Palliatieve systemische behandeling in de 1e lijn

Beoordeeld: 25-06-2024

Uitgangsvraag

Wat is de rol van eerstelijns palliatieve systemische therapie bij patiënten met een lokaal uitgebreid of gemetastaseerd galweg- of galblaascarcinoom?

Aanbeveling

Maak samen met de patiënt een afweging om wel of geen palliatieve systeemtherapie te starten. Bespreek de wensen en verwachtingen van de patiënt.

Geef bij patiënten die in aanmerking komen voor palliatieve systemische therapie gemcitabine + cisplatin.

Geef ook gemcitabine + cisplatin bij geconjungeerde hyperbilirubine op basis van galwegobstructie; bij goede drainage is het niet nodig te wachten op normaliseren van het bilirubine.

Overweeg in geval van een contra-indicatie voor cisplatin, substitutie door oxaliplatin of geef gemcitabine monotherapie.

Overwegingen

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

Sinds de publicatie van de ABC-02 studie (Valle, 2010) is er geen effectievere behandeling dan gemcitabine + cisplatin gevonden die voldoet aan de gestelde definitie van klinisch relevante overlevingswinst (een verschil van >12 weken of HR < 0,70).

De systematische search leverde vier RCT’s op waarin directe vergelijkingen tussen gemcitabine + cisplatin of gemcitabine + oxaliplatin versus andere eerstelijns behandelopties werden gemaakt (Vogel, 2018, PICCA studie; Oh, 2022, TOPAZ-1 trial; Kelley, 2023, KEYNOTE-966 trial; Leone, 2016, Vecti-BIL study). Daarnaast werd een netwerk meta-analyse geïncludeerd (Jiang, 2021) waarin de effectiviteit en veiligheid van 20 verschillende eerstelijns behandelopties werd onderzocht. Er werden in de netwerk meta-analyse voornamelijk indirecte vergelijkingen gemaakt. In de overwegingen heeft de werkgroep zich voornamelijk gebaseerd op de RCT’s waarin directe vergelijkingen werden gemaakt. Er is gekeken naar de vergelijkingen van gemcitabin + cisplatin versus andere regimes (vergelijking 1) en gemcitabine + oxaliplatin versus andere regimes (vergelijking 2).

Naast de eerdergenoemde landmarkstudie van Valle (2010) zijn recent twee relevante RCT’s gepubliceerd te weten gemcitabine + cisplatin + durvalumab versus gemcitabine + cisplatin + placebo (Oh, 2022, TOPAZ-1 trial) en gemcitabine + cisplatin + pembrolizumab versus gemcitabine + cisplatin (Kelley, 2023, KEYNOTE-966 trial). Voor beide studies geldt dat de studies wel een statistisch significante absolute winst in mediane OS toonden, respectievelijk 1,3 en 1,8 maanden, maar dat deze winst volgens de beroepsgroep als onvoldoende klinisch relevant wordt beoordeeld (PASKWIL criteria). Naar analogie bij andere tumortypen is de verwachting dat er in de toekomst subgroepen geïdentificeerd zullen worden die meer baat hebben bij de toevoeging van durvalumab dan wel pembrolizumab aan gemcitabine + cisplatin.

Voor graad 3-4 toxiciteit werden in de RCT’s geen klinisch relevante verschillen gevonden. Voor kwaliteit van leven werden geen data gerapporteerd

In de netwerk meta-analyse werden klinisch relevante verschillen in overleving ten gunste van gemcitabine + cisplatin gevonden vergeleken met: (1) best supportive care; (2) 5-FU + leucovorin (FUFA); en (3) 5-FU + cisplatin + radiotherapie. Een verschil in het nadeel van gemcitabine + cisplatin werd gevonden in vergelijking met gemcitabine + sorafenib. De werkgroep adviseert deze laatste combinatie niet, omdat dit verschil gebaseerd was op indirecte vergelijkingen tussen behandelopties en de bewijskracht daarom zeer laag is.

Voor graad 3-4 toxiciteit werden geen klinisch relevante verschillen gevonden (zeer lage tot redelijke bewijskracht). Voor kwaliteit van leven werden geen data gerapporteerd.

In tegenstelling tot gemcitabine + cisplatin is er geen gerandomiseerde fase 3 studie verricht met gemcitabine + oxaliplatin. Deze combinatie van middelen wordt buiten Europa wel vaak toegepast. De werkgroep adviseert de combinatie gemcitabine + oxaliplatin niet als standaard zorg. Omdat voor toediening van cisplatin een behouden nierfunctie nodig is, is het bij patiënten met een verminderde nierfunctie (egfr< 50 ml/min) een optie om cisplatin door oxaliplatin te vervangen of alleen gemcitabine monotherapie te geven. Helaas is er geen RCT verricht die gemcitabine + oxaliplatin met gemcitabine monotherapie vergeleken heeft. Er is daarom geen uitspraak te doen welk regimen (gemcitabine + oxaliplatin of gemcitabine monotherapie) de voorkeur heeft bij een onvoldoende nierfunctie.

Bij patiënten met een hyperbilirubinemie veroorzaakt door galwegobstructie waarbij ondanks adequate drainage het bilirubine niet genormaliseerd is, kan wel gemcitabine + cisplatin gestart worden (Lamarca, 2015).

Omdat het mediane aantal cycli gemcitabine + cisplatin in de landmark studie (Valle, 2010) acht cycli was en er onvoldoende bewijslijst is om langer dan 6 maanden te behandelen, is het advies na 6 maanden behandeling met gemcitabine + cisplatin te pauzeren. Bij progressie> 3 maanden na staken van gemcitabine + cisplatin en eerdere goede tolerantie, kan overwogen worden gemcitabine + cisplatin te herintroduceren. Indien er sprake is van gecombineerde histologie van galweg/galblaascarcinoom en hepatocellulair carcinoom (HCC), wordt de keuze van systeemtherapie bepaald op basis van de histologie die het meest prominent aanwezig is, of op basis van tumormarkerdominantie (Alfa FP en Ca 19.9). Omdat de geïncludeerde studies ook patiënten met lokaal gevorderde tumoren bevatten, zijn deze aanbevelingen ook in deze situatie van toepassing.

Aantonen maligniteit

Voor de start van systemische behandeling is het nodig om weefsel van de tumor te verkrijgen om de diagnose van kanker te bevestigen. Bij alle patiënten met galweg- of galblaascarcinoom is er vaak sprake van afstandsmetastasen bij presentatie. Vooral peritoneale en lever metastasen zijn geschikt voor een percutaan biopt. Bij iCCA is een percutaan biopt van de primaire tumor een goed alternatief, omdat er meestal sprake is van 1 of meer grote tumoren in de lever.

Bij perihilair cholangiocarcinoom (pCCA) en distaal cholangiocarcinoom (dCCA) is er sprake van (kleine) tumoren in de extrahepatische galweg. Vaak is op CT zelfs geen tumor zichtbaar en slechts een strictuur of abrupte stop van de galwegen. Een percutaan biopt is dan niet zinvol. In de praktijk is de standaard om bij patiënten met pCCA en dCCA de tumor cytologisch te benaderen middels een galgangbrush ten tijde van de galwegdrainage. De sensitiviteit (35-60%), specificiteit (89-100%), positive predictive value (59%) and negative predictive value (89-100%) van galwegcytologie is echter niet optimaal (Hacihasanoglu, 2018; Ponsioen, 199). Nieuwe technieken worden onderzocht voor het verkrijgen van histologie (Laquière, 2020; Wen, 2020). Echter, een zekere diagnose van dysplasie of maligniteit in galgang brushes is vaak lastig door overlappende kenmerken met reactieve atypie door ontsteking bij PSC, stenen en stent. Vanaf 1 januari 2024 is vanuit de NVVP besloten tot een gestandaardiseerde benadering van pancreas- en galwegcytologie en biopten conform WHO “Reporting System for Pancreaticobiliary Cytopathology” (IAC-IARC-WHO, 2022; Pitman, 2023) in plaats van de classificatie volgens Papanicolaou Society of Cytopathology (PSC) Systeem uit 2015 (Pitman, 2015).

Bij twijfel aan de diagnose maligniteit op basis van de morfologie, kan moleculair onderzoek helpen om, in geval van pathogene mutaties, de diagnose van galwegcarcinoom te bevestigen. Next generation sequencing (NGS) kan worden verricht op paraffine gefixeerd materiaal dan wel op cytologisch bewerkt materiaal (Giemsa weefselglaasjes). Ook kunnen aanvullende immunohistochemische kleuringen op paraffine materiaal worden verricht (bv. P53, NTRK, MMR eiwitten, Her-2) (Hilburn, 2022; Macias, 2022; Vogel, 2023).

Waarden en voorkeuren van patiënten (en evt. hun verzorgers)

Doelen van patiënten kunnen zijn vergroten van overleving, verbetering/behoud van kwaliteit van leven. Deze voorkeuren zijn heel persoonlijk en dienen geëxploreerd te worden in een gezamenlijk gesprek. Eventuele voordelen van de behandeling met palliatieve systeemtherapie kunnen zijn langer leven en minder klachten ervaren indien de tumor door de behandeling kleiner wordt. Maar nadelen kunnen de bijwerkingen van de chemotherapie zijn die een negatief effect op de kwaliteit van leven kunnen geven en de belasting van de frequente gang naar het ziekenhuis met bijbehorende afspraken voor onderzoeken, gesprekken en behandelingen. Door middel van Samen Beslissen kan tot een keuze worden gekomen om wel of niet te starten met palliatieve systeemtherapie. Helaas is het van tevoren niet te voorspellen wat het effect van de behandeling op de tumor zal zijn. Wel is van de gerandomiseerde studie (Valle, 2010) bekend dat bij gemcitabine + cisplatin op de 1^e CT evaluatie bij 80% van de patiënten stabiele ziekte en respons toonde. Het is bekend dat de response rate bij gemcitabine + cisplatin het hoogste is voor de groep met galblaastumoren in vergelijking met de galwegtumoren. Naast data uit gerandomiseerde studies kunnen ook gegevens over effectiviteit besproken worden aan de hand van data uit de dagelijkse praktijk. NKR data tonen bij patiënten die starten met palliatieve systeemtherapie een 1 jaarsoverleving van 34% (perihilair galwegcarcinoom 43%, galblaas 22%) (NKR 2017-2021). In geval van best supportive care is de mediane overleving 1.5-3 maanden (NKR 2017-2021). Dit zijn allemaal gegevens die betrekking hebben op de hele groep, maar niet op de individuele patiënt.

Kosten (middelenbeslag)

De chemotherapie is uit patent en is daarmee geen dure behandeling. Echter, er zijn ook kosten voor de dagbehandeling en bijbehorende onderzoeken en gesprekken met zorgverleners.

Aanvaardbaarheid, haalbaarheid en implementatie

Alleen gemcitabine + cisplatin, gemcitabine + oxaliplatin, en gemcitabine monotherapie zijn te overwegen in de eerste lijn. Andere behandelingen zijn ineffectief, alleen indirect vergeleken, óf voldoen niet aan de Nederlandse criteria voor voldoende effectiviteit. De aanbevelingen zijn in overeenstemming met de huidige zorg.

Onderbouwing

Achtergrond

Meer dan twee-derde van de patiënten met galweg-of galblaascarcinoom komt niet in aanmerking voor een in opzet curatieve resectie omdat er sprake is van een lokaal uitgebreide tumor of omdat er metastasen op afstand zijn. In de Nederlandse richtlijn uit 2013 werd een combinatie van gemcitabine met cisplatin als eerstelijns palliatieve systemische therapie geadviseerd indien de conditie dit toeliet. Dit advies is gebaseerd op de ABC-02 trial die een voordeel in overleving liet zien van 12 maanden na gemcitabine met cisplatin vergeleken met 8 maanden na alleen gemcitabine (HR 0,64; 95% CI: 0,52-0,80) (Valle, 2010). Sindsdien zijn er diverse trials uitgevoerd naar een verscheidenheid aan systemische regimes, met of zonder doelgerichte therapieën of immuuntherapieën. Doel van deze module is adviezen te formuleren met medenemen van de nieuwe trials welke systemische behandeling de voorkeur heeft bij patiënten met een lokaal uitgebreid galweg- of galblaascarcinoom. Ook wordt er beschreven welk diagnostisch onderzoek toegepast wordt om maligniteit aan te tonen alvorens palliatieve systeemtherapie te starten.

Conclusies

Gemcitabine + cisplatin

Overall survival

Very low GRADE

The evidence is very uncertain about the effect of first-line treatment with gemcitabine + cisplatin + panitumumab on overall survival when compared with gemcitabine + cisplatin in patients with a KRAS wild-type cholangiocarcinoma or gallbladder carcinoma.

Source: Vogel (2018)

Low GRADE

The evidence suggests that first-line treatment with gemcitabine + cisplatin + durvalumab does not increase or reduce overall survival when compared with gemcitabine + cisplatin in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma.

Source: Oh (2022)

High GRADE

First-line treatment with gemcitabine + cisplatin + pembrolizumab results in little to no difference in overall survival when compared with gemcitabine + cisplatin in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma.

Source: Kelley (2023)

Very low GRADE

The evidence is very uncertain about the effect of first-line treatment with

- best supportive care;

- gemcitabine monotherapy;

- S1;

- 5-FU + leucovorin (FUFA);

- gemcitabine + oxaliplatin;

- capecitabine + oxaliplatin;

- irinotecan + cisplatin;

- gemcitabine + S1;

- 5-FU + oxaliplatin;

- S1 + cisplatin;

- gemcitabine + cisplatin + S1;

- gemcitabine + capecitabine + oxaliplatin;

- gemcitabine + cisplatin + cediranib;

- gemcitabine + oxaliplatin + erlotinib;

- gemcitabine + oxaliplatin + cetuximab;

- gemcitabine + sorafenib;

- gemcitabine + cisplatin + ramucirumab;

- gemcitabine + cisplatin + merestinib;

- 5-FU + cisplatin + radiotherapy;

on overall survival when compared with gemcitabine + cisplatin

in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma

Source: Jiang (2021)

Quality of life

No GRADE

No evidence was found regarding the effect of first-line treatment with gemcitabine + cisplatin on quality of life when compared with other first-line treatment regimens in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma.

Source: -

Progression-free survival

Very low GRADE

The evidence is very uncertain about the effect of first-line treatment with gemcitabine + cisplatin + panitumumab on progression-free survival when compared with gemcitabine + cisplatin in patients with a KRAS wild-type cholangiocarcinoma or gallbladder carcinoma.

Source: Vogel (2018)

Progression-free survival

Low GRADE

The evidence suggests that first-line treatment with gemcitabine + cisplatin + panitumumab does not increase or reduce progression-free survival when compared with gemcitabine + cisplatin in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma.

Source: Oh (2022)

Progression-free survival

High GRADE

First-line treatment with gemcitabine + cisplatin + pembrolizumab does not increase or reduce progression-free survival when compared with gemcitabine + cisplatin in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma.

Source: Kelley (2023)

Progression-free survival

Very low GRADE

The evidence is very uncertain about the effect of first-line treatment with

- best supportive care;

- gemcitabine monotherapy;

- S1;

- 5-FU + leucovorin (FUFA);

- gemcitabine + oxaliplatin;

- capecitabine + oxaliplatin;

- irinotecan + cisplatin;

- gemcitabine + S1;

- 5-FU + oxaliplatin;

- S1 + cisplatin;

- gemcitabine + cisplatin + S1;

- gemcitabine + capecitabine + oxaliplatin;

- gemcitabine + cisplatin + cediranib;

- gemcitabine + oxaliplatin + erlotinib;

- gemcitabine + oxaliplatin + cetuximab;

- gemcitabine + sorafenib;

- gemcitabine + cisplatin + ramucirumab;

- gemcitabine + cisplatin + merestinib;

- 5-FU + cisplatin + radiotherapy;

on progression-free survival when compared with gemcitabine + cisplatin

in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma

Source: Jiang (2021)

Toxicity (grade ≥3)

Very low GRADE

The evidence is very uncertain about the effect of first-line treatment with gemcitabine + cisplatin + panitumumab on toxicity when compared with gemcitabine + cisplatin in patients with a KRAS wild-type cholangiocarcinoma or gallbladder carcinoma.

Source: Vogel (2018)

Toxicity (grade ≥3)

Low GRADE

The evidence suggests that first-line treatment with gemcitabine + cisplatin + panitumumab does not reduce or increase toxicity when compared with gemcitabine + cisplatin in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma.

Source: Oh (2022)

Toxicity (grade ≥3)

Moderate GRADE

First-line treatment with gemcitabine + cisplatin + pembrolizumab likely does not reduce or increase toxicity when compared with gemcitabine + cisplatin in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma.

Source: Kelley (2023)

Overall survival

Low GRADE

The evidence suggests that first-line treatment with gemcitabine + oxaliplatin + panitumumab does not increase or reduce overall survival when compared with gemcitabine + oxaliplatin in patients with a non-resectable, locally advanced or metastasized KRAS wild-type cholangiocarcinoma or gallbladder carcinoma.

Source: Leone (2016)

Very low GRADE

The evidence is very uncertain about the effect of first-line treatment with

- best supportive care;

- gemcitabine monotherapy;

- S1;

- 5-FU + leucovorin (FUFA);

- gemcitabine + cisplatin;

- capecitabine + oxaliplatin;

- irinotecan + cisplatin;

- gemcitabine + S1;

- 5-FU + oxaliplatin;

- S1 + cisplatin;

- gemcitabine + cisplatin + S1;

- gemcitabine + capecitabine + oxaliplatin;

- gemcitabine + cisplatin + cediranib;

- gemcitabine + oxaliplatin + erlotinib;

- gemcitabine + oxaliplatin + cetuximab;

- gemcitabine + sorafenib;

- gemcitabine + cisplatin + ramucirumab;

- gemcitabine + cisplatin + merestinib;

- 5-FU + cisplatin + radiotherapy;

on overall survival when compared with gemcitabine + oxaliplatin

in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma

Source: Jiang (2021)

Quality of life

No GRADE

No evidence was found regarding the effect of first-line treatment with gemcitabine + oxaliplatin on quality of life when compared with other first-line treatment regimens in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma.

Source: -

Progression-free survival

Low GRADE

The evidence suggests that first-line treatment with gemcitabine + oxaliplatin + panitumumab does not increase or reduce progression-free survival when compared with gemcitabine + oxaliplatin in patients with a non-resectable, locally advanced or metastasized KRAS wild-type cholangiocarcinoma or gallbladder carcinoma.

Source: Leone (2016)

Very low GRADE

The evidence is very uncertain about the effect of first-line treatment with

- best supportive care;

- gemcitabine monotherapy;

- S1;

- 5-FU + leucovorin (FUFA);

- gemcitabine + cisplatin;

- capecitabine + oxaliplatin;

- irinotecan + cisplatin;

- gemcitabine + S1;

- 5-FU + oxaliplatin;

- S1 + cisplatin;

- gemcitabine + cisplatin + S1;

- gemcitabine + capecitabine + oxaliplatin;

- gemcitabine + cisplatin + cediranib;

- gemcitabine + oxaliplatin + erlotinib;

- gemcitabine + oxaliplatin + cetuximab;

- gemcitabine + sorafenib;

- gemcitabine + cisplatin + ramucirumab;

- gemcitabine + cisplatin + merestinib;

- 5-FU + cisplatin + radiotherapy;

on progression-free survival when compared with gemcitabine + oxaliplatin in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma

Source: Jiang (2021)

Toxicity (grade ≥3)

Low GRADE

The evidence suggests that first-line treatment with gemcitabine + oxaliplatin + panitumumab does not increase or reduce toxicity when compared with gemcitabine + oxaliplatin in patients with a non-resectable, locally advanced or metastasized KRAS wild-type cholangiocarcinoma or gallbladder carcinoma.

Source: Leone (2016)

Samenvatting literatuur

Description of studies

Leone (2016) conducted a randomized controlled phase II trial (the Vecti-BIL study) of patients with KRAS wild-type advanced biliary tract cancer in 12 Italian university hospitals and cancer institutes. Patients were randomized (1:1) to receive either gemcitabine (1000 mg/m²), oxaliplatin (100 mg/m²) and panitumumab (6 mg/kg) (n=45) or gemcitabine (1000 mg/m²) and oxaliplatin (100 mg/m²) (n=44). Outcome measures included progression-free survival, overall survival, and toxicity.

Vogel (2018) conducted a randomized controlled phase II trial (the PICCA study) of patients with KRAS wild-type advanced biliary cancer in Germany. Patients were randomized (2:1) to receive either gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) with panitumumab (9 mg/kg) (n=62) or gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) (n=28). Outcome measures included overall survival, progression-free survival and toxicity.

Oh (2022) conducted a randomized controlled phase III trial (the TOPAZ-1 trial) in 17 countries in Asia, Europe, North America, and South America. Patients were randomized (1:1) to receive either gemcitabine (1000 mg/m²), cisplatin (25 mg/m²) and durvalumab (1500 mg) (n=341) or gemcitabine (1000 mg/m²), cisplatin (25 mg/m²), and placebo (n=344). Outcome measures included overall survival, progression-free survival, and toxicity.

Kelley (2023) conducted a randomized controlled phase III trial (the KEYNOTE-966 trial) in 175 centres in Asia-Pacific, Europe, North America, and South America. Patients were randomized (1:1) to receive gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) and either pembrolizumab (n=533) or placebo (n=536). Outcome measures included overall survival, progression-free survival, and toxicity.

The systematic review and network meta-analysis by Jiang (2021) included RCTs published between 2010 and 2020 on patients with advanced biliary tract carcinoma who received first-line chemotherapy. The diagnosis had to be confirmed by histology. Outcome measures should include overall survival, progression-free survival, overall response rate, or adverse events (grade ≥3 neutropenia, vomiting, diarrhea, and fatigue). Studies focused on a patient population with specific gene mutations were excluded from the review.

Twenty-four studies were included in the review, two of which were retrospective cohort studies which is noteworthy as the inclusion criteria state that studies should be phase II or III RCTs. The authors of the review did not provide an explanation why these studies were included. These 24 studies involved a total of 3,555 patients and twenty different regimens of first-line treatment, including:

best supportive care;
chemotherapy mono-therapy (n=2; gemcitabine or S-1);
chemotherapy combination treatment (n=10; 5-FU + leucovorin (FUFA), gemcitabine + oxaliplatin, capecitabine + oxaliplatin, gemcitabine + cisplatin, irinotecan + cisplatin, gemcitabine + S1, 5-FU + oxaliplatin, S1 + cisplatin, gemcitabine + cisplatin + S1, gemcitabine + capecitabine + oxaliplatin);
chemotherapy and targeted therapy (n=6; gemcitabine + cisplatin + cediranib, gemcitabine + oxaliplatin + erlotinib, gemcitabine + oxaliplatin + cetuximab, gemcitabine + sorafenib, gemcitabine + cisplatin + ramucirumab, gemcitabine + cisplatin + merestinib)
chemoradiotherapy (n=1; 5-FU + cisplatin + radiotherapy)

The current clinical question is focused on the comparison between gemcitabine and cisplatin or gemcitabine and oxaliplatin with best supportive care or any of the other regimens.

The systematic review by Jiang (2021) included 10 studies in which gemcitabine + cisplatin was used in one of the treatment arms. Direct comparisons were available for the following regimens:

(1) gemcitabine + cisplatin + cediranib (Valle, 2015);

(2) gemcitabine monotherapy (Valle, 2010; Okusaka, 2010);

(3) irinotecan + cisplatin (Dos Santos, 2020);

(4) gemcitabine + S1 (Huang, 2015; Morizane, 2019);

(5) gemcitabine + S1 (Sakai, 2018);

(6) gemcitabine + capecitabine + oxaliplatin (Markussen, 2020);

(7) gemcitabine + cisplatin + ramucirumab (Valle, 2020);

(8) gemcitabine + cisplatin + merestinib (Valle, 2020);

(9) gemcitabine + oxaliplatin (Ramaswamy, 2017, retrospective cohort study).

The systematic review by Jiang (2021) included eight studies in which gemcitabine + oxaliplatin was used in one of the treatment arms. Direct comparisons were available for the following regimens:

(1) 5-FU + leucovorin (FUFA) (Sharma, 2010);

(2) best supportive care (Sharma, 2010);

(2) capecitabine + oxaliplatin (Kim, 2019);

(3) gemcitabine + oxaliplatin + cetuximab (Malka, 2014; Chen, 2015);

(4) gemcitabine + oxaliplatin + erlotinib (Lee, 2012; Kim, 2015);

(5) 5-FU + cisplatin + radiotherapy (Philip, 2015);

(6) gemcitabine + cisplatin (Ramaswamy, 2017, retrospective cohort study).

A Bayesian network meta-analysis was conducted using a random effects model.

Risk of bias was assessed using the Cochrane reviewer bias risk assessment criteria. Jiang (2021) judged that there was a low risk of bias with regard to blinding of outcome assessment and incomplete outcome data. There was a high risk of bias with regard to blinding of participants and personnel. In several studies, there was an unclear risk of bias for random sequence generation, allocation concealment, selective reporting, and other bias.

Results

Comparison 1: gemcitabine + cisplatin versus other first-line regimens

Overall survival

In the RCT by Vogel (2018), median overall survival was 12.8 months for patients who received gemcitabine + cisplatin + panitumumab and 20.1 months for patients who received gemcitabine + cisplatin. The HR was 0.70 (95%CI 0.41 to 1.18). The difference in weeks fulfills the minimal clinically (patient) relevant difference of > 16 weeks, however the hazard ratio does not fulfill the minimal clinically (patient) relevant difference of HR < 0.7.

In the RCT by Oh (2022), median overall survival was 12.8 months (95%CI 11.1 to 14.0) in patients receiving gemcitabine + cisplatin + durvalumab and 11.5 months (95%CI 10.1 to 12.5) in patients receiving gemcitabine + cisplatin + placebo. This difference was considered not clinically relevant, as the gain in median overall survival was less than 16 weeks and the hazard ratio was > 0.7: HR 0.80 (95%CI: 0.66 to 0.97; p=0.021).

In the RCT by Kelley (2023), the median overall survival was 12.7 months (95%CI 11.5 to 13.6) for patients who received gemcitabine + cisplatin + pembrolizumab and 10.9 months (95%CI 9.9 to 11.6) for patients who received gemcitabine + cisplatin + placebo. This difference was considered not clinically relevant, as the gain in overall survival was less than 16 weeks and the hazard ratio was > 0.7: HR 0.83 (95%CI: 0.72 to 0.95; p=0.034)

In the network meta-analysis by Jiang (2021), overall survival was reported by 23 studies.

Table 1 shows outcome data for overall survival, progression-free survival, and toxicity (only clinically relevant differences are shown) between patients who received gemcitabine + cisplatin and patients who received other regimens.

Patients who received gemcitabine + cisplatin showed a clinically relevant longer overall survival (HR< 0.7 or >1.43) compared with:

- best supportive care (indirect comparisons only);

- 5-FU + leucovorin (FUFA) (indirect comparisons only);

- 5-FU + cisplatin + radiotherapy (indirect comparisons only);

Patients who received gemcitabine + cisplatin showed a clinically relevant shorter overall survival (HR<0.7 or >1.43) compared with:

- gemcitabine + sorafenib (indirect comparisons only);

Quality of life

Neither RCTs by Vogel (2018), Oh (2022) and Kelley (2023) nor the systematic review and network meta-analysis by Jiang (2021) provided any data on quality of life.

Progression-free survival

In the RCT by Vogel (2018), median progression-free survival was 6.5 months for patients who received gemcitabine + cisplatin + panitumumab and 8.3 months for patients who received gemcitabine + cisplatin. This difference was considered not clinically relevant as the gain in PFS was shorter than 16 weeks and the hazard ratio was > 0.70: HR 0.73 (95%CI 0.45 to 1.21).

In the RCT by Oh (2022), median progression-free survival was 7.2 months (95%CI 6.7 to 7.4) in patients receiving gemcitabine + cisplatin + durvalumab and 5.7 months (95%CI 5.6 to 6.7) in patients receiving gemcitabine + cisplatin + placebo. This difference was considered not clinically relevant, as the gain in PFS was shorter than 16 weeks and the hazard ratio was > 0.7: HR 0.75 (95% CI 0.63 to 0.89; p=0.001).

In the RCT by Kelley (2023) median progression-free survival was 6.5 months (95%CI 5.7 to 6.9) for patients who received gemcitabine + cisplatin + pembrolizumab and 5.6 months (95%CI 5.1 to 6.6) for patients who received gemcitabine + cisplatin + placebo. This difference was considered not clinically relevant, as the gain in PFS was shorter than 16 weeks and the hazard ratio was > 0.7: HR 0.86 (95%CI: 0.75 to 1.00; p=0.023).

In the network meta-analysis by Jiang (2021), progression-free survival was reported by 23 studies.

Patients who received gemcitabine + cisplatin showed a clinically relevant longer progression-free survival (HR< 0.7 or >1.43) compared with:

- best supportive care (indirect comparisons only);

- S1 (indirect comparisons only);

Patients who received gemcitabine + cisplatin showed a clinically relevant shorter progression-free survival (HR<0.7 or >1.43) compared with:

- gemcitabine + oxaliplatin (direct comparison from retrospective study);

- capecitabine + oxaliplatin (indirect comparisons only);

- 5-FU + oxaliplatin (indirect comparisons only);

- gemcitabine + oxaliplatin + erlotinib (indirect comparisons only);

- gemcitabine + oxaliplatin + cetuximab (indirect comparisons only);

- gemcitabine + sorafenib (indirect comparisons only);

Toxicity

In the RCT by Vogel (2018), the most common grade 3 or 4 events were leucopenia 13/59 (22%) in the gemcitabine, cisplatin and panitumumab group vs. 2/28 (29%) in the gemcitabine and cisplatin group), neutropenia (26/59 [44%] vs. 13/28 [47%]), thrombopenia (18/59 [21%] vs 12/28 [43%]), anemia (7/59 [12%] vs. 3/28 [11%]) and infection (6/59 [10%] vs 6/28 [21%]). In the panitumumab group, grade ≥3 rash was observed in 7/59 patients (12%) and grade ≥3 acne was observed in 10/59 patients (17%). None of these differences were considered clinically relevant.

In the RCT by Oh (2022), 256/338 (75.7%) of patients who received gemcitabine, cisplatin and durvalumab experienced a grade 3 or 4 event, compared with 266/342 (77.8%) of patients who received gemcitabine and cisplatin. The most common grade 3 or 4 events were neutropenia (65/338=19.2% in the intervention group versus 69/342=20.2% in the control group) and anemia (64/338=18.9% in the intervention group versus 64/342=18.7% in the control group). None of these differences were considered clinically relevant.

In the RCT by Kelley (2023)) 369/534 (70%) of patients who received gemcitabine, cisplatin and pembrolizumab experienced a grade 3 or 4 event, compared with 367/536 (69%) of patients who received gemcitabine, cisplatin and placebo. The most common grade 3 or 4 events were decreased neutrophil count (grade 3: 167/529 [32%] versus 171/534 [32%], grade 4: 90/529 [17%] versus 82/534 [15%]), anaemia (grade 3: 150/529 [28%] versus 150/534 [28%], grade 4: 2/529 [<1%] versus 4/534 [1%]), decreased platelet count (grade 3: 64/529 [12%] versus 67/534 [13%], grade 4: 30/529 [6%] versus 40/534 [7%]), fatigue (grade 3: 25/529 [5%] versus 22/534 [4%], grade 4: 1/529 [<1%] versus 0/534 [0%]), and decreased white blood cell count (grade 3: 57/529 [11%] versus 44/534 [8%], grade 4: 4/529 [1%] versus 3/534 [1%]). None of these differences were considered clinically relevant.

For the network meta-analysis by Jiang (2021), only hazard ratios were reported. Based on these data, it is not possible to judge whether any differences are considered clinically relevant.

Level of evidence of the literature

Comparison 1: gemcitabine + cisplatin versus other first-line regimens

The evidence was derived from 1 systematic review of (mainly) RCTs, but with indirect comparisons, and three additional RCTs. Therefore, the level of evidence for all reported outcome measures started at ‘high quality’.

Overall survival

Vogel (gemcitabine + cisplatin + panitumumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure overall survival was downgraded by three levels because of study limitations (-1; risk of bias because of a lack of information about randomization and allocation procedures); and number of included patients (-2; imprecision because the 95% confidence interval of the hazard ratio overlaps with the boundary for clinical relevance and this was a single small study.

Oh (gemcitabine + cisplatin + durvalumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure overall survival was downgraded by two levels because the 95% confidence interval of the hazard ratio overlaps with the boundary for clinical relevance and this was a single study (-2; imprecision).

Kelley (gemcitabine + cisplatin + pembrolizumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure overall survival was not downgraded.

Jiang (gemcitabine + cisplatin versus 19 other first-line regimens)

The level of evidence regarding the outcome measure overall survival was downgraded by three levels because of study limitations (-1; risk of bias because of incomplete reporting of study methodology); (-1; indirectness because several results were based on indirect comparisons only); and number of included patients (-1; imprecision because the 95% confidence interval of all hazard ratios overlap with the boundary for clinical relevance).

Progression-free survival

Vogel (gemcitabine + cisplatin + panitumumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure progression-free survival was downgraded by three levels because of study limitations (-1; risk of bias because of a lack of information about randomization and allocation procedures); and number of included patients (-2; imprecision because the 95% confidence interval of the hazard ratio overlaps with the boundary for clinical relevance and this was a single small study.

Oh (gemcitabine + cisplatin + durvalumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure progression-free survival was downgraded by two levels because the 95% confidence interval of the hazard ratio overlaps with the boundary for clinical relevance and this was a single study (-2; imprecision).

Kelley (gemcitabine + cisplatin + pembrolizumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure progression-free survival was not downgraded.

Jiang (gemcitabine + cisplatin versus 19 other first-line regimens)

The level of evidence regarding the outcome measure progression-free survival was downgraded by three levels because of study limitations (-1; risk of bias because of incomplete reporting of study methodology); (-1; indirectness because several results were based on indirect comparisons only); and number of included patients (-1; imprecision because the 95% confidence interval of all hazard ratios overlap with the boundary for clinical relevance).

Toxicity

Vogel (gemcitabine + cisplatin + panitumumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure toxicity was downgraded by three levels because of study limitations (-1; risk of bias because of a lack of information and randomization and allocation procedures); and number of included patients (-2; imprecision because this was a single study with low numbers of adverse events).

Oh (gemcitabine + cisplatin + durvalumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure toxicity was downgraded by two levels (-2; imprecision because this was a single study with low numbers of adverse events).

Kelley (gemcitabine + cisplatin + pembrolizumab versus gemcitabine + cisplatin)

The level of evidence regarding the outcome measure toxicity was downgraded by one level (-1; imprecision because this was a single study with low numbers of adverse events).

Comparison 2: gemcitabine + oxaliplatin versus other first-line regimens

Overall survival

In the RCT by Leone (2016), median overall survival was 9.9 months (95%CI 5.4 to 14.3) in patients receiving gemcitabine + oxaliplatin + panitumumab and 10.2 months (95%CI 6.4 to 13.9) in patients receiving gemcitabine + oxaliplatin. This difference was considered not clinically relevant, as the gain in median overall survival was less than 16 weeks and the hazard ratio was > 0.7: HR 0.83 (95% CI 0.53 to 1.3; p=0.42).

In the network meta-analysis by Jiang (2021), overall survival was reported by 23 studies.

Patients who received gemcitabine + oxaliplatin showed a clinically relevant longer overall survival (HR< 0.7 or > 1.43) compared with:

- best supportive care (direct comparison from one RCT);

- 5-FU + leucovorin (FUFA) (direct comparison from one RCT);

- 5-FU + cisplatin + radiotherapy (direct comparison from one RCT);

Patients who received gemcitabine + oxaliplatin showed a clinically relevant shorter overall survival (HR<0.7 or >1.43) compared with:

- gemcitabine monotherapy (indirect comparisons only);

- gemcitabine + S1 (indirect comparisons only);

- S1 + cisplatin (indirect comparisons only);

- gemcitabine + cisplatin + S1 (indirect comparisons only);

- gemcitabine + sorafenib (indirect comparisons only).

Quality of life

Neither the RCT by Leone (2016) nor the systematic review and network meta-analysis by Jiang (2021) provided any data on quality of life.

Progression-free survival

In the RCT by Leone (2016), median progression-free survival was 5.3 months (95%CI 3.3 to 7.2) in patients receiving gemcitabine + oxaliplatin + panitumumab and 4.4 months (95%CI 2.6 to 6.2) in patients receiving gemcitabine + oxaliplatin. This difference was considered not clinically relevant, as the gain in PFS was shorter than 16 weeks and the hazard ratio was > 0.7: HR 0.78 (95% CI 0.51 to 1.21; p=0.27).

In the network meta-analysis by Jiang (2021), progression-free survival was reported by 23 studies. Table 2 shows the outcomes with a clinically relevant difference between patients who received gemcitabine + oxaliplatin and patients who received other regimens.

Patients who received gemcitabine + oxaliplatin showed a clinically relevant longer progression-free survival (HR < 0.7 or > 1.43) compared with:

- best supportive care (direct comparison from one RCT);

- gemcitabine monotherapy (indirect comparisons only);

- S1 (indirect comparisons only);

- 5-FU + leucovorin (FUFA) (direct comparison from one RCT);

- gemcitabine + cisplatin (direct comparison from retrospective study);

- irinotecan + cisplatin (indirect comparisons only);

- gemcitabine + S1 (indirect comparisons only);

- S1 + cisplatin (indirect comparisons only);

- gemcitabine + cisplatin + S1 (indirect comparisons only);

- gemcitabine + capecitabine + oxaliplatin (indirect comparisons only);

- gemcitabine + cisplatin + cediranib; (indirect comparisons only);

- gemcitabine + cisplatin + ramucirumab (indirect comparisons only);

- gemcitabine + cisplatin + merestinib (indirect comparisons only);

- 5-FU + cisplatin + radiotherapy (direct comparison from one RCT).

Toxicity

In the RCT by Leone (2016), the most frequently observed grade ≥3 events included cholestasis/hepatic toxicity (9/45=20% in the intervention group and 6/44=14% in the control group), skin toxicity (6/45=13% in the intervention group and 1/44=2% in the control group), diarrhea (6/45=13% in the intervention group and 3/44=7% in the control group), asthenia (5/45=11% in the intervention group and 3/44=7% in the control group), and nausea (4/45=9% in the intervention group and 2/44=5% in the control group). None of these differences were considered clinically relevant.

For the network meta-analysis by Jiang (2021), only hazard ratios were reported. Based on these data, it is not possible to judge whether any differences are considered clinically relevant.

Level of evidence of the literature

Comparison 2: gemcitabine + oxaliplatin versus other first-line regimens

The evidence was derived from 1 systematic review of (mainly) RCTs and one additional RCT. Therefore, the level of evidence for all reported outcome measures started at ‘high quality’.

Overall survival

Leone (gemcitabine + oxaliplatin + panitumumab versus gemcitabine + oxaliplatin)

Jiang (gemcitabine + oxaliplatin versus 19 other first-line regimens)

Progression-free survival

Leone (gemcitabine + oxaliplatin + panitumumab versus gemcitabine + oxaliplatin)

Jiang (gemcitabine + oxaliplatin versus 19 other first-line regimens)

The level of evidence regarding the outcome measure progression-free survival was downgraded by three levels because of study limitations (-1; risk of bias because of incomplete reporting of study methodology); (-1; indirectness because several results were based on indirect comparisons only); and number of included patients (-1; imprecision because the 95% confidence intervals of most hazard ratios overlap with the boundary for clinical relevance).

Toxicity

Leone (gemcitabine + oxaliplatin + panitumumab versus gemcitabine + oxaliplatin)

The level of evidence regarding the outcome measure toxicity was downgraded by two levels because this was a single small study (-2; imprecision).

Zoeken en selecteren

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

What are the (un)beneficial effects of systemic first-line palliative systemic therapy in patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma?

P:	patients with non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma
I:	systemic therapy other than gemcitabine combined with cisplatin or oxaliplatin only or no systemic therapy
C:	gemcitabine combined with cisplatin or oxaliplatin
O:	overall survival, quality of life, progression-free survival, toxicity

Relevant outcome measures

The working group considered overall survival and quality of life as critical outcome measures for decision making; and progression-free survival and toxicity 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:

(using the PASKWIL criteria for palliative treatment with OS standard arm ≤ 12 months and > 12 months where possible and other criteria):

OS standard arm ≤ 12 months:

Overall survival: absolute difference in OS > 12 weeks and hazard ratio (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.
Toxicity: ≥ 5% difference in fatal adverse events, ≥ 25% difference in grade ≥ 3 adverse events.

OS standard arm > 12 months:

Overall survival: absolute difference in OS of > 16 weeks 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.
Progression-free survival: absolute difference in OS of > 16 weeks and HR < 0.7.
Toxicity: ≥ 5% difference in lethal adverse events and ≥ 25% difference in serious (grade ≥3) adverse events

Search and select (Methods)

A broad systematic literature search was performed to identify relevant publications involving patients with biliary tract cancer. The databases Medline (via OVID) and Embase (via Embase.com) were searched for systematic reviews with relevant search terms until August 31, 2021. Medline (via OVID) and Embase (via Embase.com) were also searched until 12-01-2021 for trials with relevant search terms. The detailed search strategy is depicted under the tab Methods. The systematic literature searches resulted in 1861 hits (547 systematic reviews and 1304 RCTs).

A preselection of systematic reviews and RCTs was made by advisors from the Knowledge Institute of the Dutch Association of Medical Specialists, based on study population and study design. An inclusive approach was followed, in case of any doubt about the eligibility of a publication, the publication was included in the preselection. In total, 74 systematic reviews related to palliative systemic treatment were included in the preselection.

Subsequently, publications were screened based on title and abstract using the following selection criteria: (a) full-text publication in English or Dutch; (b) systematic review of RCTs; (c) involving patients with a non-resectable, locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma; and (d) comparing at least one of the aforementioned outcome measures between patients who received palliative systemic therapy and patients who received another regimen of palliative systemic therapy or no palliative systemic therapy. This resulted in 31 systematic reviews.

After reading the full text, one systematic review including a network meta-analysis was selected (Li, 2019). The guideline working group was aware of another, more recent, systematic review that also included a network meta-analysis (Jiang, 2021). After analysis of both reviews, the working group decided to select the more recent review by Jiang (2021) and supplement this with two studies (Leone, 2016; Vogel, 2018) that were included in the review by Li (2019) but not in the review by Jiang (2021). The reason these studies were not included in the review by Jiang (2021) is that these studies were focused on a patient population with a specific gene mutation, which was an exclusion criterion in the review by Jiang (2021).

The preselection also included 38 RCTs. These publications were screened based on title and abstract using the following selection criteria: (a) full text publication in English or Dutch; (b) RCT; (c) involving patients with a locally advanced or metastasized cholangiocarcinoma or gallbladder carcinoma; and (d) comparing at least one of the aforementioned outcome measures between patients who received gemcitabine combined with cisplatin or oxaliplatin and patients who received systemic therapy other than gemcitabine combined with cisplatin or oxaliplatin only or no systemic therapy. After reading the full text, all 38 studies were excluded (see the table with reasons for exclusions under the tab Methods). The guideline working group was aware of two recent RCTs providing relevant information (Oh, 2022; Kelley, 2023). In total, the literature summary includes one systematic review and four RCTs.

Results

One systematic review (Jiang (2021)) and four additional RCTs (Leone, 2016; Vogel, 2018; Oh, 2022; Kelley, 2023) were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence table. The assessment of the risk of bias is summarized in the risk of bias table.

Referenties

International Academy of Cytology and International Agency for Research on Cancer. World Health Organization Joint Editorial Board. WHO Reporting System for Pancreaticobiliary Cytopathology. Lyon (France): International Agency for Research on Cancer; forthcoming. (IAC-IARC-WHO cytopathology reporting systems series. 1st ed.; Vol 2).
Jiang Y, Zeng Z, Zeng J, et al. Efficacy and safety of first-line chemotherapies for patients with advanced biliary tract carcinoma: a systematic review and network meta-analysis. Front Oncol. 2021;11:736113. doi: 10.3389/fonc.2021.736113. PMID: 34650920.
Kelley RK, Ueno M, Yoo C, Finn RS, Furuse J, Ren Z, Yau T, Klümpen HJ, Chan SL, Ozaka M, Verslype C, Bouattour M, Park JO, Barajas O, Pelzer U, Valle JW, Yu L, Malhotra U, Siegel AB, Edeline J, Vogel A; KEYNOTE-966 Investigators. Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 Apr 14:S0140-6736(23)00727-4. doi: 10.1016/S0140-6736(23)00727-4. Epub ahead of print. PMID: 37075781.
Lamarca A, Benafif S, Ross P, Bridgewater J, Valle JW. Cisplatin and gemcitabine in patients with advanced biliary tract cancer (ABC) and persistent jaundice despite optimal stenting: Effective intervention in patients with luminal disease. Eur J Cancer. 2015 Sep;51(13):1694-703. doi: 10.1016/j.ejca.2015.05.018. Epub 2015 Jun 8. PMID: 26066735.
Leone F, Marino D, Cereda S, et al. Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild-type KRAS advanced biliary tract cancer: a randomized phase 2 trial (Vecti-BIL study). Cancer. 2016;122(4):574-81. doi: 10.1002/cncr.29778. PMID: 26540314.
Oh DY, Ruth He A, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1(2). doi: 10.1056/EVIDoa2200015.
Pitman MB, Layfield L. The Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology. 1st ed. New York: Springer Cham; 2015. XV, 96
Pitman MB, Centeno BA, Reid MD, Saeig M, Siddiqui MT, Layfield LJ, Perez-Machado M, Weynand B, Stelow EB, Lozano MD, Fukushima N, Cree IA, Mehrotra R, Schmitt FC, Field AS. A brief review of the WHO reporting system for pancreaticobiliary cytopathology. J Am Soc Cytopathol. 2023 Jul-Aug;12(4):243-250. doi: 10.1016/j.jasc.2023.03.002. Epub 2023 Mar 7. PMID: 37003924.
Vogel A, Kasper S, Bitzer M, et al. PICCA study: panitumumab in combination with cisplatin/gemcitabine chemotherapy in KRAS wild-type patients with biliary cancer-a randomised biomarker-driven clinical phase II AIO study. Eur J Cancer. 2018;92:11-19. doi: 10.1016/j.ejca.2017.12.028. PMID: 29413685.

Evidence tabellen

Evidence table for systematic reviews of RCTs and observational studies

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison/control (C)

Follow-up

Outcome measures and effect size

Comments

Jiang (2021)

Type of study:

Systematic review and network meta-analysis

Literature search:

PubMed, Embase, and Cochrane Library, up to August 10, 2020

Included studies:

A: Sharma (2010)

B: Kim (2019)

C: Valle (2015)

D: Valle (2010)

E: Dos Santos (2020)

F: Huang (2015)

G: Morizane (2019)

H: Li (2016)

I: Schinzari (2017)

J: Okusaka (2010)

K: Malka (2014)

L: Lee (2012)

M: Phelip (2015)

N: Moehler (2014)

O: Chen (2015)

P: Novarino (2013)

Q: Sasaki (2013)

R: Morizane (2013)

S: Kang (2012)

T: Sakai (2018)

U: Markussen (2020)

V: Kim (2015)

W: Valle (2020)

X: Ramaswamy (2017)

Study design:

A: single-center, open-label, randomized trial

B: multicenter, open-label, randomized phase III trial

C: multicenter, randomized double-blind, placebo-controlled phase II trial

D: multicenter, open-label, randomized phase III trial

E: single-center, open-label, randomized phase II trial

F: randomized trial

G: multicenter, open-label, randomized phase III trial

H: single-center, open-label, randomized trial

I: randomized phase II trial

J: multicenter, randomized phase II trial

K: multicenter, open-label, randomized phase II trial

L: multicenter, open-label, randomized phase III trial

M: multicenter, open-label, randomized phase II trial

N: multicenter, randomized, double-blind, placebo-controlled phase II trial

O: multicenter, open-label, randomized phase II trial

P: retrospective cohort study

Q: multicenter, open-label, randomized phase II trial

R: multicenter, open-label, randomized phase II trial

S: single-center, open-label, randomized phase II trial

T: multicenter, open-label, randomized phase III study

U: multicenter, open-label, randomized phase II trial

V: multicenter, open-label, randomized phase III trial

W: multicenter, randomized, double-blind phase II trial

X: retrospective match pair analysis

Setting and country:

A: 1 cancer hospital in India

B: 10 tertiary hospitals in South Korea

C: hepatobiliary oncology referral centers in the UK

D: 37 centers in the UK

E: 1 cancer hospital in Brazil

F: China

G: 33 institutions in Japan

H: 1 tertiary hospital in China

I: Italy

J: 9 study centers in Japan

K: university hospitals and cancer centers in France and Germany

L: 11 tertiary hospitals in South Korea

M: 12 hospitals in France

N: 11 hospital in Germany

O: 12 hospital in Tawain

P: 1 university hospital in Italy

Q: 12 hospitals in Japan

R: 19 hospitals in Japan

S: 1 university hospital in South Korea

T: 39 institutions in Japan

U: 2 hospitals in Denmark

V: 11 tertiary hospitals in South Korea

W: 81 hospitals in 18 countries (USA, Taiwan, South Korea, Turkey, Argentina, France, Russia, Spain, UK, Germany, Australia, Belgium, Hungary, Czech Republic, Sweden, Mexico, Denmark, Austria)

X: 1 hospital in India

Source of funding:

The review was supported by the Guangxi Natural Science

Foundation.

The source of funding for the included studies is not reported.

Conflicts of interest:

The authors of the review declare that there was no conflict of interest for this review.

Inclusion criteria:

study type: published RCT of II/III period
subjects: advanced biliary tract cancer confirmed by histology
patients with advanced BTC receiving first-line chemotherapy
primary outcome indicators: reported progression-free survival, overall survival, and objective remission rate
secondary outcome indicators: adverse events (neutropenia grade ≥ 3, vomiting, diarrhea, and fatigue)

Exclusion criteria:

studies in which patients were treated with cisplatin-based double or multiple concurrent agents
letters, reviews, case reports, non-human studies, and articles that do not provide raw data
non-English articles
non-randomized controlled single-arm studies
research includes a comparison of chemotherapy with adjuvant or neoadjuvant treatment
studies that only included patients with specific gene mutations

N total at baseline:

A: I1/I2/C: N = 27/28/27

B: I/C: N = 108/114

C: I/C: N = 62/62

D: I/C: N = 206/204

E: I/C: N = 24/23

F: I/C: N = 32/34

G: I/C: N = 179/175

H: I/C1/C2: N = 25/25/25

I: I/C: N = 25/23

J: I/C: N = 42/41

K: I/C: N = 76/74

L: I/C: N = 135/133

M: I/C: N = 18/16

N: I/C: N = 52/50

O: I/C: N = 62/60

P: I/C: N = 22/18

Q: I/C: N = 30/32

R: I/C: N = 51/50

S: I/C: N = 47/49

T: Randomized: N = 246

U: I/C: N = 50/50

V: I/C: N = 49/54

W: I1/I2/C1+C2: N = 106/102/101

X: I/C: N = 163/163

Important characteristics:

Age, median, years:

A: I1/I2/C: 51/47/49

B: I/C: 62/64

C: I/C: 68/65

D: I/C: 63/64

E: not reported

F: not reported

G: I/C: 67/67

H: I/C1/C2: 57/55/57

I: I/C: 62/61

J: I/C: 66/65

K: I/C: 61/62

L: I/C: 59/61

M: I/C: 69/75

N: I/C: 64/65

O: I/C: 61/59

P: I/C: 62/65

Q: I/C: 68/75

R: I/C: 66/63

S: I/C: 60/59

T: not reported

U: I/C: 65/65

V: I/C: 59/62

W: not reported

X: I/C: 52/52

Sex, n/N (%) male:

A: I1/I2/C: I: 6/27 (22%)/ 5/28 (18%)/ 5/26 (19%)

B: I/C: 74/108 (69%)/ 70/114 (61%)

C: I/C: 34/62 (55%)/ 28/62 (45%)

D: I/C: 98/206 (48%)/ 96/204 (47%)

E: not reported

F: I/C: 19/32 (59%)/ 22/34 (65%)

G: I/C: 97/179 (54%)/ 99/175 (57%)

H: I/C1/C2: 19/25 (76%)/ 16/25 (64%)/ 19/25 (76%)

I: I/C: 11/25 (44%)/ 10/23 (43%)

J: I/C: 21/42 (50%)/ 18/41 (44%)

K: I/C: 43/76 (57%)/ 42/74 (57%)

L: I/C: 91/135 (67%)/ 79/133 (59%)

M: I/C: 7/18 (39%)/ 8/16 (50%)

N: I/C: 29/49 (59%)/ 25/48 (52%)

O: I/C: 28/62 (45%)/ 30/60 (50%)

P: I/C: 11/22 (50%)/ 12/18 (67%)

Q: I/C: 16/30 (53%)/ 20/32 (63%)

R: I/C: 27/51 (53%)/ 28/50 (56%)

S: I/C: 31/47 (66%)/ 31/49 (63%)

T: not reported

U: I/C: 23/47 (49%)/ 23/49 (47%)

V: I/C: 33/49 (67%)/ 35/54 (65%)

W: not reported

X: I/C: 53/163 (33%)/ 53/163 (33%)

A: I1: best supportive care; I2: fluorouracil (425 mg/m² bolus infusion weekly for 30 wks) + folinic acid (20 mg/² bolus infusion weekly for 30 wks)

B: capecitabine (1000 mg/m² p.o. b.i.d. on day 1-14) + oxaliplatin (130 mg/m² infused over 120 min on day 1)

C: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (25 mg/m² on day 1 and 8 every 3 wks) + cediranib (20 mg p.o. q.d.)

D: gemcitabine (1000 mg/m² i.v. on day 1, 8 and 15 every 4 wks for 6 cycles)

E: irinotecan (65 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (60 mg/m² i.v. on day 1 every 3 wks)

F: gemcitabine (1000 mg/m² i.v. on day 1 and 15 every 4 wks) + S-1 (80-120 mg/m² p.o. b.i.d. on day 1-14 every 4 wks)

G: gemcitabine (1000 mg/m² i.v. on day 1, 8 and 15 every 3 wks) + S-1 (80-100 mg/m² p.o. b.i.d. on day 1-14 every 3 wks)

H: gemcitabine (1000 mg/m² infused over 30 min on day 1 and 15 every 4 wks) + S-1 (80-120 mg/m² p.o. b.i.d. on day 1-14 every 4 wks)

I: leucovorin (100 mg/m² infused over 2 hrs on day 1 and 2 every 2 wks) + 5-fluorouracil (400 mg/m² bolus infusion on day 1 and 2 and 1200 mg/m² infused over 46 hrs every 2 wks) + oxaliplatin (85 mg/m² infused over 2 hrs min on day 1 every 2 wks)

J: gemcitabine (1000 mg/m² i.v. on day 1, 8 and 15 every 4 wks)

K: gemcitabine (1000 mg/m² infused over 100 min on day 1 every 2 wks) + oxaliplatin (100 mg/m² infused over 120 min on day 2 every 2 wks) + cetuximab (500 mg/m² infused over 150 min on day 1 or 2 every 2 wks)

L: gemcitabine (1000 mg/m² infused over 100 min on day 1 every 2 wks) + oxaliplatin (100 mg/m² infused over 120 min on day 2 every 2 wks) + erlotinib (100 mg p.o. q.d. from day 1)

M: 5-fluorouracil (300 mg/m² infused continuously for 5 days/wk for 5 wks) + cisplatin (20 mg/m² on day 1-4 and 29-32) + radiotherapy (50 Gy in 25 fractions)

N: gemcitabine (1000 mg/m2 i.v. on day 1, 8, 15, 29, 36 and 43 of the first cycle and on day 1, 8 and 15 of all subsequent cycles every 4 wks) + sorafenib (400 mg p.o. b.i.d.)

O: gemcitabine (800 mg/m² infused at FDR of 10 mg/m² per min every 2 wks) + oxaliplatin (85 mg/m² infused over 120 min every 2 wks) + cetuximab (500 mg/m² i.v. on day 1 every 2 wks)

P: oxaliplatin (85 mg/m² infused over 1 hr on day 1 every 2 wks) + 5-fluorouracil (400 mg/m² bolus infusion on day 1 and 2 and 600 mg/m² infused over 22 hrs every on day 1 and 2 every 2 wks) + folinic acid (200 mg/m² infused over 2 hr on day 1 and 2 every 2 wks)

Q: gemcitabine (1000 mg/m² infused over 30 min on day 1 and 15 every 4 wks) + S-1 (80-120 mg/m² p.o. b.i.d. on day 1-14 every 4 wks)

R: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + S-1 (60-100 mg/m² p.o. b.i.d. on day 1-14 every 3 wks)

S: S-1 (80-120 mg/m² p.o. b.i.d. on day 1-14 every 3 wks) + cisplatin (60 mg/m² infused over 90 min on day 1 every 3 wks)

T: gemcitabine (1000 mg/m² i.v. on day 1 every 2 wks) + cisplatin (25 mg/m² i.v. on day 1 every 2 wks) + S-1 (80 mg/m² p.o. q.d. on day 1-7 every 2 wks)

U: gemcitabine (1000 mg/m² infused over 30 min every 2 wks) + oxaliplatin (50 mg/m² infused over 30 min every 2 wks) + capecitabine (650 mg/m² p.o. b.i.d. on day 1-14)

V: gemcitabine (1000 mg/m² infused over 100 min 1 every 2 wks) + oxaliplatin (100 mg/m² infused over 120 min every 2 wks) + erlotinib (100 mg p.o. q.d.)

W: I1: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks for a maximum of 8 cycles) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks for a maximum of 8 cycles) + ramucirumab (8 mg/kg i.v. on day 1 and 8 every 3 weeks); I2: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks for a maximum of 8 cycles) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks for a maximum of 8 cycles) + merestinib (80 mg p.o. q.d.)

X: gemcitabine (1000 mg/m² i.v. on day 1 every 2 wks) + oxaliplatin (100 mg/m² i.v. on day 1 every 2 wks)

A: gemcitabine (900 mg/m² i.v. on day 1 and 8 every 3 wks for a maxmium of 6 cycles) + oxaliplatin (80 mg/m² i.v. on day 1 and 8 every 3 wks for a maxmium of 6 cycles)

B: gemcitabine (1000 mg/m² infused over 100 min on day 1 and 8) + oxaliplatin (100 mg/m² infused over 120 min on day 1)

C: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 21 days) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks) + placebo

D: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 21 days)

E: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (60 mg/m² i.v. on day 1 every 3 wks)

F: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks)

G: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks)

H: C1: gemcitabine (1000 mg/m² infused over 30 min on day 1, 8 and 15 every 4 wks); C2: S-1 (80-120 mg/m² p.o. b.i.d. on day 1-14 every 4 wks)

I: leucovorin (100 mg/m² infused over 2 hrs on day 1 and 2 every 2 wks) + 5-fluorouracil (400 mg/m² bolus infusion on day 1 and 2 and 1200 mg/m² infused over 46 hrs every 2 wks)

J: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks)

K: gemcitabine (1000 mg/m² infused over 100 min on day 1 every 2 wks) + oxaliplatin (100 mg/m² infused over 120 min on day 2 every 2 wks)

L: gemcitabine (1000 mg/m² infused over 100 min on day 1 every 2 wks) + oxaliplatin (100 mg/m² infused over 120 min on day 2 every 2 wks)

M: gemcitabine (1000 mg/m² infused over 100 min on day 1 every 2 wks for 12 cycles) + oxaliplatin (100 mg/m² infused over 120 min starting 1 hr after the end of the gemcitabine infusion every 2 wks for 12 cycles)

N: gemcitabine (1000 mg/m2 i.v. on day 1, 8, 15, 29, 36 and 43 of the first cycle and on day 1, 8 and 15 of all subsequent cycles every 4 wks) + placebo

O: gemcitabine (800 mg/m² infused at FDR of 10 mg/m² per min every 2 wks) + oxaliplatin (85 mg/m² infused over 120 min every 2 wks)

P: gemcitabine (1250 mg/m² infused over 30 min on day 1-8 every 3 wks)

Q: gemcitabine (1000 mg/m² infused over 30 min on day 1, 8 and 15 every 4 wks)

R: S-1 (80-120 mg/m² p.o. b.i.d. on day 1-28 every 6 wks)

S: gemcitabine (1000 mg/m² infused at FDR of 10 mg/m² on day 1 and 8 every 3 wks) + cisplatin (60 mg/m² infused over 90 min on day 1 every 3 wks)

T: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks)

U: gemcitabine (1000 mg/m² infused over 30 min on day 1 and 8 every 3 wks) + cisplatin (25 mg/m² infused over 60 min on day 1 and 8 every 3 wks)

V: gemcitabine (1000 mg/m² infused over 100 min every 2 wks) + oxaliplatin (100 mg/m² infused over 120 min every 2 wks)

W: C1: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks for a maximum of 8 cycles) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks for a maximum of 8 cycles) + placebo (i.v.); C2: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks for a maximum of 8 cycles) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks for a maximum of 8 cycles) + placebo (p.o. q.d.)

X: gemcitabine (1000 mg/m² i.v. on day 1 and 8 every 3 wks) + cisplatin (25 mg/m² i.v. on day 1 and 8 every 3 wks)

Length of follow-up:

Not reported.

Loss to follow-up or missing outcome data:

Not reported.

Overall survival

Months, median

A: I1/I2/C: 4.5/4.6/9.5

B: I/C: 10.6/10.4

C: I/C: 14.1/11.9

D: I/C: 8.1/11.7

E: I/C: 11.9/9.8

F: I/C: 8.2/10.2

G: I/C: 15.1/13.4

H: I/C1/C2: 11/10/6

I: I/C: 13/7.5

J: I/C: 7.7/11.2

K: I/C: 11/12.4

L: I/C: 9.5/9.5

M: I/C: 13.5/19.9

N: I/C: 8.4/11.2

O: I/C: 10.6/9.8

P: I/C: 14.1/8.3

Q: I/C: 8.9/9.2

R: I/C: 12.5/9

S: I/C: 9.9/10.1

T: I/C: 13.5/12.6

U: I/C: 8.7/12

V: I/C: 10.2/8

W: I1/I2/C1+C2: 10.45/14.03/13.04

X: I/C: 7.79/8.02

See Tables 1 and 2 for hazard ratios

Progression-free survival

Months, median

A: I1/I2/C: 2.8/3.5/8.5

B: I/C: 5.8/5.3

C: I/C: 8/7.4

D: I/C: 5/8

E: I/C: 5.3/7.8

F: I/C: 5.6/6.5

G: I/C: 6.8/5.8

H: I/C1/C2: 4.9/3.7/1.6

I: I/C: 5.2/2.8

J: I/C: 3.7/5.8

K: I/C: 6.1/5.5

L: I/C: 5.8/4.2

M: I/C: 5.8/11

N: I/C: 3/4.9

O: I/C: 6.7/4.1

P: I/C: 5.4/3.9

Q: I/C: 5.6/4.3

R: I/C: 7.15/4.2

S: I/C: 5.4/5.7

T: I/C: 7.4/5.5

U: I/C: 5.7/7.3

V: I/C: 6.1/3

W: I1/I2/C1+C2: 6.47/6.97/6.64

X: not reported

See Tables 1 and 2 for hazard ratios

Safety

Neutropenia grade ≥ 3

n/N (%)

A: I1/I2/C: I: N.A./ 2/28 (7%)/ 10/26 (38%)

B: I/C: 5/106 (5%)/ 16/110 (15%)

C: I/C: 26/62 (42%)/ 23/62 (37%)

D: I/C: 33/199 (17%)/ 50/198 (25%)

E: not reported

F: I/C: n = 21/20

G: I/C: 106/177 (60%)/ 104/171 (61%)

H: not reported

I: I/C: 2/25 (8%)/ 1/23 (4%)

J: I/C: 16/42 (38%)/ 23/41 (56.1%)

K: I/C: 17/76 (22%)/ 11/68 (16%)

L: I/C: 3/135 (2%)/ 5/131 (4%)

M: I/C: 0/17 (0%)/ 4/16 (25%)

N: I/C: 2/49 (4%)/ 4/48 (8%)

O: I/C: 11/62 (18%)/ 2/60 (3%)

P: I/C: 6/22 (27%)/ 5/18 (28%)

Q: I/C: 10/30 (33%)/ 7/32 (63%)

R: I/C: 31/51 (61%)/ 2/50 (4%)

S: I/C: 14/47 (30%)/ 24/49 (49%)

T: not reported

U: I/C: 0/47 (0%)/ 21/49 (43%)

V: not reported

W: I1/I2/C1+C2: 51/104 (49%)/ 48/102 (47%)/ 33/100 (33%)

X: I/C: 4/163 (2%)/ 12/163 (7%)

See Tables 1 and 2 for hazard ratios

Abbreviations:

BSC = best supportive care

FUFA = fluorouracil + folinic acid

GEMOX = gemcitabine + oxaliplatin

GP = gemcitabine + cisplatin

XELOX = capecitabine + oxaliplatin

Review authors’ conclusion:

This network meta-analysis demonstrated that chemotherapy combined with targeted therapy has better efficacy and lower incidence of adverse events than chemotherapy alone.

Evidence table for intervention studies

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison/control (C)

Follow-up

Outcome measures and effect size

Comments

Leone (2016)

(Vecti-BIL trial)

Type of study:

Multicenter, open-label, randomized phase II trial

Setting and country:

12 university hospitals and cancer centers in Italy

Source of funding:

Amgen provided funding support. This work was supported by grants from the Fondazione Piemontese per l’Oncologia, the Fondazione Piemontese per la Ricerca sul Cancro Onlus, and the Associazione Italiana Ricerca Contro il Cancro.

Conflicts of interest:

One author has received consulting fees from and has served on advisory boards for Celgene, Clovis, Genentech, Lilly, Boehringer-Ingelheim, and Merck Serono outside the submitted work; this author has also received personal fees from Baxalta and grants from Pharma-Mar outside the submitted work. One author has served on advisory boards for Amgen, Bayer, Sanofi-Aventis, Roche, and Ignyta. One author reports personal fees from Amgen and non-financial support from Roche and Eli Lilly outside the submitted work. One author reports personal fees from Amgen outside the submitted work. One author reports non-financial support from Amgen, Merck, and Roche outside the submitted work. One author reports serving as a consultant or on advisory boards for Roche, Sanofi, Marck-Serono, and Eli Lilly outside the submitted work. The other authors declare no competing interests.

Patients with advanced, non-resectable or metastatic biliary tract cancer and wild-type KRAS mutation status

Inclusion criteria:

histologically or cytologically documented unresectable or metastatic biliary tract adenocarcinoma either at diagnosis or as a relapse after surgery
wild-type KRAS mutation status for the primary or metastatic tumor
ECOG performance status 0-2
adequate bone marrow, renal and hepatic function

Exclusion criteria:

prior systemic treatment, either chemotherapy or targeted agents
serious comorbidities
unability to fulfill the protocol requirements

N total at baseline:

Randomized: N = 89

I: N = 45

C: N = 44

Important characteristics:

Age, median (range):

I: 63.9 y (46.7-78.5)

C: 64.2 y (36.8-78.5)

Sex, n/N (%) male:

I: 17/45 (38%)

C: 15/44 (34%)

Performance status

0-1

I: 45/45 (100%)

C: 43/44 (97.7%)

I: 0/45 (0%)

C: 1/44 (2.3%)

Primary tumor site

Intrahepatic bile duct

I: 21/45 (46.7%)

C: 21/44 (47.7%)

Extrahepatic bile duct

I: 12/45 (26.7%)

C: 7/44 (15.9%)

Gallbladder

I: 12/45 (26.7%)

C: 16/44 (36.4%)

Groups were comparable at baseline.

Gemcitabine (1000 mg/m² on day 1 of each 2-wk cycle) + oxaliplatin (100 mg/m² on day 2 of each 2-wk cycle) + panitumumab (6 mg/kg on day 1 of each 2-wk cycle)*

Gemcitabine (1000 mg/m² on day 1 of each 2-wk cycle) + oxaliplatin (100 mg/m² on day 2 of each 2-wk cycle)*

Length of follow-up:

Median 10.1 months

Loss to follow-up or missing outcome data:

All patients were included in the intention-to-treat analysis

Overall survival

Overall survival for all tumors

Months, median

I: 9.9 (95%CI: 5.4 to 14.3)

C: 10.2 (95%CI: 6.4 to 13.9)

HR 0.83 (95%CI: 0.53 to 1.3)

Overall survival for intrahepatic cholangiocarcinoma

Months, median

I: 15.1 (95%CI: 9.3 to 20.9)

C: 11.8 (95%CI: 9.2 to 14.4)

Overall survival for extrahepatic cholangiocarcinoma and gallbladder carcinoma

Months, median

I: 7.9 (95%CI: 5.1 to 10.7)

C: 8.1 (95%CI: 5.7 to 10.4)

Progression-free survival

Progression-free survival for all tumors (primary endpoint)

Months, median

I: 5.3 (95%CI: 3.3 to 7.2)

C: 4.4 (95%CI: 2.6 to 6.2)

HR 0.78 (95%CI: 0.51 to 1.21)

Progression-free survival for intrahepatic cholangiocarcinoma

Months, median

I: 5.7 (95%CI: 2.7 to 8.7)

C: 6.2 (95%CI: 3.1 to 9.2)

Progression-free survival for extrahepatic cholangiocarcinoma and gallbladder carcinoma

Months, median

I: 4.9 (95%CI: 2.4 to 7.4)

C: 3.8 (95%CI: 2.3 to 5.3)

Safety (toxicity grade ≥ 3)

Anemia

I: 3/45 (6.6%)

C: 3/44 (6.8%)

Neutropenia

I: 3/45 (6.6%)

C: 2/44 (4.5%)

Thrombocytopenia

I: 1/45 (2.2%)

C: 2/42 (4.5%)

Skin toxicity

I: 6/45 (6.6%)

C: 1/44 (2.2%)

Conjunctivitis

I: 0/45 (0%)

C: 0/44 (0%)

Ungeal toxicity

I: 1/45 (2.2%)

C: 0/44 (0%)

Neurotoxicity

I: 2/45 (4.4%)

C: 2/44 (4.5%)

Diarrhea

I: 6/45 (6.6%)

C: 3/44 (6.8%)

Constipation

I: 0/45 (0%)

C: 0/44 (0%)

Hypokalemia

I: 1/45 (2.2%)

C: 0/44 (0%)

Definitions:

* Wild-type KRAS mutation status was defined as no mutations in exon 2, codons 12-13.

Remarks:

Authors conclusion:

The results confirm the marginal role of anti-EGFR therapy even for wild-type KRAS-selected biliary tract cancer.

Vogel (2018)

(PICCA trial)

Type of study:

Multicenter, open-label, randomized phase II trial

Setting and country:

17 centers in Germany

Source of funding:

This study was supported by Amgen.

Conflicts of interest:

One author reports personal fees from Amgen, outside the submitted work.

One author reports personal fees from BMS, MSD, Bayer Health Care and Ipsen, outside the submitted work. One author reports personal fees from Amgen, Merck, Roche, Bayer, Lilly and BMS, outside the submitted work. One author reports personal fees from MSD, BMS, Novartis, Boehringer and Pfizer, grants and personal fees from Roche and AZ, grants from Bruker, outside the submitted work. All other authors do not have any conflict of interest.

Patients with advanced biliary tract cancer and wild-type KRAS mutation status

Inclusion criteria:

age ≥ 18 y
histologically documented cholangiocarcinoma or gallbladder carcinoma
wild-type KRAS mutation status
ECOG performance status 0-2
no prior systemic therapy
life expectancy ≥ 12 wks

Exclusion criteria:

Not reported.

N total at baseline:

Randomized: N = 90

I: N = 62

C: N = 28

Important characteristics:

Age, median (range):

I: 62 y (18-82)

C: 59.5 y (22-76)

Sex, n/N (%) male:

I: 36/62 (58%)

C: 14/28 (50%)

Performance status

I: 39/62 (63%)

C: 17/28 (61%)

I: 19/62 (31%)

C: 11/28 (39%)

I: 2/62 (3%)

C: 0/28 (0%)

Groups were comparable at baseline, but not all patient characteristics could be compared due to unclear reporting.

Gemcitabine (1000 mg/m²), cisplatin (25 mg/m²) and panitumumab (9 mg/kg) on days 1 and 8 of a 21-day cycle

Gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²) on days 1 and 8 of a 21-day cycle

Length of follow-up:

Not reported.

Loss to follow-up or missing outcome data:

An intention-to-treat analysis including all 90 randomised patients was included for OS and PFS.

87 (I: 59/C:28) patients received at least one application of study therapy and were included in the toxicity assessment

Clinical outcomes

Progression-free survival

Months, median

I: 6.5

C: 8.3

HR 0.73 (95%CI: 0.45-1.21)

Overall survival

Months, median

I: 12.8

C: 20.1

HR 0.70 (95%CI: 0.41-1.18)

Safety

Toxicity grade ≥ 3

Leukopenia

I: 13/59 (22%)

C: 8/28 (29%)

p = 0.5939

Neutropenia

I: 26/59 (44%)

C: 13/28 (47%)

p = 1.0000

Febrile neutropenia

I: 3/59 (5%)

C: 0/28 (0%)

p = 0.5480

Thrombocytopenia

I: 18/59 (31%)

C: 12/28 (43%)

p = 0.3350

Anemia

I: 7/59 (12%)

C: 3/28 (11%)

p = 1.0000

Dry skin

I: 3/59 (5%)

C: 0/28 (0%)

p = 0.5480

Nail changes

I: 1/59 (2%)

C: 0/28 (0%)

p = 1.0000

Rash

I: 7/59 (12%)

C: 0/28 (0%)

p = 0.0912

Acne

I: 10/59 (17%)

C: 0/28 (0%)

p = 0.0268

Diarrhea

I: 3/59 (5%)

C: 0/28 (0%)

p = 0.5480

Mucositis

I: 0/59 (0%)

C: 1/28 (4%)

p = 0.3218

Nausea

I: 2/59 (3%)

C: 1/28 (4%)

p = 1.0000

Fatigue

I: 4/59 (7%)

C: 0/28 (0%)

p = 0.3005

Fever

I: 0/59 (0%)

C: 0/28 (0%)

p = 0.10000

Infection

I: 6/59 (10%)

C: 6/28 (21%)

p = 0.1890

Neuropathy

I: 0/59 (0%)

C: 0/28 (0%)

p = 0.10000

Dyspnea

I: 1/59 (2%)

C: 0/28 (0%)

p = 0.10000

Definitions:

* Wild-type KRAS mutation status was defined as no mutations in exon 2, codons 12-13.

Remarks:

Authors conclusion:

Panitumumab in combination with chemotherapy does not improve progression-free survival and overall survival in patients with KRAS wild-type, advanced biliary cancer. Genetic profiling should be included in cholangiocarcinoma trials to identify and validate predictive and prognostic biomarkers.

Oh (2022)

TOPAZ-1 trial

Type of study:

Multicenter, double-blind randomized phase III trial

Setting and country:

105 centers in 17 countries

Source of funding:

AstraZeneca sponsored the trial and collaborated with the

steering committee on the trial design and collection, analysis,

and interpretation of the data. Data analyses were

completed by PHASTAR, London, United Kingdom, and

AstraZeneca. Durvalumab was provided by AstraZeneca.

Conflicts of interest:

Several authors reported multiple conflicts of interest

Patients with advanced biliary tract cancer

Inclusion criteria:

- Adults 18 years of age or older;

- histologically confirmed

unresectable, locally advanced, or metastatic adenocarcinoma

of the biliary tract, - previously untreated disease that was unresectable

or metastatic at initial diagnosis as well as those who

developed recurrent disease more than 6 months after surgery

with curative intent and more than 6 months after the

completion of adjuvant therapy;

- ECOG

performance status of 0 or 1;

- one or more measurable

lesions per RECIST v1.1;,

- no prior exposure to

immune-mediated therapy.

Exclusion criteria:

- ampullary

carcinoma;

- active or prior

documented

autoimmune or

inflammatory

disorders;

- known allergy

or hypersensitivity to any study treatment.

N total at baseline:

Randomized: N = 685

I: N = 341

C: N = 344

Important characteristics:

Age, median (range):

I: 64 y (20-84)

C: 64 y (31-85)

Sex, n/N (%) male:

I: 169/341 (49.6%)

C: 176/344 (51.2%)

Primary tumor type

Intrahepatic cholangiocarcinoma

I: 190/341 (55.7%)

C: 193/344 (56.1%)

Extrahepatic cholangiocarcinoma

I: 66/341 (19.4%)

C: 65/344 (18.9%)

Gallbladder

I: 85/341 (24.9%)

C: 86/344 (25.0%)

Performance status

I: 173/341 (50.7%)

C: 163/344 (47.4%)

Groups were comparable at baseline

Gemcitabine,

cisplatin and durvalumab were administered intravenously on a 21-day cycle for up to eight cycles.

Durvalumab (1500mg) was administered on day 1 of each cycle, in combination

with gemcitabine (1000 mg/m2) and cisplatin (25mg/m²), which were administered on days 1 and 8 of each cycle.

Gemcitabine, cisplatin and placebo were administered intravenously on a 21-day cycle for up to eight cycles.

Placebo (1500mg) was administered on day 1 of each cycle, in combination

with gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²), which were administered on days 1 and 8 of each cycle.

Length of follow-up:

I: Median duration of 16.8 months (95%CI 14.8 to 17.7 months)

C: median duration of 15.9 months (95%CI 14.9 to 16.9)

Loss to follow-up or missing outcome data: All patients were evaluated for overall survival and progression-free survival. 338/341 (99%) and 342/342 (99%) received ≥1 dose of study treatment and were included in the safety analysis.

Overall survival

Months, median

I: 12.8 (95%CI 11.1 to 14.0)

C: 11.5 (95%CI: 10.1 to 12.5)

HR 0.80 (95%CI: 0.66 to 0.97; p=0.021)

Progression-free survival

Months, median

I: 7.2 (95%CI: 6.7 to 7.4)

C: 5.7 (95%CI: 5.6 to 6.7)

HR 0.75 (95%CI: 0.63 to 0.89)

Safety (toxicity grade ≥ 3)

Any grade 3 or 4 event

I: 256/338 (75.7%)

C: 266/342 (77.8%)

Neutropenia

I: 65/338 (19.2%)

C: 69/342 (20.2%)

Anemia

I: 64/338 (18.9%)

C: 64/342 (18.7%)

Thrombocytopenia

I: 12/338 (3.6%)

C: 18/342 (5.3%)

Fatigue

I: 9/338 (2.7%)

C: 8/342 (2.3%)

Leukopenia

I: 7/338 (2.1%)

C: 2/342 (0.6%)

Asthenia

I: 4/338 (1.2%)

C: 7/342 (2.0%)

Review authors’ conclusion

The global, phase 3 TOPAZ-1 trial, at a preplanned

interim analysis, met the primary objective of a

statistically significant improvement in overall survival in patients with advanced biliary tract cancer; this occurred with similar percentages of Grade 3 and 4 adverse events in both groups. The trial is ongoing toward completion.

Kelley (2023)

(KEYNOTE-966 study)

Type of study:

Multicenter, double-blind randomized phase III trial

Setting and country:

175 centres in Asia-Pacific, Europe, North America, and South America

Source of funding: The study was funded by Merck Sharp & Dohme. In collaboration with the academic authors, authors employed by the study funder contributed to study design, data analysis, data interpretation, and writing of the report. The funder maintained the study database and ensured data were collected according to the protocol.

Conflicts of interest:

An extensive list of potential conflicts of interest is reported

Patients with advanced biliary tract cancer

Inclusion criteria:

- age 18 years or older;

- histologically confirmed unresectable locally advanced or metastatic extrahepatic cholangiocarcinoma (including mixed hepatocellular carcinoma and cholangiocarcinoma), gallbladder cancer, or intrahepatic cholangiocarcinoma;

- disease measurable per RECIST version1.1;

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;

- provided tumour tissue for biomarker assessment;

- adequate organ function;

- life expectancy of more than 3 months;

- the only previous systemic therapy permitted was neoadjuvant or adjuvant therapy completed at least 6 months before the diagnosis of unresectable or metastatic disease.

Exclusion criteria: - ampullary cancer;

- active autoimmune disease that required systemic treatment in the previous 2 years;

N total at baseline:

Randomized: N = 1068

I: N = 533

C: N = 536

Important characteristics:

Age, median (range):

I: 64 y (57-71)

C: 63 y (55-70)

Sex, n/N (%) male:

I: 280/533 (53%)

C: 272/536 (51%)

Primary tumor type

Intrahepatic cholangiocarcinoma

I: 320/533 (60%)

C: 313/536 (58%)

Extrahepatic cholangiocarcinoma

I: 98/533 (18%)

C: 105/536 (20%)

Gallbladder

I: 115/533 (22%)

C: 118/536 (22%)

Performance status

I: 258/533 (48%)

C: 228/536 (43%)

I: 274/533 (51%)

C: 308/536 (57%)

³ 2

I: 1/533 (<1%)

C: 0

Groups were comparable at baseline

Gemcitabine 1000 mg/m²and cisplatin 25 mg/m²were administered intravenously on days 1 and 8 of 3 week cycles.

Pembrolizumab 200 mg was administered intravenously once every 3 weeks

Gemcitabine 1000 mg/m²and cisplatin 25 mg/m²were administered intravenously on days 1 and 8 of 3 week cycles.

Saline placebo was administered intravenously once every 3 weeks

Length of follow-up:

Median duration of 25.6 months (95%CI 21.7 to 30.4 months)

Loss to follow-up or missing outcome data:

All patients were evaluated for overall survival and progression-free survival.

Overall survival

Months, median

I: 12.7 (95%CI 11.5 to 13.6)

C: 10.9 (95%CI: 9.9 to 11.6)

HR 0.83 (95%CI: 0.72 to 0.95; p=0.034)

Subgroup analyses for overall survival

Age

<65: HR 0.88 (95% 0.73 to 1.05)

³65: HR 0.79 (95%CI 0.65 to 0.97)

Sex

Female: HR 0.85 (95%CI 0.70 to 1.03)

Male: HR 0.83 (95%CI 0.69 to 1.00)

Geographical region

Asia: HR 0.88 (95%CI 0.72 to 1.08)

Not Asia: HR 0.80 (5%CI 0.67 to 0.96)

ECOG performance status

0: HR 0.87 (95%CI 0.71 to 1.07)

1: HR 0.84 (95%CI 0.70 to 1.00)

Smoking status

Current: HR 0.90 (95%CI 0.58 to 1.40)

Former: HR 0.87 (95%CI 0.70 to 1.09)

Never: HR 0.82 (95%CI 0.68 to 0.98)

Antibiotic use within 1 month of study start

No: HR 0.86 (95%CI 0.71 to 1.05)

Yes: HR 0.81 (95%CI 0.68 to 0.98)

Site of origin

Extrahepatic: HR 0.99 (95%CI 0.73 to 1.35)

Gallbladder: HR 0.96 (95%CI 0.73 to 1.26)

Intrahepatic: HR 0.76 (95%CI 0.64 to 0.91)

Disease status

Locally advanced: HR 0.69 (95%CI 0.45 to 1.06)

Metastatic: HR 0.85 (95%CI 0.74 to 0.98)

Biliary stent or drain

No: HR 0.85 (95%CI 0.74 to 0.98)

Yes: HR 0.72 (95%CI 0.43 to 1.19)

Previous chemotherapy

No: HR 0.86 (95%CI 0.75 to 0.99)

Yes: HR 0.66 (95%CI 0.41 to 1.08)

PD-L1 combined positive score

<1: HR 0.84 (95%CI 0.62 to 1.14)

³1: HR 0.85 (95%CI 0.72 to 1.00)

Unknown: HR 0.77 (95%CI 0.51 to 1.18)

Progression-free survival

Months, median

I: 6.5 (95%CI: 5.7 to 6.9)

C: 5.6 (95%CI: 5.1 to 6.6)

HR 0.86 (95%CI: 0.75 to 1.00; p=0.023)

Safety (toxicity grade ≥ 3)

Any grade 3 or 4 event

I: 369/529 (70%)

C: 367/534 (69%)

Decreased neutrophil count

Grade 3

I: 167/529 (32%)

C: 171/534 (32%)

Grade 4

I: 90/529 (17%)

C: 82/534 (15%)

Anaemia

Grade 3

I: 150/529 (28%)

C: 150/534 (28%)

Grade 4

I: 2/529 (<1%)

C: 4/534 (1%)

Decreased platelet count

Grade 3

I: 64/529 (12%)

C: 67/534 (13%)

Grade 4

I: 30/529 (6%)

C: 40/534 (7%)

Fatigue

Grade 3

I: 25/529 (5%)

C: 22/534 (4%)

Grade 4

I: 1/529 (<1%)

C: 0

Decreased white blood cell count

Grade 3

I: 57/529 (11%)

C: 44/534 (8%)

Grade 4

I: 4/529 (1%)

C: 3/534 (1%)

Review authors’ conclusion

KEYNOTE966 met its primary endpoint as pembrolizumab plus gemcitabine and cisplatin resulted in a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin alone without new safety signals in participants with previously untreated metastatic or unresectable biliary tract cancer. Pembro lizumab plus gemcitabine and cisplatin could be a new treatment option for this population.

Risk of bias assessment

Table of quality assessment for systematic reviews of RCTs and observational studies

Study reference

Appropriate and clearly focused question?¹

Yes

Unclear

Comprehensive and systematic literature search?²

Yes

Unclear

Description of included and excluded studies?³

Yes

Unclear

Description of relevant characteristics of included studies?⁴

Yes

Unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes

Unclear

Not applicable

Assessment of scientific quality of included studies?⁵

Yes

Unclear

Enough similarities between studies to make combining them reasonable?⁶

Yes

Unclear

Potential risk of publication bias taken into account?⁷

Yes

Unclear

Potential conflicts of interest reported?⁸

Yes

Unclear

Jiang (2021)

Yes

The research question is: ‘What is the best treatment strategy for the first-line treatment of patients with advanced biliary tract cancer?’

Unclear

The full search strategy is not reported. Instead, MeSH terms are listed. The search was conducted in PubMed, Embase, and Cochrane Library (articles published before August 10, 2020) and resulted in 1668 hits.

No information is provided about potentially relevant studies that were excluded after reading the full text (n=134)

Yes

Relevant characteristics of included studies are provided in Table 1.

Not applicable

Yes

Two researchers independently assessed the quality of all included literature based on RCT Cochrane Reviewer bias risk assessment criteria: (1) generation of random sequences; (2) allocation concealment or not; (3) blind method or not; (4) complete results or not; (5) selective reporting or not; (6) other biases. These key points are divided into three levels: low risk, high risk, and unclear risk. Differences between investigators are resolved through discussion.

Unclear

Yes

Publication bias was assessed using funnel plots, but the results are not explicitly addressed.

The review was supported by the Guangxi Natural Science

Foundation.

The source of funding for the included studies is not reported.

The authors of the review declare that there was no conflict of interest for this review.

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.

Risk of bias assessment of intervention studies (randomized controlled trials)

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 measure^g

LOW

SOME CONCERNS

HIGH

Leone (2016)

Probably yes;

Patients were randomized through a computed system with permuted-block randomization and stratified according to the ECOG performance status and the site of the primary tumor.

Probably yes;

Patients were randomized through a computed system. However, it is unclear whether the randomization was performed at a site remote from the trial location.

Definitely no;

Open-label study. Participants, investigators, and trial staff were made aware of treatment allocations.

Probably yes;

Loss to follow-up was infrequent and reasons for discontinuation of treatment were similar between the groups

Definitely yes;

All outcome measures described in the trial register are reported in this article.

Probably yes;

SOME CONCERNS

(overall survival, progression-free survival, toxicity)

Vogel (2018)

No information;

Definitely no;

Open-label study

Probably yes;

Loss to follow-up was infrequent

Definitely yes;

All outcome measures described in the trial register are reported in this article.

Probably yes;

HIGH

(overall survival, progression-free survival, toxicity)

Oh (2022)

Probably yes;

The randomization scheme will be produced by a computer software program

that incorporates a standard procedure for generating randomization numbers.

One randomization list will be produced for each of the randomization stratum. A blocked

randomization will be generated, and all centers will use the same list in order to minimize

any imbalance in the number of patients assigned to each treatment group.

Definitely yes;

Randomization codes

will be assigned strictly sequentially, within each stratum, as patients become eligible for

randomization. The interactive voice/web response system will provide the kit identification number to be allocated to

the patient at the randomization visit and subsequent treatment visits.

Definitely yes;

The study will be conducted in a double-blind manner. The patient, the Investigator, and

study center staff will be blinded to the durvalumab/placebo allocation and will remain

blinded to each patient’s assigned study treatment throughout the course of the study. No member of the extended study team at AstraZeneca, at the investigational centers, or any

Contract Research Organization handling data will have access to the randomization scheme

until the time of the final data analysis (ie, the primary PFS analysis) or any interim analysis

data where a decision is made to unblind the study.

Definitely yes;

All patients were evaluated for overall survival and progression-free survival.

338/341 (99%) and 342/342 (99%) received ≥1 dose of study treatment and were included in the safety analysis.

Probably no;

According to the trial register and the methods section of the paper, quality of life was also assessed but this outcome was not reported.

Probably no;

AstraZeneca sponsored the trial and collaborated with the steering committee on the trial design and collection, analysis,

and interpretation of the data.

Data analyses were

completed by PHASTAR, London, United Kingdom, and AstraZeneca.

Because a statistically significant improvement

in overall survival in the durvalumab arm compared with the placebo arm was observed at the planned interim

analysis, the key secondary end point of progression-free

survival was formally evaluated at this interim analysis.

SOME CONCERNS

(overall survival, progression-free survival, toxicity)

Kelley (2023)

(KEYNOTE-966 trial)

Probably yes;

Participants were randomly assigned (1:1) to pembrolizumab or placebo (normal saline) by study investigators using a central interactive voiceresponse system (Almac Clinical Technologies, Souderton, PA, USA) and a randomisation list generated by the study funder. Randomisation was stratified by geographical region, disease stage, and site of origin.

Definitely yes;

Participants, investigators, and those collecting or analysing the data, including representatives of the sponsor, were masked to treatment assignment. Pembrolizumab and saline placebo were packaged identically to ensure participants and investigators remained masked to treatment assignment.

Definitely yes;

All patients were evaluated for overall survival and progression-free survival.

529/533 (99%) and 534/536 (99%) received ≥1 dose of study treatment and were included in the safety analysis.

Definitely yes;

All outcome measures described in the trial register are reported in this article.

Probably no;

Merck Shard & Dohme funded the study.

In collaboration with the academic authors, authors employed by the study funder contributed to study design, data analysis, data interpretation, and writing of the report. The funder maintained the study database and ensured data were collected according to the protocol.

SOME CONCERNS

(overall survival, progression-free survival, toxicity)

^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 (e.g. 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 excluded studies

Author and year	Reason for exclusion
Reviews
Kamarajah (2020)	Wrong intervention: neoadjuvant treatment
Belkouz (2019)	Wrong topic: biomarkers for chemotherapy
Lamarca (2019)	Wrong publication type: not a systematic review
Li (2019)	More recent review available
Javle (2019)	Wrong publication type: narrative review
Ying (2019)	Wrong intervention: second-line treatment
Hakeem (2019)	Wrong intervention: neoadjuvant treatment
Zhang (2019)	Wrong publication type: case report and narrative review
Zheng (2019)	More recent review available
Cai (2018)	More comprehensive review available
Zhuang (2017)	More comprehensive review available
Sun (2017)	More comprehensive review available
Zhao (2016)	More comprehensive review available
Vogel (2018)	Wrong publication type: not a systematic review
Chen (2016)	More comprehensive review available
Moriwaki (2016)	Wrong topic: correlation of survival with other outcome measures
Simo (2016)	Wrong intervention: not limited to systemic treatment
Tampellini (2016)	Wrong publication type: not a systematic review
Park (2015)	More comprehensive review available
Boehm (2015)	Wrong intervention: locoregional treatment
Liu (2014)	More comprehensive review available
Valle (2014)	More comprehensive review available
Zhu (2014)	Wrong intervention: adjuvant treatment
Eckel (2014)	More comprehensive review available
Fiteni (2014)	More comprehensive review available
Grendar (2014)	Wrong intervention: neoadjuvant treatment
Lamarca (2014)	Wrong intervention: second-line treatment
Yang (2013)	More comprehensive review available
Sun (2013)	More comprehensive review available
Roth (2012)	Wrong publication type: not a systematic review
RCTs
Abou-Alfa (2020)	Wrong study design: not an RCT
Abou-Alfa (2020)	Wrong intervention: second-line treatment
Davis (2018)	Wrong study design: not an RCT
Demols (2019)	Wrong publication type: abstract only
Demols (2020)	Wrong intervention: second-line treatment
Javle (2018)	Wrong study design: not an RCT
Kataria (2019)	Wrong publication type: abstract only
Kim (2020)	Wrong intervention: second-line treatment
Kim (2019)	Included in review by Jiang (2021)
Lamarca (2020)	Wrong study design: not an RCT (post-hoc analysis)
Morizane (2019)	Included in review by Jiang (2021)
Yoon (2018)	Wrong publication type: abstract only
Zheng (2018)	Wrong intervention: second-line treatment
Chiang (2018)	Wrong study design: not an RCT
Feng (2020)	Wrong study design: not an RCT
Harding (2019)	Wrong publication type: abstract only
Hollebecque (2018)	Wrong study design: not an RCT
Ikeda (2018)	Wrong study design: not an RCT
Iyer (2018)	Wrong study design: not an RCT
Javle (2018)	Wrong publication type: abstract only
Jensen (2020)	Wrong study design: not an RCT
Kim (2019)	Wrong study design: not an RCT
Kim (2018)	Wrong study design: not an RCT
Kim (2020)	Wrong study design: not an RCT
Kim (2020)	Wrong study design: not an RCT
Klein (2020)	Wrong study design: not an RCT
Larsen (2018)	Wrong study design: not an RCT
Markussen (2020)	Included in review by Jiang (2021)
Okano (2020)	Wrong study design: not an RCT
Perkhofer (2019)	Wrong publication type: study protocol
Sahai (2018)	Wrong study design: not an RCT
Sgouros (2020)	Wrong study design: not an RCT
Shroff (2019)	Wrong study design: not an RCT
Subbiah (2020)	Wrong study design: not an RCT
Sun (2019)	Wrong study design: not an RCT
Yoo (2018)	Wrong study design: not an RCT
Javle (2019)	Wrong publication type: study protocol
Yang (2020)	Wrong intervention: systemic treatment and locoregional treatment

Verantwoording

Autorisatiedatum en geldigheid

Laatst beoordeeld : 25-06-2024

Laatst geautoriseerd : 25-06-2024

Geplande herbeoordeling : 25-06-2027

Initiatief en autorisatie

Initiatief:

Nederlandse Vereniging voor Heelkunde

Geautoriseerd door:

Nederlandse Internisten Vereniging
Nederlandse Vereniging van Maag-Darm-Leverartsen
Nederlandse Vereniging voor Heelkunde
Nederlandse Vereniging voor Pathologie
Nederlandse Vereniging voor Radiologie
Verpleegkundigen en Verzorgenden Nederland
Nederlandse Federatie van Kankerpatiëntenorganisaties
Patiëntenplatform Zeldzame Kankers

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 Kwaliteitsgelden Medisch Specialisten (SKMS). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Overzicht modules

Tranche 1 (deze modules zijn in 2023 geautoriseerd)

Hoofdstuk	Nr	Moduletitel	Vorm
Diagnostiek	1	Meerwaarde PET bij biliare tumoren	Nieuw ontwikkeld
Behandeling	2	Preoperatieve galwegdrainage	Nieuw ontwikkeld
Pathologie	3	Verslag en aanvraag pathologie	Update van bestaande module
Communicatie en besluitvorming	4	Communicatie en besluitvorming	Nieuw ontwikkeld
Nazorg	5	Nazorg en nacontrole	Update van bestaande module

Tranche 2 (huidige autorisatieronde)

Hoofdstuk		Moduletitel	Vorm
Diagnostiek	6	Cross-sectionele beeldvorming	Update van bestaande module
Behandeling	7	Locoregionale behandeling met TACE of SIRT voor iCCA	Nieuw ontwikkeld
Behandeling	8	Preoperatieve vena porta embolisatie	Update van bestaande module
Behandeling	9	Indicatie resectie	Update van bestaande module
Behandeling	10	Adjuvante systemische behandeling	Update van bestaande module
Behandeling	11	Palliatieve systemische behandeling in de 1^e lijn	Update van bestaande module
Behandeling	12	Palliatieve systemische behandeling na de 1^e lijn	Update van bestaande module

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodule is in 2020 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 galweg- of galblaascarcinoom.

Werkgroep

Dr. B. (Bas) Groot Koerkamp, Chirurg/ Epidemioloog, Erasmus MC, Rotterdam, NVvH (voorzitter)
Dr. J.I. (Joris) Erdmann, Chirurg, Amsterdam UMC, Amsterdam, NVvH
Dr. P.R. (Philip) de Reuver, Chirurg, Radboudumc, Nijmegen, NVvH
Dr. M.T. (Marieke) de Boer, Chirurg, UMCG, Groningen, NVvH ((tot mei 2022)
Dr. F.J.H. (Frederik) Hoogwater, Chirurg, UMCG, Groningen, NVvH (vanaf mei 2022)
Dr. H.J. (Heinz-Josef) Klümpen, Internist-oncoloog, Amsterdam UMC, Amsterdam, NIV
Dr. N. (Nadia) Haj Mohammad, Internist-oncoloog, UMC Utrecht, Utrecht, NIV
Drs. F.E.J.A. (Franꞔois) Willemsen, Abdominaal radioloog, Erasmus MC, NVvR
Prof. dr. O.M. (Otto) van Delden, interventieradioloog, Amsterdam UMC, Amsterdam, NVvR
Dr. L.M.J.W. van Driel, maag-darm-leverarts, Erasmus MC, Rotterdam, NVMDL
Prof. dr. J. (Joanne) Verheij, klinisch patholoog, Amsterdam UMC, Amsterdam, NVVP
Dr. R.S. (Chella) van der Post, patholoog, Radboudumc, Nijmegen, NVVP (vanaf februari 2022)
C. (Chulja) Pek, Verpleegkundig specialist, Erasmus MC, Rotterdam, V&VN
Drs. M.A. (Marga) Schrieks, Projectleider Patiëntenplatform Zeldzame Kankers, NFK
A. (Anke) Bode MSc, Patiëntvertegenwoordiger, NFK (tot april 2023)
Drs. A.C. (Christine) Weenink, Patiëntvertegenwoordiger/huisarts, NFK (vanaf april 2023)

Met dank aan

M. (Mike) van Dooren, arts-onderzoeker, Radboudumc, Nijmegen

Met ondersteuning van

Drs. M. Oerbekke, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. N. Elbert, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
Dr. L.J.M. Oostendorp, Senior 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
Groot Koerkamp	Chirurg en epidemioloog, Erasmus MC	Onbetaald: * secretaris wetenschappelijke commisssie van de Ducth Pancreatic Cancer Group (DPCG) * bestuurslid van de Dutch Hepatocellular and Cholangiocarcinoma Group (DHCG) * Lid van de audit commissie van de Nederlandse Vereniging voor Heelkunden (NVvH) * Voorzitter van de werkgroep cholangiocarcinoom van de DHCG * Lid van de wetenschappelijke commissie van de DHCG	Intellectuele belangen en reputatie Expertise op gebied van intra-arteriele chemotherapie. Ik ben PI vna een door KWF gefinancierde klinische studie van intra-arteriele chemotherapie voor niet-resectabel intrathepatisch cholangiocarcinoom	Geen restricties (in deze herziening komt het onderwerp Hepatic Arterial Infusion niet aan de orde)
Erdmann	Chirurg, Amsterdam UMC	Geen	Geen	Geen restricties
De Reuver	Chirurg gastro-enterologische chirurgie, Radboudumc, Nijmegen	Geen	Extern gefinancierd onderzoek PI van onderzoek naar Galblaascarcinoom, in 2017 gefinancieerd door Stichting ADP. Stichting heeft geen belang in het advies of de richtlijn.	Geen restricties
De Boer	Chirurg UMCG afdeling chirurgie, HPB chirurgie en levertransplantatie	Geen	Geen	Geen restricties
Hoogwater	Chirurg, Hepato-Pancreato-Biliaire Chirurgie en Levertransplantatie, Universitair Medisch Centrum Groningen	* Bestuurslid - Dutch Hepatocellular & Cholangiocarcinoma Group (DHCG), onbetaald * Commissielid - Continue Professionele Educatie van de NVvH, onbetaald * Lid - Wetendchappelijke Commissie Dutch Hepato Biliary Audit (DHBA), vacatiegeld * Bestuurslid Nederlandse Vereniging Chirurgische Oncologie (NVCO), onbetaald	Geen	Geen restricties
Klümpen	Internist-oncoloog in Amsterdam UMC	* Subdomain leader for biliary tract cancer EURACAN (onbetaald) * Lid wetenschappelijke commissie van de DHCG (onbetaald) * Dutch representative for European Cooperation in Science and Technology COST (biliary tract cancer) grant by HORIZON 2020 (onbetaald, wel worden reizen vergoed die door COST georganiseerd worden) * Member of European Network for the Study of Cholangiocarcinoma ENSCCA (onbetaald) * Member international billary tract cancer consortium IBTCC (onbetaald)	Extern gefinancierd onderzoek KWF financieert de ACTICCA studie en PUMP 2 studie, deze studies zijn gesloten voor inclusie Het Amsterdam UMC met mij als lokale PI doet mee en heeft meegedaan aan studies voor galweg en galblaascarcinoom: * TAS-120 studie van TAIHO (fase I/II) * SIRCCA studie van SIRTEX (fase III, is vroegtijdig gestopt) * KEYNOTE 966 studie van MSD (fase III studie)	Geen restricties tenzij een van de middelen uit het extern gefinancierd onderzoek toch aan de orde komt in deze herziening. In dat geval volgt uitsluiting van de formulering van de aanbevelingen over de middelen in de betreffende trials. TAS-120: futibatinib (TAIHO) SIRCCA: selective internal radiotherapy SIRT met 90-Y microspheres i.c.m. chemotherapie (SIRTEX) KEYNOTE-966: pembrolizumab (MSD)
Haj Mohammad	Internist-oncoloog, Universitair Medisch Centrum Utrecht	* Penningmeester Dutch Upper GI Cancer (DUCG), onbetaald * Lid Wetenschappelijke raad DHCG, onbetaald * Member of European Network for the Study of Cholangiocarcinoma ENSCCA, onbetaald Advisory boards: Astra Zenca, Servier, BMS, Merck, Lilly, betaald aan mijn afdeling	Extern gefinancierd onderzoek * Merck – MK 966 gemetastaseerd BTC fase 3, gem cis + placebo vs gem cis + pembrolizumab (lokale PI) * Incyte – FIGHT-302: FGFR fusie, fase 3 gerandomiseerd gem cis vs pemigatinib (lokale PI) * KWF - PUMP-2: irresectabel intrahepatisch cholangiocarcinoom, fase 2 haalbaarheid intrahepatische chemotherapie gecombineerd met systemische chemotherapie (lokale PI) * KWF - ACTICCA: adjuvant, fase 3 gerandomiseerd gem cis vs capecitabine (lokale PI)	Bij aanvang van het project waren geen restricties geformuleerd. Bij het herbevestigen van belangen werden een aantal nieuwe belangen gemeld. Om de onafhankelijkheid van de richtlijn te waarborgen zijn de betreffende modules meegelezen door twee onafhankelijke deskundigen vanuit de NIV.
Willemsen	Abdominaal radioloog Erasmus MC te Rotterdam	Geen	Geen	Geen restricties
Van Delden	Interventieradioloog, Amsterdam UMC	Geen	Geen	Geen restricties
Van Driel	MDL-arts, staflid, Erasmus MC Rotterdam - fulltime aanstelling	Geen	Geen	Geen restricties
Verheij	Klinisch patholoog (1 fte) met specialisme Hepato-pancreatobiliaire pathologie Amsterdam UMC	* Lid medisch Advies Raad Nederlandse Leverpatiënten Vereniging (NLV) (onbetaald) * Voorziter sectie HPB, Expertise Groep Gastrointestinale Pathologie, NVVP (onbetaald)	Geen	Geen restricties
Van der Post	Klinisch patholoog, Radboud Universitair medisch centrum	* Commissie lid Wetenschap NVVP (onbetaald) * Programmacommissie lid Kwaliteitsprojecten SKMS (vacatiegelden) * Voorzitter expertisegroep gastrointestinale pathologen EGIP, onderdeel NVVP (onbetaald)	Extern gefinancierd onderzoek * Stichting ADP - From bench to bedside, the molecular characteristics of galbladder cancer - Projectleider * KWF kankerbestrijding - Dissecting the role of aberrant E-cadherin signaling in the initiation and progression of diffuse-type gastric cancer - Projectleider * Stichting Hanarth Fonds - Unmasking the invisible cancer: digital detection of diffuse-type gastric carcinomas - Projectleider	Geen restricties
Pek	Verpleegkundig specialist Erasmus MC Rotterdam. Pancreas- en galwegchircurgie specialist obstructie icterus	Geen	Geen	Geen restricties
Schrieks	Projectleider Patiëntenplatform Zeldzame Kanker	Geen	Geen	Geen restricties
Bode	* Patiënt vertegenwoordiger * Kinderfysiotherapeut MSc in ruste Zorggroep Almere (niet meer werkzaam) * Vrijwilliger bij patiëntenplatform Zeldzame kankers	Geen	Geen	Geen restricties
Weenink	Patiënt vertegenwoordiger Huisarts bij HAP Binnenstad Utrecht	Geen	Geen	Geen restricties

Inbreng patiëntenperspectief

Er werd aandacht besteed aan het patiëntenperspectief door het uitnodigen van het Patiëntenplatform Zeldzame Kankers om deel te nemen in de werkgroep en aan de schriftelijke knelpuntenanalyse. 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 zal tevens voor commentaar worden voorgelegd aan Patiëntenplatform Zeldzame Kankers.

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijn is conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uitgevoerd of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling zijn richtlijnmodules op verschillende domeinen getoetst (zie het stroomschema op de Richtlijnendatabase).

Uit de kwalitatieve raming blijkt dat er waarschijnlijk geen substantiële financiële gevolgen zijn, zie onderstaande tabel.

Module	Uitkomst raming	Toelichting
Module ‘Palliatieve systemische behandeling in de 1^e lijn’	Geen substantiële financiële gevolgen	Uit de toetsing volgt dat de aanbevelingen niet breed toepasbaar zijn (<5.000 patiënten) en daarom naar verwachting geen substantiële financiële gevolgen zullen hebben voor de collectieve uitgaven.

Implementatie

Inleiding

Dit plan is opgesteld ter bevordering van de implementatie van de richtlijn Galweg- en galblaascarcinoom. Voor het opstellen van dit plan is een inventarisatie gedaan van de mogelijk bevorderende en belemmerende factoren voor het toepassen en naleven van de aanbevelingen. Daarbij heeft de richtlijnwerkgroep een advies uitgebracht over het tijdspad voor implementatie, de daarvoor benodigde randvoorwaarden en de acties die voor verschillende partijen ondernomen dienen te worden.

Werkwijze

De werkgroep heeft per aanbeveling geïnventariseerd:

• per wanneer de aanbeveling overal geïmplementeerd moet kunnen zijn;

• de verwachtte impact van implementatie van de aanbeveling op de zorgkosten;

• randvoorwaarden om de aanbeveling te kunnen implementeren;

• mogelijk barrières om de aanbeveling te kunnen implementeren;

• mogelijke acties om de implementatie van de aanbeveling te bevorderen;

• verantwoordelijke partij voor de te ondernemen acties.

Voor iedere aanbevelingen is nagedacht over de hierboven genoemde punten. Echter niet voor iedere aanbeveling kon ieder punt worden beantwoord. Er kan een onderscheid worden gemaakt tussen “sterk geformuleerde aanbevelingen” en “zwak geformuleerde aanbevelingen”. In het eerste geval doet de richtlijncommissie een duidelijke uitspraak over iets dat zeker wel of zeker niet gedaan moet worden. In het tweede geval wordt de aanbeveling minder zeker gesteld (bijvoorbeeld “Overweeg om …”) en wordt dus meer ruimte gelaten voor alternatieve opties. Voor “sterk geformuleerde aanbevelingen” zijn bovengenoemde punten in principe meer uitgewerkt dan voor de “zwak geformuleerde aanbevelingen”. Bij elke module is onderstaande tabel opgenomen.

Aanbeveling

Tijdspad voor implementatie:
< 1 jaar,

1 tot 3 jaar of

> 3 jaar

Verwacht effect op kosten

Randvoorwaarden voor implementatie (binnen aangegeven tijdspad)

Mogelijke barrières voor implementatie¹

Te ondernemen acties voor implementatie²

Verantwoordelijken voor acties³

Overige opmerkingen

¹ Barrières kunnen zich bevinden op het niveau van de professional, op het niveau van de organisatie (het ziekenhuis) of op het niveau van het systeem (buiten het ziekenhuis). Denk bijvoorbeeld aan onenigheid in het land met betrekking tot de aanbeveling, onvoldoende motivatie of kennis bij de specialist, onvoldoende faciliteiten of personeel, nodige concentratie van zorg, kosten, slechte samenwerking tussen disciplines, nodige taakherschikking, et cetera.

² Denk aan acties die noodzakelijk zijn voor implementatie, maar ook acties die mogelijk zijn om de implementatie te bevorderen. Denk bijvoorbeeld aan controleren aanbeveling tijdens kwaliteitsvisitatie, publicatie van de richtlijn, ontwikkelen van implementatietools, informeren van ziekenhuisbestuurders, regelen van goede vergoeding voor een bepaald type behandeling, maken van samenwerkingsafspraken.

³ Wie de verantwoordelijkheden draagt voor implementatie van de aanbevelingen, zal tevens afhankelijk zijn van het niveau waarop zich barrières bevinden. Barrières op het niveau van de professional zullen vaak opgelost moeten worden door de beroepsvereniging. Barrières op het niveau van de organisatie zullen vaak onder verantwoordelijkheid van de ziekenhuisbestuurders vallen. Bij het oplossen van barrières op het niveau van het systeem zijn ook andere partijen, zoals de NZA en zorgverzekeraars, van belang. Echter, aangezien de richtlijn vaak enkel wordt geautoriseerd door de (participerende) wetenschappelijke verenigingen is het aan de wetenschappelijke verenigingen om deze problemen bij de andere partijen aan te kaarten.

Implementatietermijnen

Voor “sterk geformuleerde aanbevelingen” geldt dat zij zo spoedig mogelijk geïmplementeerd dienen te worden. Voor de meeste “sterk geformuleerde aanbevelingen” betekent dat dat zij komend jaar direct geïmplementeerd moeten worden en dat per 2025 dus iedereen aan deze aanbevelingen dient te voldoen.

Werkwijze

AGREE

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

Knelpuntenanalyse en uitgangsvragen

Tijdens de voorbereidende fase inventariseerden de werkgroep de knelpunten in de zorg voor patiënten met een galweg- of galblaascarcinoom. De werkgroep beoordeelde de aanbeveling(en) uit de eerdere richtlijnmodules (NVvH, 2013) op noodzaak tot revisie. Tevens zijn er knelpunten aangedragen door de patiëntenvereniging en genodigde partijen tijdens de schriftelijke knelpuntenanalyse. De notulen van de tweede werkgroepvergadering waarin de resultaten van de schriftelijke knelpuntenanalyse zijn besproken zijn opgenomen als bijlage. 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 is te vinden onder ‘Zoeken en selecteren’ onder Onderbouwing. Indien mogelijk werd de data uit verschillende studies gepoold in een random-effects model. Review Manager 5.4 werd gebruikt voor de statistische analyses. De beoordeling van de kracht van het wetenschappelijke bewijs wordt hieronder toegelicht.

Beoordelen van de kracht van het wetenschappelijke bewijs

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

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

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

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

Overwegingen (van bewijs naar aanbeveling)

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

Formuleren van aanbevelingen

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

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

Implicaties van sterke en zwakke aanbevelingen voor verschillende richtlijngebruikers

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

Organisatie van zorg

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

Commentaar- en autorisatiefase

De conceptrichtlijnmodules werden 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 werden de conceptrichtlijnmodules aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodules werden aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.

Literatuur

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

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

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

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

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

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

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

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

Zoekverantwoording

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

Galweg- en galblaascarcinoom

Galweg- en galblaascarcinoom

Uitgangsvraag

Aanbeveling

Overwegingen

Onderbouwing

Achtergrond

Conclusies

Samenvatting literatuur

Zoeken en selecteren

Referenties

Evidence tabellen

Verantwoording

Autorisatiedatum en geldigheid

Initiatief en autorisatie

Algemene gegevens

Samenstelling werkgroep

Belangenverklaringen

Inbreng patiëntenperspectief

Module

Implementatie

Werkwijze

Zoekverantwoording

Bijlagen

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