delivered in the cervical areas adjacent to an involved lymph node area. Electron beams were used to give a boost to the posterior cervical lymph nodes. The dose to the spinal cord was kept below 44 Gy. Computed tomography scan dosimetry was performed to evaluate the maximal and minimal tumor doses.
Remarks: -
Authors conclusion: Calais (1999): The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.
Denis (2004): Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity. Anemia was the most important prognostic factor for survival in both arms. |
Chitapanarux (2013) |
Type of study: Single-center, randomized phase III trial
Setting and country: Thailand
Source of funding: Not reported.
Conflicts of interest: Not reported. |
Patients with locoregionally advanced squamous-cell carcinoma of the head and neck
Inclusion criteria:
Exclusion criteria: Not reported
N total at baseline: Randomized: N = 102* I: N = 48 C: N = 37
Important characteristics: Age, median (range) I: 58.5 y (28-70) C: 63.5 y (40-77)
Sex, n/N (%) male I: 38/48 (79%) C: 55/63 (70%)
Primary tumor site Larynx I: 25/48 (52%) C: 16/37 (44%)
Oropharynx I: 8/48 (17%) C: 6/37 (16%)
Hypopharynx I: 2/48 (4%) C: 2/37 (5%)
Oral cavity I: 13/48 (27%) C: 13/37 (35%)
Groups were comparable at baseline, except for age. |
Standard fractionated radiotherapy† (total dose of 66 Gy in 6.5 wk at 2 Gy/fraction, 5 days/wk) + carboplatin (i.v. bolus of 70 mg/m2 per day for 4 days on day 1-4, day 22-25 and day 43-46) and fluorouracil (600 mg/m2 per day infused continuously for 4 days on day 1-4, day 22-25 and day 43-46) |
Hybrid accelerated radiotherapy† (total dose of 70 Gy in 6 wk at 5 fractions of 2 Gy per wk until 40 Gy, followed by a first daily fraction of 1.8 Gy and a second daily fraction of 1.2 Gy for the remaining 30 Gy) |
Length of follow-up: Median 43 months (range: 3-102)
Loss to follow-up or missing outcome data: None. |
Clinical outcomes Overall survival at 5 years I: 76.1% (95%CI: 57.8-87.3) C: 63.5 (95%CI: 42.0-78.8)
Overall survival curves were compared using the log-rank test: p = 0.05
Safety Acute toxic effects grade ≥ 3 Skin toxicity I: 12/48 (25.0%) C: 6/37 (16.2%) p = 0.33
Mucositis I: 20/48 (41.7%) C: 25/37 (67.6%) p = 0.01
Anemia I: 1/48 (2.1%) C: 0/37 (0%) p ≥ 0.05
Leukopenia I: 9/48 (18.8%) C: 0/37 (0%) p ≥ 0.05
Thrombocytopenia I: 3/48 (6.3%) C: 0/37 (0%) p ≥ 0.05
Nephrotoxicity I: 0/48 (0%) C: 0/37 (0%) p = 1.00
Late toxic effects grade ≥ 3 at > 6 months Skin I: 3/46 (6.5%) C: 2/25 (8.0%) p ≥ 0.05
Subcutaneous tissue I: 0/46 (0%) C: 1/25 (4.0%) p = 0.28
Mucosa I: 1/46 (2.2%) C: 2/25 (8.0%) p ≥ 0.05
Salivary glands I: 2/46 (4.3%) C: 1/25 (4.0%) p ≥ 0.05 |
Definitions: † A shrinking field technique was used with the primary field arrangement, which included two opposed lateral fields to treat the primary tumor and upper neck nodes, and low anterior neck fields (supraclavicular fields) were treated to cover the lower neck nodes. For lateral fields, in general, the anterior border was placed at a 2-cm margin beyond the primary tumor, the posterior border was placed behind the spinous process, the superior border was placed to cover a 2-cm margin above the tumor, and the inferior border was placed at the arytenoid cartilage. The spinal cord was blocked at a dose of 40 Gy. An electron beam with appropriate energy was used to give a dose to the posterior neck field bilaterally. The low anterior low-neck field was treated with conventional fractionation to a dose of 50 Gy in both arms. All patients were treated with a 6-MV linear accelerator. Neither 3D conformal radiotherapy nor intensity-modulated radiation therapy were used in this study.
Remarks: Due to poor accrual, the study was terminated and a final analysis was done in May 2012. We expected a 5-year OS of 25% in both treatment groups. In the overall survival analysis, in order to determine with 80% power, using a one-sided type I error of 0.20, the non-inferiority at 5-year overall survival of the two treatment arms, at least 106 patients per group had to be observed. Instead, 102 patients were enrolled and randomized.
* Efficacy was analyzed on an as-treated basis, based on the data of 85 patients. Prior to the initiation of therapy, the remaining 17 patients refused to participate in the study and were referred to other centers near their residential area.
Authors conclusion: our results indicated that concurrent chemoradiotherapy produced a trend towards better outcome compared or hybrid accelerated radiotherapy. However, the higher hematologic toxicities and poor radiotherapy compliance rate are important limiting factors to be considered regarding this treatment. |
Olmi (2003)
(ORO 93-01 trial) |
Type of study: Multicenter, randomized phase III trial
Setting and country: 18 centers of radiation therapy and medical oncology in Italy
Source of funding: Supported in part by a grant from the Consiglio Nazionale delle Ricerche.
Conflicts of interest: Not reported. |
Patients with locoregionally advanced, unresectable epidermoid tumors of the oropharynx
Inclusion criteria:
Exclusion criteria:
N total at baseline: Randomized: N = 127 I: N = 64 C: N = 63
Important characteristics: Age, < 50 y I: 18/64 (28%) C: 19/63 (30%)
50-65 y I: 34/64 (53%) C: 34/63 (54%)
> 65 y I: 12/64 (19%) C: 10/63 (16%)
Sex, n/N (%) male I: 58/64 (91%) C: 55/63 (87%)
Karnofsky performance score 70 I: 5/60 (8%) C: 3/59 (5%)
80 I: 13/60 (22%) C: 12/59 (20%)
90+ I: 42/60 (70%) C: 44/59 (75%)
Groups were comparable at baseline. |
Standard fractionated radiotherapy† (66-70 Gy in 33-35 fractions in 6.5-7 wk at 2 Gy/fraction, 5 days/wk) + carboplatin (bolus of 75 mg/m2 per day infused in 30 min for 4 days in 1st, 5th and 9th wk) and fluorouracil (1000 mg/m2 infused continuously in 96 hr for 4 days in 1st, 5th and 9th week) |
Standard fractionated radiotherapy† (66-70 Gy in 33-35 fractions in 6.5-7 wk at 2 Gy/fraction, 5 days/wk) |
Length of follow-up: Not reported.
Loss to follow-up or missing outcome data: None. |
Clinical outcomes Overall survival at 2 years I: 51% C: 40%
Overall survival curves were compared using the log-rank test: p = 0.129
Disease-free survival at 2 years I: 42% C: 23%
Disease-free survival curves were compared using the log-rank test: p = 0.022
HR 1.76 (95%CI: 1.15-2.91)
Safety Acute radiotherapy-related toxic effects grade ≥ 3 Skin I: 8/50 (16%) C: 2/54 (4%) p = 0.0461
Mucosa I: 24/50 (48%) C: 8/54 (15%) p = 0.0003
Ear I: 0/50 (0%) C: 0/54 (0%) p = 1.00
Salivary glands I: 0/50 (0%) C: 0/54 (0%) p = 1.00
Pharynx I: 12/50 (24%) C: 6/54 (11%) p = 0.1191
Larynx I: 1/50 (2%) C: 0/54 (0%) p = 0.4808
Acute chemotherapy-related toxic effects grade ≥ 3 Nausea/vomiting I: 0/44 (0%)
Leukopenia I: 10/44 (23%)
Anemia I: 1/44 (2%)
Thrombocytopenia I: 2/44 (5%)
Alopecia I: 0/44 (0%)
Anorexia I: 1/44 (2%)
Nephrotoxicity I: 1/44 (2%)
Neurotoxicity I: 0/44 (0%)
Late toxic effects grade ≥ 3 at 2 years Skin I: 1/39 (3%) C: 0/35 (0%) p = 1.00
Subcutaneous tissue I: 2/39 (5%) C: 0/35 (0%) p = 0.4946
Mucosa I: 2/39 (5%) C: 1/35 (3%) p = 1.00
Salivary glands I: 2/39 (5%) C: 2/35 (6%) p = 1.00
Spinal cord I: 0/39 (0%) C: 0/35 (0)%) p = 1.00
Larynx I: 0/39 (0%) C: 1/35 (3%) p = 0.4730 |
Definitions: * Defined as a leukocyte count ≥ 4000/µL and a platelet count ≥ 150.000/µL.
† Irradiation was performed with photon beams from 60Co machines (focus-skin distance 80 cm) or 4-6-MeV linear accelerators. High-energy electron beams were used to treat the posterior regions of the neck after the spinal cord dose tolerance level was reached. The primary tumor and both cervical regions were included in the initial treatment volume and irradiated through parallel-opposed fields (for each treatment session). The supraclavicular area was irradiated with a centrally shielded anterior direct field in case of nodal involvement of the neck.
Remarks: The trial was officially closed in June 1998 before reaching the planned accrual of 260 patients; because the accrual rate had slowed down over the years, it was considered impractical to prolong the trial any further.
Authors conclusion: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity. |
Staar (2001), Semrau (2006) |
Type of study: Multicenter, randomized phase III trial
Setting and country: 3 university centers and 2 community hospitals in Germany
Source of funding: Supported by Deutsche Krebshilfe (German Cancer Aid).
Conflicts of interest: Not reported. |
Patients with locoregionally advanced, unresectable oro- and hypopharyngeal carcinomas
Inclusion criteria:
Exclusion criteria: Not reported.
N total at baseline: Randomized: N = 263* I: N = 113 C: N = 127
Important characteristics: Age, median (range) I: 57 (38-73) C: 56 (28-73)
Sex, n/N (%) male I: 96/113 (85%) C: 108/127 (85%)
Tumor site Oropharynx I: 87/113 (77%) C: 91/127 (72%)
Hypopharyx I: 26/113 (23%) C: 36/127 (28%)
Groups were comparable at baseline. |
Hyperfractionated accelerated radiotherapy† (total dose of 69.9 Gy in 5.5 wk, using a concomitant boost regimen in the last 2.5 wk (wk 1-3: 1.8 Gy/fraction per day, 5 days/wk; wk 4-5.5: first daily fraction of 1.8 Gy and a second daily fraction of 1.5 Gy, 5 days/wk)) + carboplatin (i.v. bolus of 70 mg/m2 on day 1-5 and day 29-33) and fluorouracil (600 mg/m2 infused continuously on day 1-5 and day 29-33) |
Hyperfractionated accelerated radiotherapy† (total dose of 69.9 Gy in 5.5 wk, using a concomitant boost regimen in the last 2.5 wk (wk 1-3: 1.8 Gy/fraction per day, 5 days/wk; wk 4-5.5: first daily fraction of 1.8 Gy and a second daily fraction of 1.5 Gy, 5 days/wk)) |
Length of follow-up: Staar (2001): median 22.3 months (range: 6-53)
Semrau (2006): median 57.3 months (range: 10.7-84.4)
Loss to follow-up or missing outcome data: None. |
Clinical outcomes Overall survival at 1 year for all tumors I: 66% (95%CI: 57-75) C: 60% (95%CI: 51-69)
Overall survival at 2 years for all tumors I: 48% (95%CI: 38-58) C: 39% (95%CI: 30-48)
Staar (2001): overall survival curves were compared using the log-rank test: p = 0.1139
Overall survival at 1 year for oropharyngeal tumors I: 68% C: 57% 95%CI: ± 10
Staar (2001): overall survival curves were compared using the log-rank test: p = 0.0468
Overall survival at 1 year for hypopharyngeal tumors No statistically significant difference in survival curves.
Overall survival at 5 years for all tumors I: 25.6% (95%CI: 15.8-35.4) C: 15.8% (95%CI: 9.1-22.4)
Semrau (2006): overall survival curves were compared using the log-rank test: p = 0.016
Overall survival at 5 years for oropharyngeal tumors I: 26.1% (95%CI: 14.3-37.8) C: 13.0% (95%CI: 5.3-20.6)
Semrau (2006): overall survival curves were compared using the log-rank test: p = 0.008
Overall survival at 5 years for hypopharyngeal tumors I: 22.2% C: 22.2%
Semrau (2006): overall survival curves were compared using the log-rank test: p = 0.722
Safety Acute toxic effects grade ≥ 3 Mucositis I: 68% C: 52% p = 0.01
Dermatitis I: 30% C: 28%
Leukopenia I: 18% C: 0%
Thrombocytopenia I: 5% C: 0%
Anemia I: 0% C: 1%
Neurotoxicity I: 0% C: 0% p = 1.00
Ototoxicity I: 0% C: 0% p = 1.00
Nephrotoxicity I: 0% C: 0% p = 1.00
Late toxic effects grade ≥ 3 Feeding tube I: 51% C: 25% p = 0.02 |
Definitions: † Radiotherapy was delivered by 4-6-MeV photons with immobilizing patients in thermoplastic masks for reproducible treatment. The total dose to the spinal cord should not exceed 45 Gy.
Remarks: * For 240 of 263 randomized patients (91%), therapy started until the end of April 1999, the closure of patient enrollment. The remaining 23 patients (9%) did not start therapy, for the following reasons: (a) refusal (n = 7); (b) not qualified for protocol (n = 7); (c) infection of feeding tube (n = 3); (d) alcohol excess (n = 2); (e) distant metastases (n = 2); and (f) unknown (n = 2).
Authors conclusion: Staar (2001): With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated radiotherapy. Oropharyngeal carcinomas showed better local-regional control after hyperfractionated accelerated radiochemotherapy versus hyperfractionated accelerated radiotherapy; hypopharyngeal carcinomas did not. Prophylactic granulocyte-colony stimulating factor resulted in an unexpected reduced local control and should be given in radiotherapy regimen only with strong hematologic indication.
Semrau (2006): Hyperfractionated-accelerated concurrent radiochemotherapy is superior to hyperfractionated and accelerated radiotherapy alone in oropharyngeal carcinomas. |
Risk of bias assessment
Risk of bias assessment of intervention studies
Study reference |
Was the allocation sequence adequately generated?a
Definitely yes Probably yes Probably no Definitely no |
Was the allocation adequately concealed?b
Definitely yes Probably yes Probably no Definitely no |
Was knowledge of the allocated interventions adequately prevented?c
Were patients blinded?
Were healthcare providers blinded?
Were data collectors blinded?
Were outcome assessors blinded?
Were data analysts blinded?
Definitely yes Probably yes Probably no Definitely no |
Was loss to follow-up (missing outcome data) infrequent?d
Definitely yes Probably yes Probably no Definitely no |
Are reports of the study free of selective outcome reporting?e
Definitely yes Probably yes Probably no Definitely no |
Was the study apparently free of other problems that could put it at a risk of bias?f
Definitely yes Probably yes Probably no Definitely no |
Overall risk of bias If applicable/necessary, per outcome measureg
LOW SOME CONCERNS HIGH |
1. Radiotherapy + cetuximab |
|||||||
Bonner (2006, 2010), Curran (2007) |
Definitely yes
An interactive voice response system (IVRS) enabled individual sites to obtain a randomisation number and treatment group for a given patient. This process was done by PharmaNet medical monitors. Randomisation was done using a minimisation technique, which used an adaptive balancing algorithm. Patients were stratified according to their Karnofsky performance score, nodal involvement, tumour stage, and radiotherapy fractionation. |
Probably yes
Authorised individuals at each institution called the IVRS system (using a pass code) and responded to certain prompts. The system then faxed the institution with details of the assigned treatment group. However, it is unclear who these ‘authorised individuals’ were and who received the details of the assigned treatment group. |
Unclear
The trial was not blinded because cetuximab was known to cause an acneiform rash. After discussions with the FDA, it was felt that physician and patient blinding was not possible. However, it is unclear whether data collectors, outcome assessors and data analysts were blinded. |
Definitely yes
The percentage of patients lost to follow-up is less than 10% and is similar between treatment groups. |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Definitely no
Several authors report having been employed by and owning equity or stock options in the sponsors of this study. The study was designed by ImClone Systems – manufacturer of cetuximab – and the study chairman in collaboration with the lead investigators and was managed by ImClone Systems and Merck. ImClone Systems collected and analyzed the data. |
HIGH (overall survival, progression-free survival, quality of life, adverse events)
It is unclear whether data collectors, outcome assessors and data analysts were blinded. One of the study sponsors collected and analyzed the data. |
2. Radiotherapy + carboplatin |
|||||||
Fountzilas (2004) |
Unclear
Not described. |
Definitely yes
Stratified randomization was performed centrally at the HeCOG Data Office in Athens. |
Unclear
Not described. |
Definitely yes
The percentage of patients lost to follow-up is less than 10% and similar between treatment groups. |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Probably no
The study suffered from a small study population (n = 79). Furthermore, it is unclear if the authors had any conflicts of interest. |
HIGH (overall survival, adverse events)
The study has a small study population and it is unclear if the allocation sequence was adequately generated and whether data collectors, outcome assessors and data analysts were blinded. Also, conflicts of interest are not reported. |
Jeremic (1997) |
Unclear
Not described. |
Unclear
Not described. |
Unclear
Not described. |
Definitely yes
The percentage of patients lost to follow-up is less than 10% and similar between treatment groups. |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Probably no
The study suffered from a small study population (n = 106) and was stopped before reaching the planned accrual of 170 patients. Furthermore, it is unclear how the study was funded and if the authors had any conflicts of interest. |
HIGH (overall survival, adverse events)
The study has a small study population and was prematurely stopped because the chief investigator had to leave the department. It is unclear if the allocation sequence was adequately generated, if the allocation was adequately concealed and whether data collectors, outcome assessors and data analysts were blinded. Also, it is unclear how the study was funded and if the authors had any conflicts of interest. |
Ruo Redda (2010) |
Unclear
Not described. |
Unclear
Not described. |
Unclear
Not described. |
Definitely yes
No patients were lost to follow-up. |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Probably no
The study suffered from a small study population (n = 164) and an imbalanced study population (i.e. higher percentage of patients with an ECOG performance status of 1 in the control group). Furthermore, it is unclear how the study was funded and if the authors had any conflicts of interest. |
HIGH (overall survival, disease-free survival, adverse events)
The study has a small study population and an imbalanced study population. It is unclear if the allocation sequence was adequately generated, if the allocation was adequately concealed and whether data collectors, outcome assessors and data analysts were blinded. Also, potential conflicts of interest are not reported. |
3. Radiotherapy + carboplatin and 5-FU |
|||||||
Bourhis (2012) |
Definitely yes
Randomisation in a 1:1:1 ratio was done centrally at the biostatistics unit of the Institut Gustave Roussy. Doctors faxed a randomisation form to a data manager who did the randomisation with a computer program. |
Definitely yes
Randomisation in a 1:1:1 ratio was done centrally at the biostatistics unit of the Institut Gustave Roussy. Doctors faxed a randomisation form to a data manager who did the randomisation with a computer program. To avoid deterministic minimisation and assure allocation concealment, the treatment which minimises the imbalance was assigned with a probability of 0.90 |
Unclear
Doctors and patients were not masked to treatment group assignment (open-label trial). It is unclear whether data collectors, outcome assessors and data analysts were blinded. |
Probably yes
The percentage of patients lost to follow-up is less than 10%, but relatively higher in the group of patients receiving accelerated radiotherapy-chemotherapy. |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Definitely yes
No potential source of bias related to the study design, baseline imbalance between treatment groups, or deviation from ITT analysis. The trial was not stopped early and the role of the funding source was clearly described. |
LOW (overall survival, progression-free survival, adverse events)
It is unclear whether data collectors, outcome assessors and data analysts were blinded. |
Calais (1999), Denis (2004) |
Unclear
Not described. |
Definitely yes
Patients were randomly assigned to a treatment group by a central office after their eligibility was established. Randomization was balanced by institution and clinical stage. |
Unclear
Not described. |
Definitely yes
No patient was lost to follow-up for assessment of survival. Three were lost to follow-up for the late toxicity assessment, but were free of local or distant recurrence (2 patients in intervention group and 1 patient in the control group). |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Probably yes
Although the study suffered from an imbalanced study population (i.e. lower percentage of patients with N3 lymph nodes and a Karnofsky performance score of 80 in the control group), it is unlikely that this biased the results in favour of the intervention. In addition, it is unclear what the role of the funding source was. However, the study was funded by a governmental agency, not a pharmaceutical company. |
SOME CONCERNS (overall survival, local recurrence, disease-free survival, adverse events)
It is unclear if the allocation sequence was adequately generated, and whether data collectors, outcome assessors and data analysts were blinded. |
Chitapanarux (2013) |
Unclear
Not described. |
Unclear
Not described. |
Unclear
Not described. |
Definitely yes
No patients were lost to follow-up. |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Definitely no
The study suffered from a small study population (n = 85), had an imbalanced study population (i.e. older patients in the control group) and was stopped before reaching the planned accrual of 106 patients. Furthermore, it is unclear how the study was funded and if the authors had any conflicts of interest. |
HIGH (overall survival, adverse events)
The study has a small study population, an imbalanced study population and was prematurely stopped due to slow accrual. It is unclear if the allocation sequence was adequately generated, if the allocation was adequately concealed, and whether data collectors, outcome assessors and data analysts were blinded. Also, it is unclear how the study was funded and if the authors had any conflicts of interest. |
Olmi (2003) |
Unclear
Not described. |
Definitely yes
Randomization was centralized after histologic confirmation and staging procedures; patients were stratified by center and clinical stage and were then randomized to one of the treatment groups. |
Unclear
Not described. |
Definitely yes
No patients were lost to follow-up. |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Definitely no
The study suffered from a small study population (n = 127) and was stopped before reaching the planned accrual of 260 patients. Because the accrual rate had slowed down over the years, it was considered impractical to prolong the trial any further. The authors claim that there seemed to be no major loss in strength for the statistical estimates. Furthermore, it is unclear if the authors had any conflicts of interest. |
HIGH (overall survival, disease-free survival, adverse events)
The study has a small study population and was prematurely stopped due to slow accrural. It is unclear if the allocation sequence was adequately generated, and whether data collectors, outcome assessors and data analysts were blinded. Also, it is unclear if the authors had any conflicts of interest. |
Staar (2001), Semrau (2006) |
Unclear
Not described. |
Unclear
Not described. |
Unclear
Not described. |
Definitely yes
No patients were lost to follow-up. |
Probably yes
All outcome measures described in the methods section are reported in the results section. However, predefined outcome measures cannot be verified in a published trial protocol. |
Probably yes
No potential source of bias related to the study design, baseline imbalance between treatment groups, or deviation from ITT analysis. The trial was not stopped early and the role of the funding source was clearly described. However it is unclear if the authors had any conflicts of interest. |
SOME CONCERNS (overall survival, adverse events)
It is unclear if the allocation sequence was adequately generated, and if the allocation was adequately concealed. However, treatment groups were comparable at baseline. It is unclear whether data collectors, outcome assessors and data analysts were blinded. Also, it is unclear if the authors had any conflicts of interest. |
Based on version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2) and suggestions by the CLARITY Group at McMaster University.
a Randomization: generation of allocation sequences have to be unpredictable, for example computer generated random-numbers or drawing lots or envelopes. Examples of inadequate procedures are generation of allocation sequences by alternation, according to case record number, date of birth or date of admission.
b Allocation concealment: refers to the protection (blinding) of the randomization process. Concealment of allocation sequences is adequate if patients and enrolling investigators cannot foresee assignment, for example central randomization (performed at a site remote from trial location). Inadequate procedures are all procedures based on inadequate randomization procedures or open allocation schedules.
c Blinding: neither the patient nor the care provider (attending physician) knows which patient is getting the special treatment. Blinding is sometimes impossible, for example when comparing surgical with non-surgical treatments, but this should not affect the risk of bias judgement. Blinding of those assessing and collecting outcomes prevents that the knowledge of patient assignment influences the process of outcome assessment or data collection (detection or information bias). If a study has hard (objective) outcome measures, like death, blinding of outcome assessment is usually not necessary. If a study has “soft” (subjective) outcome measures, like the assessment of an X-ray, blinding of outcome assessment is necessary. Finally, data analysts should be blinded to patient assignment to prevents that knowledge of patient assignment influences data analysis.
d If the percentage of patients lost to follow-up or the percentage of missing outcome data is large, or differs between treatment groups, or the reasons for loss to follow-up or missing outcome data differ between treatment groups, bias is likely unless the proportion of missing outcomes compared with observed event risk is not enough to have an important impact on the intervention effect estimate or appropriate imputation methods have been used.
e Results of all predefined outcome measures should be reported; if the protocol is available (in publication or trial registry), then outcomes in the protocol and published report can be compared; if not, outcomes listed in the methods section of an article can be compared with those whose results are reported.
f Problems may include: a potential source of bias related to the specific study design used (e.g. lead-time bias or survivor bias); trial stopped early due to some data-dependent process (including formal stopping rules); relevant baseline imbalance between intervention groups; claims of fraudulent behavior; deviations from intention-to-treat (ITT) analysis; (the role of the) funding body. Note: The principles of an ITT analysis implies that (a) participants are kept in the intervention groups to which they were randomized, regardless of the intervention they actually received, (b) outcome data are measured on all participants, and (c) all randomized participants are included in the analysis.
g Overall judgement of risk of bias per study and per outcome measure, including predicted direction of bias (for example favors experimental, or favors comparator). Note: the decision to downgrade the certainty of the evidence for a particular outcome measure is taken based on the body of evidence, i.e. considering potential bias and its impact on the certainty of the evidence in all included studies reporting on the outcome.
Table of quality assessment for systematic reviews of RCTs and observational studies
Study reference |
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?5
Yes No Unclear |
Enough similarities between studies to make combining them reasonable?6
Yes No Unclear |
Potential risk of publication bias taken into account?7
Yes No Unclear |
Potential conflicts of interest reported?8
Yes No Unclear |
Iocca (2018) |
Yes |
Unclear
The search strategy is not reported. However, the search seems comprehensive as it was conducted in PubMed, Embase, Cochrane Central Register of Controlled trials, Clinical-Trials.gov, and ASCO abstracts (from 1 January 2020 up to 1 September 2017). The search resulted in 4828 hits. |
Yes |
Yes |
Not applicable (only RCTs are included) |
Yes
This assessment involved all 57 RCTs included in the review, while only 4 RCTs are relevant for the current clinical question. Results are only presented at an aggregate level. |
Not applicable (only results of individual studies are reported) |
Yes
Publication bias was assessed for the systematic review as a whole, but it was not possible to assess publication bias only for the relevant comparisons because there were fewer than ten studies available. |
No
The authors declared that there was no funding source for this review.
The authors declared that there was no conflict of interest for this review.
The source of funding for the included studies was not reported. |
- Based on AMSTAR (Shea BJ, et al. BMC Med Res Methodol. 2007;7:10) and the PRISMA Statement (Moher D, et al. PLoS Med. 2009;6:e1000097).
- Research question (PICO) and inclusion criteria should be appropriate (in relation to the research question to be answered in the clinical guideline) and predefined.
- Search period and strategy should be described; at least Medline searched.
- Potentially relevant studies that are excluded at final selection (after reading the full text) should be referenced with reasons.
- Characteristics of individual studies relevant to the research question (PICO) should be reported.
- Quality of individual studies should be assessed using a quality scoring tool or checklist (preferably QUADAS-2; COSMIN checklist for measuring instruments) and taken into account in the evidence synthesis.
- Clinical and statistical heterogeneity should be assessed; clinical: enough similarities in patient characteristics, diagnostic tests (strategy) to allow pooling? For pooled data: at least 5 studies available for pooling; assessment of statistical heterogeneity and, more importantly (see Note), assessment of the reasons for heterogeneity (if present)? Note: sensitivity and specificity depend on the situation in which the test is being used and the thresholds that have been set, and sensitivity and specificity are correlated; therefore, the use of heterogeneity statistics (p-values; I2) is problematic, and rather than testing whether heterogeneity is present, heterogeneity should be assessed by eye-balling (degree of overlap of confidence intervals in Forest plot), and the reasons for heterogeneity should be examined.
- There is no clear evidence for publication bias in diagnostic studies, and an ongoing discussion on which statistical method should be used. Tests to identify publication bias are likely to give false-positive results, among available tests, Deeks’ test is most valid. Irrespective of the use of statistical methods, you may score “Yes” if the authors discuss the potential risk of publication bias.
- Sources of support (including commercial co-authorship) should be reported in both the systematic review and the included studies. Note: To get a “yes”, source of funding or support must be indicated for the systematic review and for each of the included studies.
Table of excluded studies
Author and year |
Reason for exclusion |
Initial search (N = 40) |
|
Aguiar Jr (2016) |
Wrong comparison |
Bernier (2007) |
Not a systematic review |
Browman (2001) |
Outdated review |
Guan (2016) |
Review does not include relevant comparison |
Ho (2016) |
Not a systematic review |
Huang (2016) |
Review does not include relevant comparison |
Iocca (2018) |
Review including multiple comparisons, most of which are not relevant |
Jeremic (2020) |
Review does not include relevant comparison |
Kim (2017) |
Review does not include relevant comparison |
Krstevska (2009) |
Not a systematic review |
Kuhnt (2003) |
German language |
Laban (2013) |
Review does not include relevant comparison |
Larizadeh (2017) |
Review including multiple comparisons, most of which are not relevant |
Lefebvre (2005) |
Review does not include relevant comparison |
Levy (2011) |
Outdated review |
Liang (2018) |
Review does not include relevant comparison |
Masterson (2014a) |
Wrong study population |
Masterson (2014b) |
Wrong study population |
Matzinger (2009) |
Not a systematic review |
Nwizu (2012) |
Not a systematic review |
Petrelli (2014) |
Review does not include relevant comparison |
Peyrade (2011) |
French language |
Pignon (2009) |
Outdated review |
Porceddu (2019) |
Not a systematic review |
Porceddu (2020) |
Not a systematic review |
Reeves (2011) |
Review including multiple comparisons, most of which are not relevant |
Rowan (2010) |
Not a systematic review |
Seiwert (2005) |
Not a systematic review |
Seiwert (2007) |
Not a systematic review |
Strojan (2007) |
Not a systematic review |
Suntharalingam (2003) |
Not a systematic review |
Suton (2018) |
Review does not include relevant comparison |
Suton (2019) |
Review does not include relevant comparison |
Taberna (2019) |
Not a systematic review |
Tang (2020) |
Wrong comparison |
Tian (2018) |
Wrong comparison |
Vanderveken (2015) |
Wrong drug: gemcitabine |
Vanderveken (2016) |
Wrong drug: gemcitabine |
Winquist (2017a) |
Review including multiple comparisons, most of which are not relevant |
Winquist (2017b) |
Not a systematic review |
Update of the search performed by Iocca (2018) (N = 40) |
|
Addeo (2019) |
Wrong study design |
Al-Saleh (2019) |
Wrong comparison |
Bahig (2020) |
Wrong study population |
Barney (2018) |
Wrong study population |
Beckham (2020) |
Wrong study design |
Bibault (2016) |
Wrong study design |
Buglione (2017) |
Wrong comparison |
Corry (2017) |
Wrong study design |
De Felice (2019) |
Wrong study design |
Economopoulou (2019) |
Wrong study population |
Fung (2021) |
Wrong study design |
Gebre-Medhin (2021) |
Wrong comparison |
Gillison (2019) |
Wrong study population |
Hall (2015) |
Wrong study design |
Hamauchi (2019) |
Wrong study design |
Helfenstein (2019) |
Wrong study design |
Janoray (2020) |
Wrong comparison |
Jones (2020) |
Wrong study population |
Lee (2020) |
Wrong study design |
Maddalo (2020) |
Wrong comparison |
Mehanna (2019) |
Wrong study population |
Mei (2020) |
Wrong study design |
Merlano (2020) |
Wrong intervention |
Mesía (2017) |
Wrong study design |
Mishra (2016) |
Wrong comparison |
Rischin (2021) |
Wrong study population |
Rosenberg (2021) |
Wrong study design |
Ruo Redda (2010) |
RCT included via review by Iocca (2018) |
Saraswathula (2019) |
Wrong study design |
Swiecicki (2020) |
Wrong study population |
Szturz (2019) |
Wrong study design |
Tao (2017) |
Wrong study design |
Tao (2020) |
Wrong comparison |
Venkateshulu (2021a) |
Wrong comparison |
Venkateshulu (2021b) |
Wrong comparison |
Ventz (2019) |
Wrong study design |
Xiang (2018) |
Wrong study design |
Xiang (2019) |
Wrong study design |
Yokota (2020) |
Wrong study design |
Zhao (2019) |
Wrong study design |
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. |
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
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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.
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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.
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.
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Zoekverantwoording
Zoekacties zijn opvraagbaar. Neem hiervoor contact op met de Richtlijnendatabase.