Welke palliatieve systeemtherapie wordt geadviseerd bij patiënten met een (niet lokaal behandelbaar)-HCC?
Uitgangsvraag
Welke palliatieve systeemtherapie wordt geadviseerd bij patiënten met een (niet lokaal behandelbaar)-HCC?
Aanbeveling
Maak samen met de patiënt een afweging om wel of geen palliatieve systeemtherapie te starten. Bespreek de wensen en verwachtingen van de patiënt.
Bepaal voorafgaand aan de behandeling de leverfunctie. Een voldoende behouden leverfunctie is een voorwaarde om te starten met systeemtherapie (waarbij terughoudendheid bij een hoog geconjugeerd bilirubine wordt geadviseerd). Hierbij is een Child Pugh C niet goed genoeg voor systeemtherapie; bij A en B zal in het levercentrum de leverfunctie beoordeeld worden.
Geef bij patiënten met een behouden leverfunctie, die met eerstelijns palliatieve systeemtherapie behandeld willen worden, atezolizumab plus bevacizumab. Verifieer voor start dat er een gastroscopie is die niet ouder is dan 6 maanden met behandelde varices alvorens de behandeling te starten.
Geef sorafenib of lenvatinib bij patiënten die met palliatieve systeemtherapie behandeld willen worden die een behouden leverfunctie hebben, maar een contra-indicatie voor atezolizumab en bevacizumab. Hierbij heeft sorafenib de voorkeur gezien uitgebreidere ervaring en kosten, en kan er een voorkeur zijn voor lenvatinib gezien het hogere responspercentage.
Overweeg sorafenib in tweedelijn bij progressie op atezolizumab plus bevacizumab.
Overweeg regorafenib in de volgende lijn bij progressie op sorafenib.
Overwegingen
Voor- en nadelen van de interventie en de kwaliteit van het bewijs
Er is literatuuronderzoek verricht naar de verschillen in klinische uitkomsten tussen de verschillende (eerste, tweede en derdelijns) behandelingen die in Nederland aangeboden worden. Tot en met 15 april 2022 werden er vier gerandomiseerde gecontroleerde studies (RCTs) gevonden in de eerstelijnsbehandeling en één studie in de tweedelijnsbehandeling. Er zijn geen studies gevonden naar een derdelijns behandeling bij gevorderd of gemetastaseerd hepatocellulair carcinoom. Na de zoekdatum is er een update beschikbaar gekomen van één van de geïncludeerde RCTs. Deze is ook meegenomen in de literatuuranalyse (Cheng, 2022).
Binnen de eerstelijnsbehandeling werden vier RCTs gevonden, waarbij sorafenib vergeleken werd met placebo (Llovet, 2008; Cheng, 2009), lenvatinib met sorafenib (Kudo, 2018) en atezolizumab + bevacizumab met sorafenib (Finn, 2020; Cheng, 2022). De systematische literatuuranalyse laat zien dat de behandeling met sorafenib vergeleken met placebo een positief effect zou kunnen hebben op de algemene overleving, evenals de behandeling van atezolizumab + bevacizumab vergeleken met sorafenib. Lenvantib is non inferieur aan sorafenib. De overall bewijskracht van de literatuur binnen de eerstelijnsbehandelingen werd gegradeerd als laag en zeer laag. Dit heeft te maken met de imprecisie van de bevindingen (kleine aantal studies) en beperkingen in studie opzet (risk of bias).
Voor de tweedelijns behandeling werd één RCT gevonden, waarbij regorafenib vergeleken werd met placebo (Bruix, 2017). De systematische literatuuranalyse laat zien dat de behandeling met regorafenib positieve effecten zou kunnen hebben op de totale en ziektevrije overleving. Voor de uitkomstmaten tumor respons, complicaties en kwaliteit van leven waren er geen positieve klinische effecten te zien. De overall bewijskracht van de literatuur binnen de tweedelijnsbehandelingen werd gegradeerd als laag. Dit heeft te maken met imprecisie van de bevindingen doordat de bevindingen gebaseerd zijn op één studie. De Celestial studie is niet geselecteerd omdat patiënten met tweedelijns en derdelijns palliatieve systeemtherapie geïncludeerd werden, zonder dat hiervoor gestratificeerd werd. De overlevingswinst van deze groepen samen waren wel statistisch significant maar voldeden niet aan de oude PASKWIL criteria (OS van 10,2 versus 8,0 maanden; Δ 2,2 maanden, HR: 0,76; 95%-BI: 0,63- tot 0,92; P = 0,005).
Al de geïncludeerde fase III studies bevatten patiënten met Child-Pugh A (behalve Cheng, 2009) waardoor er geen uitspraak te doen is over patiënten met een Child-Pugh B leverrcirose. Op basis van retrospectieve data is terughoudendheid geboden voor behandeling met palliatieve systeemtherapie bij de groep met Child–Pugh B (Labeur, 2018) omdat deze data tonen dat de effectiviteit van de systeemtherapie minder is dan in de originele studie gezien werd. Tevens geldt dat terughoudendheid in acht moet worden genomen bij een geconjugeerd bilirubine van 3 keer ULN omdat dat in de meeste studies een exclusiecriterium was
Overige overwegingen
Waarden en voorkeuren van patiënten (en eventuele hun verzorgers)
Indien er een mogelijkheid is voor palliatieve systeemtherapie, is het wenselijk om de beslissing samen met de patiënt te nemen. Doel van palliatieve systeemtherapie is verlenging van overleving en vergroting van kwaliteit van leven. Persoonlijke voorkeuren van de patiënt zijn van grote invloed op deze keuze om wel of niet palliatieve systeemtherapie te starten.
In geval van wens voor palliatieve systeemtherapie heeft in eerstelijn atezolizumab met bevacizumab een grotere winst op OS (19.2 maanden versus 13.4 maanden, HR 0.66) en op kwaliteit van leven in vergelijking met sorafenib. De mediane tijd tot verslechtering van kwaliteit van leven was 11.2 maanden met atezolizumab plus bevacizumab versus 3.6 maanden met sorafenib (HR 0.73 95% CI 0.46 tot 0.85). Behandelgerelateerde bijwerkingen graad 3/4 waren gelijk namelijk 43 % in de groep met atezolizumab en bevacizumab versus 46% met sorafenib. Aspecten die gecontroleerd dienen te worden zijn of er contra-indicaties zijn voor immuuntherapie en of er therapeutische antistolling gebruikt wordt. Daar moet rekening mee gehouden worden in de behandeling met atezoluzimab plus bevacizumab. Daarnaast moet de leverfunctie voldoende zijn en dienen oesophagusvarices behandeld te zijn, indien geïndiceerd.
Indien er een contra-indicatie voor atezolizumab en/of bevacizumab is, heeft de behandelend arts in samenspraak met de patiënt de keuze om te starten met sorafenib of lenvatinib. Vanwege de langere ervaring met sorafenib versus lenvantinib en de lagere kosten heeft sorafenib de voorkeur boven lenvatinib. Echter, indien een snelle respons gewenst is, is lenvatinib te prefereren boven sorafenib (ORR lenvantinib 40.6% vergeleken met 12.4% met sorafenib). Behandelgerelateerde graad 3-4 bijwerkingen van sorafenib versus lenvatinib waren vergelijkbaar, maar het bijwerkingen patroon was verschillend. Dus bij toxiciteit van sorafenib kan een switch gemaakt worden naar lenvantinib.
De tweedelijns studie met regorafenib versus placebo toont een bescheiden overlevingswinst en geen verschil in kwaliteit van leven in vergelijking met placebo. Overweeg deze behandeling alleen bij fitte patiënten die progressief zijn onder behandeling met sorafenib en een goede leverfunctie hebben, en sorafenib goed hebben verdragen.
Er is nog geen wetenschappelijk bewijs voor tweedelijns behandeling na atezolizumab en bevacizumab. In dit geval zal op basis van klinische expertise, bijwerkingen profiel een afweging voor sorafenib conform de add-on gemaakt worden.
Op basis van exploratieve analyses zijn in zijn algemeenheid enkele prognostisch slechte factoren te duiden, te weten aanwezigheid van macrovasculaire invasie en een hoog alpha FP.
Bij patiënten met een fibrolamellair HCC zal casus per casus overwogen moet worden welke behandeling het best toepasbaar is, omdat deze patiënten bij elke interventiestudie met HCC geëxcludeerd werden.
Kosten (middelenbeslag)
Er zijn geen studies verricht naar kosteneffectiviteit van atezolizumab en bevacizumab versus sorafenib. De kosten van atezolizumab zijn substantieel hoger dan die van sorafenib. Echter, omdat de effectiviteit van atezolizumab en bevacizumab zo duidelijk groter is, spelen de kosten een ondergeschikte rol bij de afweging.
Aanvaardbaarheid, haalbaarheid en implementatie
Bij voorkeur behandelen in gespecialiseerd centrum waar multidisciplinaire kennis is van het HCC conform SONCOS-normeringen.
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies
Persoonlijke voorkeuren van de patiënt zijn van grote invloed op deze keuze om wel of niet palliatieve systeemtherapie te starten, zeker gezien de verwachte winst in overleving versus de kwaliteit van leven. Daarom is de aanbeveling zo geformuleerd dat altijd in overleg met de patiënt wordt besloten of er wel of niet met palliatieve systeemtherapie wordt gestart.
Alhoewel in studies een CP score aangehouden wordt is het advies naast de getalsmatige criteria ook klinische parameters een grote impact te geven. Daarom is gekozen voor de term behouden leverfunctie, die ook in de internationale richtlijnen toegepast wordt. In geval van twijfel overleg met een expertisecentrum.
Onderbouwing
Achtergrond
In de vorige richtlijnen was sorafenib de enig geregistreerde palliatieve behandeling voor het HCC. Nadien zijn er meerdere middelen in eerste en tweede lijn onderzocht en geregistreerd. Het doel van de module is de plaatsbepaling van deze middelen in de Nederlandse situatie te beschrijven.
Conclusies
First-line treatment
Conclusions
Overall survival (crucial)
Sorafenib versus placebo
Low GRADE |
Treatment with sorafenib may result in a higher overall survival when compared with placebo in patients with hepatocellular carcinoma.
Sources: (Llovet, 2008; Cheng, 2009) |
Atezolizumab + Bevacizumab versus Sorafenib
Low GRADE |
Treatment with atezolizumab + bevacizumab may result in a higher overall survival when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Cheng, 2022) |
Lenvatinib versus Sorafenib
Low GRADE |
Treatment with lenvatinib may result in little to no difference in overall survival when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Kudo, 2018) |
Progression-free survival (crucial)
Sorafenib versus placebo
Very low GRADE |
The evidence is very uncertain about the effect of sorafenib on progression-free survival when compared with placebo in patients with hepatocellular carcinoma.
Sources: (Llovet, 2008; Cheng, 2009) |
Atezolizumab + Bevacizumab versus Sorafenib
Low GRADE |
Treatment with atezolizumab + bevacizumab may result in higher progression-free survival when compared with sorafenib in patients with hepatocellular carcinoma.
Sourcse: (Cheng, 2022) |
Lenvatinib versus Sorafenib
Low GRADE |
Treatment with lenvatinib may result in a higher progression-free survival when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Kudo, 2018) |
Tumour response rate (important)
Sorafenib versus placebo
Very Low GRADE |
The evidence is very uncertain about the effect of sorafenib on tumour response rate when compared to placebo in patients with hepatocellular carcinoma.
Sources: (Llovet, 2008; Cheng, 2009) |
Atezolizumab + Bevacizumab versus Sorafenib
Low GRADE |
Treatment with atezolizumab + bevacizumab may result in a higher tumour response rate when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Cheng, 2022) |
Lenvatinib versus Sorafenib
Low GRADE |
Treatment with lenvatinib may result in a higher tumour response rate when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Kudo, 2018) |
Serious adverse events (important)
Sorafenib versus placebo
Very Low GRADE |
The evidence is very uncertain about the effect of sorafenib on serious adverse events when compared to placebo in patients with hepatocellular carcinoma.
Sources: (Llovet, 2008; Cheng, 2009) |
Atezolizumab + Bevacizumab versus Sorafenib
Low GRADE |
Treatment with atezolizumab + bevacizumab may result in little to no difference in serious adverse events when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Cheng, 2022) |
Lenvatinib versus Sorafenib
Low GRADE |
Treatment with lenvatinib may result in little to no difference in serious adverse events when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Kudo, 2018) |
Quality of life (important)
Sorafenib versus placebo
- grade |
No evidence was found regarding the effect of sorafenib on the quality of life when compared with placebo in in patients with hepatocellular carcinoma. |
Atezolizumab + Bevacizumab versus Sorafenib
Low GRADE |
Treatment with atezolizumab + bevacizumab may result in a higher quality of life when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Finn, 2020) |
Lenvatinib versus Sorafenib
Low GRADE |
Treatment with lenvatinib may result in little to no difference in quality of life when compared with sorafenib in patients with hepatocellular carcinoma.
Sources: (Kudo, 2018) |
Second-line treatment
Conclusions
Overall survival (crucial)
Regorafenib versus placebo
Low GRADE |
Treatment with regorafenib may result in a higher overall survival when compared with placebo in patients with hepatocellular carcinoma.
Sources: (Bruix, 2017) |
Progression-free survival (crucial)
Regorafenib versus placebo
Low GRADE |
Treatment with regorafenib may result in a higher progression-free survival when compared with placebo in patients with hepatocellular carcinoma.
Sources: (Bruix, 2017) |
Tumour response rate (important)
Regorafenib versus placebo
Low GRADE |
Treatment with regorafenib may result in little to no difference in tumour response rate when compared with placebo in patients with hepatocellular carcinoma.
Sources: (Bruix, 2017) |
Serious adverse events (important)
Regorafenib versus placebo
Low GRADE |
Treatment with regorafenib may result in little to no difference in serious adverse events when compared with placebo in patients with hepatocellular carcinoma.
Sources: (Bruix, 2017) |
Quality of life (important)
Regorafenib versus placebo
Low GRADE |
Treatment with regorafenib may result in little to no difference in quality of life when compared with placebo in patients with hepatocellular carcinoma.
Sources: (Bruix, 2017) |
Third-line treatment
Conclusions
Overall survival (crucial), progression-free survival (crucial), tumour response rate (important), serious adverse events (important), quality of life (important)
- GRADE |
No evidence was found in the third-line treatment setting for patients with hepatocellular carcinoma. |
Samenvatting literatuur
Park (2021) performed a systematic review and network meta-analyses (NMA) to evaluate the efficacy and safety of various systemic therapies in advanced hepatocellular carcinoma (HCC) in the first line and second line setting. Inclusion criteria were RCTs with head-to-head comparisons of at least two arms; systemic therapy in the first line or second line or later setting for advanced or metastatic HCC; and had at least one of the following clinical outcomes: objective response rate (ORR), progression-free survival (PSF) or time to progression if PFS was not reported. Three databases (PubMed, Embase, Cochrane) were searched up to April 2020. 13 first-line and 11 second-line trials were included in the final quantitative and qualitative synthesis.
Oranratnachai (2021) performed a systematic review and network meta-analyses (NMA) to evaluate the efficacy and safety of various systemic therapies in advanced hepatocellular carcinoma (HCC) in the first-line setting. Inclusion criteria were RCTs who included adults with advanced HCC who were treatment-naïve; comparing any pair of chemotherapy agents, MKIs, or placebo; and had at least one of the following clinical outcomes: OS, PFS, ORR and AE. Two databases (PubMed and SCOPUS) were searched up to November 30, 2019. 20 first-line studies were included in the final quantitative and qualitative synthesis.
Solimando (2022) performed a systematic review and network meta-analyses (NMA) to evaluate the efficacy and safety of various systemic therapies in advanced hepatocellular carcinoma (HCC) in the first-line setting. Inclusion criteria were RCTs who included adults with advanced HCC who were already treated with sorafenib; receiving a second-line systemic treatment in a phase II or phase III RCT; and had at least one of the following clinical outcomes: OS, PFS and drug withdrawal due to adverse events. Four (PubMed, SCOPUS, Web of Science, and ClincialTrials.gov) were searched up to December 31, 2020. 14 second- line studies were included in the final quantitative and qualitative synthesis.
Table 6.1 Overview and characteristics of the included studies evaluating the first-line treatments in the selected systematic reviews
RCT |
Year |
Trial/Phase |
Intervention |
Comparison |
N |
Park |
Oranratnachai (2021) |
Llovet |
2008 |
SHARP/III |
Sorafenib |
Placebo |
602 |
X |
X |
Cheng |
2009 |
NCT00492752/III |
Sorafenib |
Placebo |
226 |
X |
X |
Cheng |
2013 |
SUN1170/III |
Sunitinib |
Sorafenib |
1074 |
X |
X |
Johnson |
2013 |
BRISK-FL/III |
Brivanib |
Sorafenib |
1155 |
X |
X |
Zhu |
2015 |
SEARCH/III |
Erlotinib + Sorafenib |
Sorafenib |
720 |
X |
X |
Cainap |
2015 |
NCT01009593/III |
Linifanib |
Sorafenib |
1035 |
X |
X |
Cheng |
2015 |
NCT01033240/II |
Tigatuzumab + Sorafenib |
Sorafenib |
162 |
X |
X |
Kudo |
2017 |
NCT02400788/II |
Resminostat + Sorafenib |
Sorafenib |
- |
X |
|
Kudo |
2018 |
REFLECT/III |
Lenvatinib |
Sorafenib |
954 |
X |
X |
Yau |
2019 |
CheckMate 459/III |
Nivolumab |
Sorafenib |
743 |
X |
|
Abou-Alfa |
2019 |
CALGB80802/III |
Sorafenib + Doxorubicin |
Sorafenib |
356 |
X |
X |
Finn |
2020 |
IMbrave150/III |
Atezolizumab + Bevacizumab |
Sorafenib |
485 |
X |
|
Bi and Qin |
2020 |
NCT02645981/II-III |
Donafenib |
Sorafenib |
659 |
X |
|
Lai |
1988 |
-/III |
Doxorubicin |
No treatment |
106 |
|
X |
Mok |
1999 |
-/II |
Nolatrexed |
Doxorubicin |
54 |
|
X |
Yeo |
2005 |
-/III |
PIAF |
Doxorubicin |
188 |
|
X |
Gish |
2007 |
-/III |
Nolatrexed |
Doxorubicin |
445 |
|
X |
Qin |
2013 |
NCT00471965 /III |
FOLFOX4 |
Doxorubicin |
371 |
|
X |
Ji* |
2013 |
-/III |
Sorafenib |
No treatment |
189 |
|
X |
Palmer |
2018 |
NCT01004003 /II |
Nintedanib |
Sorafenib |
93 |
|
X |
Thomas |
2018 |
NCT00881751/II |
Bevacizumab + Erlotinib |
Sorafenib |
90 |
|
X |
Yen |
2018 |
NCT00987935 /II |
Nintedanib |
Sorafenib |
95 |
|
X |
Assenat |
2019 |
PRODIGE 10/II |
Sorafenib + GEMOX |
Sorafenib |
95 |
|
X |
Koeberle |
2016 |
SAKK77/08 and SASL 29/II |
Sorafenib + Everolimus |
Sorafenib |
105 |
|
X |
In bold the selected RCTs which are based on available therapies in the Netherlands
*Child-Pugh Class B population
Table 6.2 Overview and characteristics of the included studies evaluating the second-line treatments in the selected systematic reviews
RCT |
Year |
Trial/Phase |
Intervention |
Comparison |
N |
Park |
Solimando (2021) |
Bruix |
2017 |
RESORCE/III |
Regorafenib |
Placebo |
573 |
X |
X |
Abou-Alfa |
2018 |
CELESTIAL/III |
Cabozantinib |
Placebo |
707 |
X |
X |
Zhu |
2015 |
REACH/III |
Ramucirumab |
Placebo |
644 |
X |
X |
Zhu |
2019 |
REACH-2/III |
Ramucirumab |
Placebo |
292 |
X |
X |
Li (Qin) |
2020 |
NCT02329860/III |
Apatinib |
Placebo |
393 |
X |
|
Finn |
2019 |
KEYNOTE-240/III |
Pembrolizumab |
Placebo |
413 |
X |
X |
Llovet |
2013 |
BRISK-PS/III |
Brivanib |
Placebo |
395 |
X |
X |
Santoro |
2013 |
NCT00988741/II |
Tivantinib |
Placebo |
107 |
X |
X |
Zhu |
2014 |
EVOLVE-1/III |
Everolimus |
Placebo |
546 |
X |
X |
Kang |
2015 |
NCT01210495/II |
Axitinib |
Placebo |
202 |
X |
X |
Rimassa |
2018 |
RESORCE/III |
Tivantinib |
Placebo |
340 |
x |
|
Abou-Aifa |
2016 |
NCT01507168/III |
Codrituzumab |
Placebo |
185 |
|
X |
Kudo |
2017 |
S/CUBE/III |
S-1 |
Placebo |
333 |
|
X |
Abou-Aifa |
2018 |
ADIPEG20/III |
ADIPEG240 |
Placebo |
635 |
|
X |
Rimassa |
2018 |
METIV-HCC/III |
Tivantinib |
Placebo |
340 |
|
X |
Kudo |
2020 |
JET-HCC/III |
Tivantinib |
Placebo |
195 |
|
X |
In bold the selected RCT which is based on available therapies in the Netherlands
First-line treatment
Four RCTs were selected that assessed the systemic therapy in the first-line setting.
Sorafenib versus placebo was studied in two RCTS (Llovet, 2008; Cheng, 2009). Lenvatinib versus sorafenib was studied in one RCT (Kudo, 2018). Atezolizumab + bevacizumab versus sorafenib was studied in 1 RCT (Finn, 2020) (see table 6.1).
Second-line treatment
1 RCT was selected that assessed the systemic therapy within the second-line setting.
This study assessed the efficacy and safety of regorafenib in patients with HCC who have progressed during sorafenib treatment (Bruix, 2017) (see table 6.2).
Third-line treatment
No studies reporting efficacy and safety of third-line treatment in patients with (unresectable) HCC were included in this literature review.
Description of studies
Subquestion 1 – Which first line systemic therapy is the most effective and safe for use in patients with (unresectable) HCC?
Sorafenib versus placebo
Llovet (2008) - SHARP described a phase III, double-bind, placebo-controlled trial, which was conducted in 21 countries (121 sites) in Europe, North America, South America, and Australasia. They evaluated the efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma who had not received previous systemic therapy. A total of 602 patients were randomized to receive sorafenib (n=299) at a dose of 400 mg twice daily or placebo (n=303). The mean (SD) age was 64.9 (11.2) years in the intervention group, compared with 66.3 (10.2) years in the control group. In the intervention group 260/299 (87%) were males, compared with 264/303 (87%) in the control group. All patients had a Child-Pugh class A score. The following relevant outcome measures were included: overall survival, time to symptomatic progression, objective response (partial/complete), adverse events. This RCT was included in the systematic review by Park (2021) and Oranratnachai (2021).
Cheng (2009) - described a phase III, double-bind, placebo-controlled trial, which was conducted in 23 sites within the Asia-Pacific region, in China, Taiwan, and South-Korea. They evaluated the efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma who had not received previous systemic therapy. A total of 226 patients were randomized to receive sorafenib (n=150) at a dose of 400 mg twice daily or placebo (n=76). The median (range) age was 51 (23-86) years in the intervention group, compared with 52 (25-79) years in the control group. In the intervention group 127/150 (84.7%) were males, compared with 66/76 (86.8%) in the control group. All patients had a Child-Pugh class A score. The following relevant outcome measures were included: overall survival, time to progression, objective response (partial/complete), adverse events, quality of life. This RCT was included in the systematic review by Park (2021) and Oranratnachai (2021).
Atezolizumab + Bevacizumab versus Sorafenib
Finn (2020) – IMbrave150 described a phase III, global, open-label randomized controlled trial, which was conducted at 111 sites in 17 countries. They evaluated the efficacy and safety of atezolizumab plus bevacizumab compared to sorafenib in patients with advanced hepatocellular carcinoma who had not received previous systemic therapy. A total of 573 patients were randomized to receive atezolizumab (IV, 1200 mg on day 1 of each 21-day cycle) plus bevacizumab (IV, 15 mg/kg on day 1 of each 21 day cycle (n=336), compared with sorafenib (orally administered 400 mg twice per day on days 1-21 of each 21-day cycle) (n=165). In the intervention group 277/336 (82%) were males, compared with 137/165 (83%) in the control group. All patients had a Child-Pugh class A score. The following relevant outcome measures were included: overall survival, progression-free survival, objective response (partial/complete), adverse events, quality of life. This RCT was included in the systematic review by Park (2021) and Oranratnachai (2021). After the search date, a recent update became available which present updated data after 12 months of additional follow-up (Cheng, 2022). This study is added to the evidence table and data-synthesis.
Lenvatinib versus Sorafenib
Kudo (2018) – REFLECT described a phase III, open-label, randomized controlled non-inferiority trial which was conducted at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American region. They compared the overall survival in patients treated with lenvatinib versus sorafenib in patients with advanced hepatocellular carcinoma who had not received previous systemic therapy. A total of 954 patients were randomized to receive lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight) (n=478) or sorafenib 400 mg twice-daily in 28-day cycles (n-476). In the intervention group 405/478 (85%) were males, compared with 401/476 (84%) in the control group. All patients had a Child-Pugh Class A score. The following relevant outcome measures were included: overall survival, progression-free survival, objective response (partial/complete), adverse events, quality of life.
Subquestion 2 – Which second line systemic therapy is the most effective and safe for use in patients with (unresectable) HCC?
Regorafenib versus placebo
Bruix (2017) - RESORCE described a phase III, double-bind, placebo controlled trial, which was conducted in 21 countries (152 sites) in North America, South America, Europe, Asia, and Australia. They evaluated the efficacy and safety of regorafenib in patients with advanced hepatocellular carcinoma who tolerated sorafenib (≥400 mg/day for ≥20 of last 28 days of treatment) and progressed on sorafenib. A total of 573 patients were randomized to receive regorafenib at a dose of 160 mg every day for 3 weeks of every 4-week cycle plus best supportive care (n=379) or placebo + best supportive care (n=194). The median (range) age was 64 (54-71) years in the intervention group, compared with 62 (55-68) years in the control group. In the intervention group 333/379 (88%) were males, compared with 171/194 (88%) in the control group. All patients had a Child-Pugh class A score. The following relevant outcome measures were included: overall survival, progression-fee survival, objective response (partial/complete), adverse events. This RCT was included in the systematic review by Park (2021) and Solimando (2022).
Subquestion 3 – Which third line systemic therapy is the most effective and safe for use in patients with (unresectable) HCC?
No studies reporting efficacy and safety of third-line treatment in patients with (unresectable) HCC were included in this literature review.
The Celestial study was not included as patients with both second- and third-line treatment were permitted without preplanned subpopulations efficacies.
First-line treatment
Overall survival (OS) (crucial)
Sorafenib versus placebo
Two studies (Llovet, 2008; Cheng, 2009) reported the median overall survival.
Llovet (2008) reported OS, which was measured from the date of randomization until the date of death from any cause. The median OS was 10.7 months in the intervention group, compared with 7.9 in de control group. This resulted in a HR of 0.69 (95% CI 0.55 to 0.87). This difference is considered clinically relevant.
Cheng (2009) reported OS, which measured from the date of randomization until the date of death from any cause. The median OS was 6.5 in the intervention group, compared with 4.2 in the control group. This resulted in a HR of 0.65 (95% CI 0.53 to 0.81). This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the studies were RCTS. The level of evidence was downgraded by 2 levels, because of study limitations (risk of bias, -1 (see RoB assessment)) and because the optimal information was criteria is not met (imprecision, -1). Therefore, the level of evidence for the outcome ‘overall survival’ is considered low.
Atezolizumab + Bevacizumab versus Sorafenib
Cheng (2022) reported OS, which measured from the date of randomization until the date of death from any cause. The median OS was 19.2 in the intervention group, compared with 13.4 in the control group. This resulted in a HR of 0.66 (95% CI 0.53 to 0.81). This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘overall survival’ is considered low.
Lenvatinib versus Sorafenib
Kudo (2018) reported OS, which measured from the date of randomization until the date of death from any cause. The median OS was 13.6 in the intervention group, compared with 12.3 in the control group. This resulted in a HR of 0.92 (95% CI 0.79 to 1.06). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘overall survival’ is considered low.
Progression-free survival (PFS) (crucial)
Sorafenib versus placebo
Cheng (2009) reported the time to progression. The median time to progression was 2.8 months in the intervention group, compared with 1.4 months in the control group. This resulted in a HR of 0.57 (95% CI 0.42 to 0.79). This difference is considered clinically relevant.
Llovet (2008) reported the time to symptomatic progression. The median time to symptomatic progression was 4.1 months in the intervention group, compared with 4.9 in the control group. This resulted in a HR of 0.58 (95% CI 0.45 to 0.74). This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the studies were RCTS. The level of evidence was downgraded by 3 levels, because of study limitations (risk of bias, -1 (see RoB assessment)) and low number of patients (imprecision, -1), differences in outcome measures (indirectness, -1). Therefore, the level of evidence for the outcome ‘progression-free survival’ is considered very low.
Atezolizumab + Bevacizumab versus Sorafenib
Cheng (2022) reported PFS. The median PFS was 6.9 in the intervention group, compared with 4.3 in the control group. This resulted in a HR of 0.65 (95% CI 0.53 to 0.81). This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘progression-free survival’ is considered low.
Lenvatinib versus Sorafenib
Kudo (2018) reported PFS. The median PFS was 7.3 in the intervention group, compared with 3.6 in the control group. This resulted in a HR of 0.64 (95% CI 0.55 to 0.75. This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘progression-free survival’ is considered low.
Tumour response rate (important)
Sorafenib versus placebo
Two studies (Llovet, 2008; Cheng, 2009) reported the response rate.
Llovet (2008) reported the tumour response rate, defined as the proportion of patients with a best response of complete response or partial response according to RECIST. There were no complete responses in either group. In the intervention group 7/299 (2.3%) achieved a partial response, compared with 2/303 (0.7%) in the control group. The RD was 1.7% (95% CI -0.26 to 3.6). This difference is not considered clinically relevant.
Cheng (2009) reported the tumour response, defined as the proportion of patients with a best response of complete response or partial response according to RECIST. There were no complete responses in either group. In the intervention group 5/150 (3.3%) achieved a partial response, compared with 1/76 (1.3%) in the control group. The RD was 2% (95% CI -1.8 to 5.9). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the studies were RCTS. The level of evidence was downgraded by 3 levels, because of study limitations (risk of bias, -1 (see RoB assessment)) and low number of events (imprecision, -2). Therefore, the level of evidence for the outcome ‘tumour response rate’ is considered very low.
Atezolizumab + Bevacizumab versus Sorafenib
Cheng (2022) reported the tumour response, defined as the proportion of patients with a best response of complete response or partial response according to RECIST 1.1. In the intervention group, 25/326 (7.7%) patients achieved a complete response and 72/326 (22.1%) a partial response. In the control group 1/159 (0.6%) patients achieved a complete response and 17/159 (10.7%) a partial response. The overall response rate was 97/326 (29.8%) in the intervention group compared to 18/159 (11.3%) in the control group. The RD was 18.4% (95% CI 11.4 to 25.4). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘tumour response rate’ is considered low.
Lenvatinib versus Sorafenib
Kudo (2018) reported the tumour response, defined as the proportion of patients with a best response of complete response or partial response according to a masked independent imaging review with a modified RECIST (mRECIST). In the intervention group, 10/478 (2.1%) patients achieved a complete response and 184/478 (38.5%) a partial response. In the control group 4/476 (0.8%) patients achieved a complete response and 55/476 (11.6%) a partial response. The overall response rate was 194/478 (40.6%) in the intervention group, compared to 59/476 (12.4%) in the control group. The RD was 28.2% (95% CI 22.9 to 33.5). This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘tumour response rate’ is considered low.
Serious adverse events (important)
Sorafenib versus placebo
Two studies (Llovet, 2008; Cheng, 2009) reported the incidence of serious treatment-emergent adverse events.
Llovet (2008) reported the incidence of serious treatment-emergent adverse events.
In the intervention group was 52/297 (17.5%) patients experienced a treatment-emergent adverse event, compared with 54/302 (17.9%) in the control group. Diarrhea, weight loss, hand–foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group (intervention). The RD was -0.4% (95% CI -6.5 to 5.8). This difference is not considered clinically relevant.
Cheng (2008) reported the incidence of serious treatment-emergent adverse events. In the intervention group, 71/149 (47.7%) patients experienced a treatment-emergent adverse event, compared with 34/75 (45.3%) in the control group. Hand-foot skin reactions, diarrhoea and fatigue were more frequent in the sorafenib group (intervention). The RD was 2.3% (95% CI -11.5 to 16.1). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the studies were RCTS. The level of evidence was downgraded by 3 levels, because of study limitations (risk of bias, -1 (see RoB assessment)) and low number of events (imprecision, -2). Therefore, the level of evidence for the outcome ‘serious adverse events’ is considered very low.
Atezolizumab + Bevacizumab versus Sorafenib
Cheng (2022) reported the incidence of serious adverse events and the incidence of serious treatment-emergent adverse events. In the intervention group, 76/329 (23.1%) patients experienced a treatment-emergent adverse event, compared with 25/156 (16.0%) in the control group. Proteinuria, hypertension and fatigue was most comment with atezolizumab plus bevacizumab (intervention), whereas palmar-plantar, erythrodysesthesia syndrome and diarrhea was most common in the sorafenib arm (control). The RD was 7.1% (95% CI -0.27 to 14.4). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘serious adverse events’ is considered low.
Lenvatinib versus Sorafenib
Kudo (2018) reported the incidence of serious treatment-emergent adverse events. In the intervention group, 205/476 (43.1%) patients experienced a treatment-emergent adverse event, compared with 144/475 (30.3%) in the control group. Hypertension, diarrhea, decreased appetite, and decreased weight was most common in the lenvatinib arm (intervention), whereas palmar-plantar erythrodysaesthesia, diarrhoea, hypertension, and decreased appetite was most common in the sorafenib arm (control). The RD was 12.8% (95% CI 6.7 to 18.8). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘serious adverse events’ is considered low.
Quality of life (important)
Sorafenib versus placebo
Quality of life was not reported.
Level of evidence of the literature
The level of evidence was not graded because no study reported quality of life.
Atezolizumab + Bevacizumab versus Sorafenib
Finn (2020) reported on the patient-reported outcomes, which were evaluated with the use of the European Organization for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (EORTC QLQ–C30). Finn (2020) reported the time to deterioration of quality of life, which was defined as decrease from baseline of 10 or more point on the EORTC QLQ–C30 maintained for two consecutive assessments or a decrease of 10 points or more in one assessment followed by death from any cause within 3 weeks. The median time to deterioration of patient-reported quality of life in the intervention group was 11.2 months (95% CI, 6.0 to not estimable), compared to 3.6 months (95% CI, 3.0 to 7.0) (HR 0.73, 95% CI 0.46 to 0.85) (favours atezolizumab + bevacizumab). This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘quality of life’ is considered low.
Lenvatinib versus Sorafenib
Kudo (2018) reported the quality of life, which was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30)23,24 and the hepatocellular carcinoma-specific EORTC QLQ-HCC1825 health questionnaires. For between-group comparison, the summary score was not significantly different between the treatment arms (HR 0.87, 95% CI 0.75 to 1.01)(QLQ-C30 questionnaire). HCC18 questionnaire domains ranges between 0.79 (body image, favours lenvatinib) and 1.14 (pain, favours sorafenib). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘quality of life’ is considered low.
Second-line treatment
Overall survival (OS) (crucial)
Regorafenib versus placebo
Bruix (2017) reported the median OS, which was measured from the date of randomization until the date of death from any cause. The median OS was 10.6 months in the intervention group, compared with 7.6 in de control group. This resulted in a HR of 0.63 (95% CI 0.50 to 0.79). This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘overall survival’ is considered low.
Progression-free survival (PFS) (crucial)
Regorafenib versus placebo
Bruix (2017) reported the median PFS. The median PFS was 3.4 months in the intervention group, compared with 1.5 in de control group. This resulted in a HR of 0.43 (95% CI 0.35 to 0.52). This difference is considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘progression-free survival’ is considered low.
Tumour response rate (important)
Regorafenib versus placebo
Bruix (2017) reported the objective response rate. In the intervention group, 2/379 (0.5%) patients achieved a complete response and 38/379 (10.0%) a partial response. In the control group 0/194 (0%) patients achieved a complete response and 8/194 (4.1%) a partial response. The overall response rate was 40/379 (10.6%) in the intervention group, compared to 8/194 (4.1%) in the control group. The RD was 6.4% (95% CI 2.3 to 10.6). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘tumour response rate’ is considered low.
Serious adverse events (important)
Regorafenib versus placebo
Bruix (2017) reported the incidence of serious adverse events.
In the intervention group was 166/397 (41.8%) patients experienced a serious adverse event, compared with 90/194 (46.3%) in the control group. Diarrhea, weight loss, hand–foot skin reaction, and hypophosphatemia were more frequent in the sorafenib group (intervention). Hypertension, hand-foot skin reaction, fatigue, and diarrhea were more frequent in the regorafenib group (intervention). The RD was -2.6% (95% CI -11.2 to 6.0). This difference is not considered clinically relevant.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘serious adverse events’ is considered low.
Quality of life
Regorafenib versus placebo
Quality of life was assessed with the Functional Assessment of Cancer Therapy (FACT-G), FACT-Hepatobiliary (FACT-Hep), EQ-5D and EQ-VAS. No clinically meaningful differences were noted between the regorafenib and placebo groups in HRQoL.
Level of evidence of the literature
The level of evidence started as high, because the study was an RCT. The level of evidence was downgraded by 2 levels, because the optimal information size criteria is not met (imprecision, -2). Therefore, the level of evidence for the outcome ‘quality of life’ is considered low.
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question:
Which treatment is to be advised for patients with (unresectable) HCC?
PICO
P: Non-locally-treatable patients with a diagnosis of hepatocellular carcinoma;
I: Systemic therapy;
C: Other systemic therapy or placebo;
O: Overall survival, progression-free survival, response rate, adverse events, quality of life.
Relevant outcome measures
The guideline development group considered overall survival and progression-free survival as a crucial outcome measure for decision making; and response rate, complications/adverse events and quality of life as important outcome measures for decision making.
The guideline development group defined the outcome measures as follows:
Overall survival (OS) |
Time from randomisation to death from any cause, with a minimum follow-up of 1 years |
Progression-free survival (PFS) |
Time from randomisation or initiation of treatment to the occurrence of disease progression or death, with a minimum follow-up of 1 year |
Tumour response rate (TRR) |
Tumour response rate, with a minimum follow-up of 1 year |
Adverse events (AE) |
Grade ≥ 3 |
Quality of life (QoL) |
Overall QoL, measured with a validated and reliable instrument |
Clinically relevant difference
The guideline development group defined a minimal clinically relevant difference at a minimum ofsof:
- Overall survival: >12 weeks or HR <0.7.
- Progression-free survival: >12 weeks or HR <0.7.
And, in case of absence of a clinically relevant difference in overall survival or progression-free survival:
- Response rate: >20% difference.
- Quality of life: A minimal clinically important difference of 10 points on the quality of life instrument EORTC QLQ-C30 or a difference of a similar magnitude on other quality of life instruments.
- Adverse events: <25% difference.
Data-synthesis
Results from RCTs studies were described and synthesized (preferably by meta-analysis) separately.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until April 15th, 2022. The detailed search strategy is depicted under the tab Methods.
The systematic literature search resulted in 1115 hits. Studies were selected based on the following criteria:
- included patients HCC, ineligible for surgical intervention;
- compared systemic therapy;
- reported at least one of the outcomes of interest;
- the study design is a systematic review (SR) (preferably of randomized controlled trials; RCTs), or RCT;
- written in English language.
Based on title and abstract screening, 14 studies were initially selected. After reading the full text and thorough assessment of the studies, 11 studies were excluded (see table with reasons for exclusion under the tab Methods), and 3 systematic reviews were included.
Results
A total of three studies were included in the analysis of the literature. The important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.
Not all systemic therapies are included in the literature summary. The Committee BOM (cieBOM) makes recommendations about the procedure on the basis of the evidence relating to its efficacy and safety. Therefore, we will answer the question which of the available therapies in the Netherlands is the most effective and safe in patients with (unresectable) HCC in the first-line, second-line and third-line. An overview of all the included RCTs in the systematic reviews and the selected RCTs can be found in table 6.1 and table 6. 2.
The first line available treatments in the Netherlands are:
- Sorafenib.
- Atezolizumab + Bevacizumab.
- Lenvatinib.
The second- and further line available treatments in the Netherlands are:
- Sorafenib (add-on).
- Regorafenib.
Currently, no drugs of proven efficacy in the third-line settings are available in the Netherlands.
Referenties
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- Thomas MB, Garrett-Mayer E, Anis M, Anderton K, Bentz T, Edwards A, Brisendine A, Weiss G, Siegel AB, Bendell J, Baron A, Duddalwar V, El-Khoueiry A. A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma. Oncology. 2018;94(6):329-339. doi: 10.1159/000485384. Epub 2018 May 2. PMID: 29719302; PMCID: PMC7725004.
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Evidence tabellen
Study reference |
Study characteristics |
Patient characteristics |
Intervention (I) |
Comparison / control (C)
|
Follow-up |
Outcome measures and effect size |
Comments |
First-line treatments |
|||||||
Atezolizumab + Bevacizumab versus Sorafenib |
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Finn, 2020
(IMbrave150)
NCT03434379 |
Type of study:
Setting and country: The study was conducted at 111 sites in 17 countries (Australia, China, Czech Republic, France, Germany, Hong Kong, Italy, Japan, Republic of Korea, Poland, Russia, Singapore, Spain, Taiwan, UK, US)
Patients were enrolled between March 13, 2018, and January 30, 2019
Funding and conflicts of interest: F. Hoffmann-La Roche/Genentech
Conflicts of interest are disclosed |
Patients with unresectable HCC who had not received previous systemic treatment
Inclusion criteria:
Exclusion criteria:
N total at baseline: N = 573 Intervention: N=336 Control: N=165
Important prognostic factors: Age, median (range): I: 64 (56-74) C: 66 (59-71)
Sex, n/N (%) male: I: 277/336 (82%) C: 137/165 (83%)
Groups comparable at baseline? Yes.
|
Atezolizumab + Bevacizumab
Participants received Atezolizumab + Bevacizumab until unacceptable toxicity or loss of clinical benefit as determined by the investigator
Drug: Atezolizumab was administered by IV, 1200 mg on day 1 of each 21 day cycle
Drug: Bevacizumab was administered by IV, 15 mg/kg on day 1 of each 21 day cycle
|
Sorafenib
Participants received Sorafenib until unacceptable toxicity or loss of clinical benefit as determined by the investigator
Drug: Sorafenib Sorafenib was administered by mouth, 400 mg twice per day, on days 1-21 of each 21-day cycle
|
Length of follow-up: Median follow-up I: 8.6 months C: 8.1 months
Loss-to-follow-up & incomplete outcome data: Intervention: N=7/336 (2.1%) did not receive assigned treatment
Control: N=9/165 (N=5.5%) did not receive assigned treatment
Intervention: N=108/336 (32.1%) discontinued the trial Reasons: N=95/336 (28.3%) died N= 1/336 (0.3%) experienced disease progression per RECIST 1.1 N=12/336 (3.6%) withdrew consent
Control : 84/165 (50.1%) discontinued the trial Reasons: N=65/165 (39.4%) died N=19/165 (11.5%) withdrew consent
|
Overall survival Median OS (months) I: Could not be evaluated (NE) C: 13.2 (10.4 – NE)
HR: 0.58 (95% CI, 0.42 to 0.79)
Progression-free survival Median PFS (months) I: 6.8 (95% CI, 5.7 to 8.3) C: 4.3 (95% CI 4.0 to 5.6)
HR for disease progression or death
Objective response (RECIST 1.1) Complete response I: 18/326 (5.5%) C: -
Partial response I: 71/326 (21.8%) C: 19/159 (11.9%)
Adverse events From any cause I: 186/329 (56.5%) C: 86/156 (55.1%)
Grade 5 I: 15/329 (4.6%) C: 9/156 (5.8%) A detailed record of all adverse events is reported in the article.
Quality of life Measured with the EORTC QLQ-C30. Reported as time to deterioration of Quality of Life Median time to deterioration I: 11.2 (CI: 6.0-NE) HR: 0.73 (95% CI, 0.46-0.85)
|
Authors conclusion: “ In conclusion, treatment with atezolizumab plus bevacizumab was associated with significantly better overall survival and progression-free survival outcomes than sorafenib in patients with advanced unresectable hepatocellular carcinoma not previously treated with systemic therapy. Serious toxic effects were noted in 38% of the patients who received the combination therapy; however, no new or unexpected toxic effects were observed. The combination therapy also resulted in a longer time to deterioration of patient-reported quality of life and functioning than sorafenib.” |
Cheng, 2022
(IMbrave150)
NCT03434379 |
Updated efficacy and safety data from IMbrave150
See ‘Finn 2020’ |
See ‘Finn 2020’ |
See ‘Finn 2020’ |
See ‘Finn 2020’ |
Length of follow-up: Median (range) 15.6 (0-28.6) |
Overall survival Median OS (months) I: 19.2 (17.0-23.7) C: 13.4 (11.4-16.9)
HR: 0.66 (95% CI, 0.52 to 0.85)
Progression-free survival Median PFS (months) I: 6.9 (95% CI, 5.7 to 8.6) C: 4.3 (95% CI 4.0 to 5.6)
Objective response (RECIST 1.1) Complete response I: 25/326 (7.7%) C: 1/159 (0.6%)
Partial response I: 72/326 (22.1%) C: 17/159 (10.7%) Objective response I: 97/326 (30%) C: 18/159 (11%)
Adverse events Treatment-related AE Grade 3/4 I: 143/329 (43%) C: 72/156 (46%)
Grade 5 I: 6/329 (2%) C: 1/156 (0.6%)
Quality of life Not reported |
Authors conclusion: “In conclusion, the updated analysis showed that the safety and tolerability profile of atezolizumab plus bevacizumab remained consistent after longer follow-up. After an additional 12 months of follow-up, the clinically meaningful survival and efficacy benefits of atezolizumab plus bevacizumab over sorafenib were maintained and consistent with the primary analysis. This updated analysis demonstrated the longest median OS observed to date in a first-line phase III study in hepatocellular carcinoma, confirming this treatment combination as the standard of care for systemic treatment-naive unresectable hepatocellular carcinoma.” |
Sorafenib versus Placebo |
|||||||
Llovet, 2008
(SHARP)
NCT00105443 |
Type of study:
Setting and country: The study was conducted at 121 sites in 21 countries in Europe, North America, South America, and Australasia
Patients were enrolled between March 10, 2005 and April 11, 2006
Funding and conflicts of interest: Bayer HealthCare Pharmaceuticals-Onyx Pharmaceuticals
Conflicts of interest are disclosed |
Patients with advanced HCC who had not received previous systemic treatment
Inclusion criteria:
Exclusion criteria:
N total at baseline: N = 602 Intervention: N=299 Control: N=303
Important prognostic factors: Age, mean (SD): I: 64.9 (11.2) C: 66.3 (10.2)
Sex, n/N (%) male: I: 260/299 (87%) C: 264/303 (87%)
Groups comparable at baseline? Yes.
|
Sorafenib
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment.
|
Placebo
Sorafenib-matching placebo tablets were orally administered twice daily (bid). Follow-up / Open Label phase: Subjects on placebo who chose to switch to sorafenib, received an oral dose of 400 mg (2 x 200 mg tablets) bid; similar to the double-blind study.
|
Length of follow-up: No information
Loss-to-follow-up & incomplete outcome data: Intervention: N=2/299 (0.7%) did not receive assigned treatment
Control: N=1/303 (N=0.3%) did not receive assigned treatment
Intervention: N=226/299 (75.6%) discontinued the trial Reasons: N=81/299 (35.3%) had an adverse event N=61/299 (20.0%) had radiologic and symptomatic progression N=28/299 (9.4%) withdrew consent N=3/299 (1%) died N=1/299 (0.3%) had ECOG score of 4 N=47/299 (15.7%) had other reasons
Control: N=242/303 (79.9%) discontinued the trial Reasons: N=90/303 (29.7%) had an adverse event N=62/303 (20.4%) had radiologic and symptomatic progression N=25/303 (8.3%) withdrew consent N=7/303 (2.3%) had ECOG score of 4 N=6/303 (2.0%) died N=52/303 (17.2%) had other reasons
|
Overall survival Median OS (months) I: 10.7 (9.4-13.2) C: 7.9 (6.8-9.1) HR: 0.69 (95% CI, 0.55 to 0.87)
Progression-free survival Not reported
Time to symptomatic progression Median (months) I: 4.1 (3.5-4.8) C: 4.9 (4.2-6.3) HR: 0.58 (0.45 to 0.74)
Objective response (RECIST) Complete I: 0/299 (0%) C: 0/303 (0%)
Partial I: 7/299 (2.3%) C: 2/303 (0.7%) Numbers in tables and text are inconsistent
Adverse events Treatment-emergent adverse events Grade 3: I: 39/297 (13.1%) C: 24/302 (7.9%)
Grade 4: I: 6/297 (2.0%) C: 8/302 (2.6%)
Serious treatment-emergent adverse events I: 52/297 (17.5%) C: 54/302 (17.9%)
Data was provided in percentages per adverse event. A detailed record of all adverse events is reported in the article.
Quality of life Not reported |
Authors conclusion:
|
Cheng, 2009
NCT00492752 |
Type of study:
Setting and country: The study was conducted at 23 sites in China, South Korea and Taiwan
Patients were enrolled between September 20, 2005 and January 31, 2007
Funding and conflicts of interest: Bayer HealthCare Pharmaceuticals-Onyx Pharmaceuticals
Conflicts of interest are disclosed |
Patients with advanced HCC who had not received previous systemic treatment
Inclusion criteria:
Exclusion criteria:
N total at baseline: N = 226 Intervention: N=150 Control: N=76
Important prognostic factors: Age, median (range): I: 51 (23-86) C: 52 (25-79)
Sex, n/N (%) male: I: 127/150 (84.7%) C: 66/76 (86.8%)
Groups comparable at baseline? Yes.
|
Sorafenib
Sorafenib 400 mg was administered orally at a dose of 400 mg (2 x 200 mg tablets) twice daily; 2 dose reductions to predefined levels of 400 mg once daily (OD) and 400 mg every other day were permitted for adverse events related to study treatment
|
Placebo
Placebo tablets matching in appearance were orally administered bid (twice daily)
|
Length of follow-up: No information
Loss-to-follow-up & incomplete outcome data: Intervention: N=129/150 (86%) discontinued treatment
Control: N=72/75 (N=96%) discontinued treatment
Intervention: Reasons: N=69/150 (46%) had disease progression N=22/150 (14.7%) adverse events N=23/150 (15.3%) withdrew consent N=12/150 (8%) died N=2/150 (1.3%) lost to follow-up N=1/150 (0.7%) non-compliant to treatment
Control Reasons: N=48/76 (63.2%) had disease progression N=7/76 (9.2%) adverse events N=11/76 (14.5%) withdrew consent N=2/76 (2.6%) died N=3/76 (3.9%) lost to follow-up N=1/76 (1.3%) protocol violation
|
Overall survival Median OS (months) I: 6.5 (5.56-7.56) C: 4.2 (3.75-5.46) HR: 0.68 (95% CI, 0.50 to 0.93)
Progression-free survival Not reported
Median time to progression (months) I: 2.8 (2.63-3.58) C: 1.4 (1.35-1.55) HR: 0.57 (0.42 to 0.79)
Objective response (RECIST) Complete I: 0/150 (0%) C: 0/150 (0%)
Partial I: 5/150 (3.3%) C: 1/76 (1.3%)
Adverse events Treatment-emergent serious adverse event I: 71/149 (47.7%) C: 34/75 (45.3%)
Drug-related serious adverse events of any grade I: 122/149 (81.9%) C: 29/75 (38.7%)
Data was provided in percentages per adverse event. A detailed record of all adverse events is reported in the article.
Quality of life Not reported |
Authors conclusion:
|
Levatinib versus Sorafenib |
|||||||
Kudo, 2018
NCT01761266 |
Type of study:
Setting and country: The study was conducted at 23 sites in China, South Korea and Taiwan
Patients were enrolled between September 20, 2005 and January 31, 2007
Funding and conflicts of interest: Eisai Inc
Conflicts of interest are disclosed |
Patients with unresectable HCC
Inclusion criteria:
Exclusion criteria:
N total at baseline: N = 954 Intervention: N=478 Control: N=476
Important prognostic factors: Age, median (range): I: 63.0 (20-88) C: 62.0 (22-88)
Sex, n/N (%) male: I: 405/478 (85%) C: 401/476 (84%)
Groups comparable at baseline? Yes.
|
Lenvatinib
Participants received lenvatinib capsules 12 milligram (mg) based on the participant's body weight greater than or equal to (>=) 60 kilogram (kg) or 8 mg based on the participant's body weight less than (<) 60 kg at baseline, orally, once daily (QD) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
|
Sorafenib
Participants received sorafenib 400 mg tablets, orally, twice daily (BID) in continuous 28-day treatment cycles up to documented disease progression, development of unacceptable toxicity, participant request, or withdrawal of consent.
|
Length of follow-up: Median (months) I: 27.4 (95% CI, 26.4-29.3) C: 27.1 (95% CI, 25.9-27.7)
Loss-to-follow-up & incomplete outcome data: Intervention: N=476/478 (99.6%) received assigned treatment N-475/476 (99.8%) received assigned treatment
Intervention: 449/478 (93.9%) discontinued treatment Reasons: N=311/478 (65.1%) radiological progression N=65/478 (13.2%) adverse events N=32/478 (6.7%) clinical progression N=28/478 (5.9%) patient’s choice N=3/478 (0.6%) lost to follow-up N=9/478 (1.9%) withdrew consent N=3/478 (0.6%) other
Control: 450/476 (94.5%) discontinued treatment Reasons: N=347/476 (72.9%) radiological progression N=43/476 (9.1%) adverse events N=33/476 (7.0%) clinical progression N=14/476 (2.9%) patient’s choice N=1/476 (0.2%) lost to follow-up N=5/476 (1.1%) withdrew consent N=7/476 (1.5%) other
|
Overall survival Median OS (months) I: 13.6 (12.1-14.9) C: 12.3 (10.4-13.9) HR: 0.92 (95% CI, 0.79 to 1.06)
Progression-free survival Masked independent imaging review according to mRECIST I: 7.3 (5.6-7.5) C: 3.6 (3.6-3.7) HR: 0.64 (95% CI, 0.55-0.75)
Objective response (RECIST 1.1) Complete I: 10/478 (2.1%) C: 4/476 (0.8%)
Partial I: 184/478 (38.5%) C: 55/476 (11.6%)
Adverse events Treatment-related treatment-emergent adverse event of grade ≥3 I: 270/476 (57%) C: 231/475 (49%) A detailed record of all adverse events is reported in the article.
Quality of life For between-group comparison, the summary score was not significantly different between the treatment arms (HR 0.87, 95% CI 0.754–1.013, appendix). (QLQ-C30 questionnaire)
HCC18 questionnaire domains ranges between 0.79 (body image, favours Lenvatinib) and 1.14 (pain, favours Sorafenib)
|
Authors conclusion:
|
Second-line treatment |
|||||||
Regorafenib versus placebo |
|||||||
Study reference |
Study characteristics |
Patient characteristics |
Intervention (I) |
Comparison / control (C)
|
Follow-up |
Outcome measures and effect size |
Comments |
Bruix, 2017
(RESORCE)
NCT01774344 |
Type of study:
Setting and country: The study was conducted at 152 sites 21 countries in Asia.
Funding and conflicts of interest: Bayer
Conflicts of interest are disclosed |
Patients with HCC who have progressed during sorafenib treatment
Inclusion criteria:
Exclusion criteria:
N total at baseline: N = 573 Intervention: N=379 Control: N=194
Important prognostic factors: Age, median (range): I: 64 (54-71) C: 62 (55-68)
Sex, n/N (%) male: I: 333/379 (88%) C: 171/194 (88%)
Groups comparable at baseline? Yes.
|
Regorafenib
160 mg orally (p.o.) every day (qd) for 3 weeks of every 4 week cycle (i.e. 3 weeks on, 1 week off)
+
best supportive care
Drug: Regorafenib (Stivarga, BAY73-4506) Regorafenib, 40 mg tablets
|
Placebo
4 matching placebo tablets for 3 weeks of every 4 week cycle (i.e. 3 weeks on, 1 week off)
+
best supportive care |
Length of follow-up: Not specified
Loss-to-follow-up & incomplete outcome data: Intervention: N=5/379 (1.3%) did not receive regorafenib
Control: N=1/194 (0.5%) did not receive placebo
Intervention: 309/374 (82.6%) discontinued treatment
Primary reason: N= 149/374 (39.8%) progressive disease, radiological progression N=21/374 (5.6%) Progressive disease, clinical progression N=56/374 (14.9%) adverse event associated with disease progression N=46/374 (12.6%) adverse event not associated with disease progression N=1/374 (0.3%) adverse event N=5/374 (1.3%) death N=25/374 (6.7%) withdrawal by patient N=2/374 (0.5%) non-compliance with study drug N=1/374 (0.3%) physician decision N=1/374 (0.3%) protocol violation
Control: 183/193 (94.8%) discontinued treatment
Primary reason: N= 119/193 (61.7%) progressive disease, radiological progression N=14/193 (7.3%) Progressive disease, clinical progression N=1/193 (0.5%) Progressive disease N=28/193 (14.5%) adverse event associated with disease progression N=12/193 (6.2%) adverse event not associated with disease progression N=3/193 (1.6%) protocol violation N=5/193 (2.6%) withdrawal by patient N=1/193 (0.5%) other
|
Overall survival (ITT cohort) Median OS (months) I: 10.6 (95% CI 9.1 to 12.1) C: 7.8 (95% CI 6.3 to 8.8) HR 0.63 (95% CI 0.5 to 0.79) P<0.001
Progression-free survival Median PFS (months) (RECIST 1.1) I: 3.4 (95% CI 2.9 to 4.2) C: 1.5 (95% CI 1.4 to 1.5) HR 0.43 (95% CI 0.35 to 0.52) P<0.001 *numbers are retrieved from the supplementary file and slightly differ from the numbers presented in the article
Objective response I: 40/374 (11%) C: 8/193 (4%) P=0.0047
Adverse events Treatment-emergent Grade 3 I: 208/374 (56%) C: 61/193 (32%)
Grade 4 I: 40/374 (11%) C: 14/193 (7%)
Treatment-emergent drug-related Grade 3 I: 173/374 (46%) C: 31/193 (16%)
Grade 4 I: 14/374 (4%) C: 1/193 (1%)
A detailed record of all adverse events is reported in the article.
Quality of life EQ-5D index I: 0.76 C: 0.77 Difference = -0.01 (95% CI; -0.03 to 0.02)
EQ-5D VAS I: 71.68 C: 73.45 Difference = -1.77 (95% CI; -3.58 to 0.04)
FACT-General I: 75.14 C: 76.55 Difference = -1.41 (95% CI; -2.93 to 0.11)
FACT-Hep I: 129.31 C: 133.17 Difference = -3.85 (95% CI; -6.06 to -1.65)
|
Authors conclusion:
|
Risk of bias table
Study reference
(first author, publication year) |
Was the allocation sequence adequately generated?
Definitely yes Probably yes Probably no Definitely no |
Was the allocation adequately concealed?
Definitely yes Probably yes Probably no Definitely no |
Blinding: Was knowledge of the allocated interventions adequately prevented?
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?
Definitely yes Probably yes Probably no Definitely no |
Are reports of the study free of selective outcome reporting?
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?
Definitely yes Probably yes Probably no Definitely no |
Overall risk of bias If applicable/necessary, per outcome measure
LOW Some concerns HIGH
|
First-line treatments |
|||||||
Finn, 2020 |
Definitely yes;
Reason: Randomization was performed through an interactive voice-response or Web-response system in stratified permuted blocks |
Definitely yes;
Reason: Central allocation |
Probably no;
Reason: Open-label trial. A blinded independent review of imaging for progression-free survival was selected for the coprimary end point.
|
Probably yes; Numbers and reasons for loss to follow-up are not infrequent. Reasons for missing outcome data unlikely to be related to outcome |
Definitely yes;
Reason: All outcome measures described in the trial protocol are reported in the results |
Probably yes;
Reason: No information |
LOW |
Llovet, 2008 |
Definitely yes;
Reason: Randomization was performed by computer to achieve a balance between the two groups, with stratification before randomization |
Definitely yes;
Reason: Central allocation |
Probably yes;
Reason: Participants, care providers were blinded. Not clear whether the outcome assessors were blinded |
Probably yes; Numbers and reasons for loss to follow-up are not infrequent. Reasons for missing outcome data unlikely to be related to outcome |
Definitely yes;
Reason: All outcome measures described in the trial protocol are reported in the results |
Probably yes;
Reason: No information |
LOW |
Cheng, 2009 |
Definitely yes;
Reason: Randomization was performed by an interactive voice-response system. |
Definitely yes;
Reason: Central allocation |
Probably no;
Reason: Patients were blinded. Authors stated that investigators were unblinded to treatment assignment, but it is unclear from the text who was also blinded in this double-blind study |
Probably yes; Numbers and reasons for loss to follow-up are not infrequent. Reasons for missing outcome data unlikely to be related to outcome |
Probably no;
Reason: All outcome measures described in the trial protocol are reported in the results. Data was not shown for Quality of Life. |
Probably yes;
Reason: No information |
Some concerns |
Kudo, 2018 |
Definitely yes;
Reason: Randomization was performed by an interactive voice-response system |
Definitely yes;
Reason: Central allocation |
Probably no;
Reason: Open-label trial. A blinded independent review of imaging for progression-free survival was selected
|
Probably yes; Numbers and reasons for loss to follow-up are not infrequent. |
Definitely yes;
Reason: All outcome measures described in the trial protocol are reported in the results |
Probably yes;
Reason: No information |
LOW |
Second-line treatment |
|||||||
Bruix, 2017 |
Definitely yes;
Reason: Randomization was centralized and performed with a computer-generated allocation list |
Definitely yes;
Reason: Central allocation |
Definitely yes;
Reason: Participants, care providers, investigators and outcome assessors were blinded |
Probably yes; Numbers and reasons for loss to follow-up were slightly different between the groups. Reasons for missing outcome data unlikely to be related to outcome |
Definitely yes;
Reason: All outcome measures described in the trial protocol are reported in the results |
Probably yes;
Reason: No information |
LOW |
Table of excluded studies
Author and year |
Reason for exclusion |
Ahmed 2021 |
Study by Finn (2020) is already Included in Park (2021). The study from Lee (2020 is a phase 1b study and compares the treatment atezolizumab with or without bevacizumab in unresectable HCC (not of interest). |
An 2021 |
The RCTs that studied the comparisons of interests are already included in the selected SR. |
Chen 2021 |
The RCTs that studied the comparisons of interests are already included in the selected SR. |
Facciorusso 2021 |
The RCTs that studied the comparisons of interests are already included in the selected SR. |
Jácome 2021 |
The RCTs that studied the comparisons of interests are already included in the selected SR. |
Kudo 2021 |
Pooled results from REACH and REACH-2 studies. Comparison not of interest. |
Liu 2021 |
The RCTs that studied the comparisons of interests are already included in the selected SR. |
Rizzo 2022 |
Background article |
Ronnebaum 2022 |
The RCTs that studied the comparisons of interests are already included in the selected SR. |
Vogel 2021 |
The RCTs that studied the comparisons of interests are already included in the selected SR. |
Ziogas 2021 |
The RCTs that studied the comparisons of interests are already included in the selected SR. |
Verantwoording
Autorisatiedatum en geldigheid
Laatst beoordeeld : 01-01-2024
Laatst geautoriseerd : 01-01-2024
Geplande herbeoordeling : 01-01-2029
Algemene gegevens
De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd uit de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS).
De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.
Samenstelling werkgroep
Voor het ontwikkelen van de richtlijnmodule is in 2021 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 hepatocellulaircarcinoom.
Werkgroep
- Prof. dr. R.A de Man, MDL-arts, Erasmus MC, Rotterdam, NVMDL (voorzitter)
- Dr. K.J. van Erpecum, MDL-arts, UMC Utrecht, Utrecht, NVMDL
- Dr. E.T.T.L. Tjwa, MDL-arts, Radboud UMC, Nijmegen, NVMDL
- Dr. R.B. Takkenberg, MDL-arts, Amsterdam UMC, Amsterdam, NVMDL
- Dr. F.G.I. van Vilsteren, MDL-arts, UMCG, Groningen, NVMDL
- Dr. D. Sprengers, MDL-arts, Erasmus MC, Rotterdam, NVMDL
- Dr. M.J. Coenraad, MDL-arts, LUMC, Leiden, NVMDL
- Prof. dr. B. van Hoek, MDL-arts, LUMC, Leiden, NVMDL
- Dr. N. Haj Mohammad, Internist-oncoloog, UMC Utrecht, Utrecht, NIV
- Dr. J. de Vos-Geelen, Internist-oncoloog, MUMC, Maastricht, NIV
- Drs. J.A. Willemse, Directeur Nederlandse Leverpatiënten Vereniging
- Prof. dr. M.G.E. Lam, Nucleair geneeskundige, UMC Utrecht, Utrecht, NVNG
- Prof. dr. J. Verheij, Patholoog, Amsterdam UMC, Amsterdam, NVvP
- Dr. M. (Michail) Doukas, Patholoog, Erasmus MC, Rotterdam, NVvP
- Dr. A.M. Mendez Romero, Radiotherapeut, Erasmus MC, Rotterdam, NVvR
- Dr. A.E. Braat, Chirurg, LUMC, Leiden, NVvH
- Dr. M.W. Nijkamp, Chirurg, UMCG, Groningen, NVvH
- Prof. Dr. J.N.M. Ijzermans, Chirurg, ErasmusMC, Rotterdam, NVvH
- Drs. J.I. Erdmann, Chirurg, Amsterdam UMC, Amsterdam, NVvH
- Dr. M.C. Burgmans, Radioloog, LUMC, Leiden, NVvR
- Drs. F.E.J.A. Willemssen, Radioloog, ErasmusMC, Rotterdam, NVvR
- Prof. Dr. O.M. (Otto) van Delden, Radioloog, AmsterdamUMC, Amsterdam, NVvR
- J.I. Franken, Verpleegkundig specialist, ErasmusMC, Rotterdam, V&VN
Met ondersteuning van
- Dr. C. Gaasterland, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. D. Nieboer, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. N. Zielonke, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Drs. M. Oerbekke, Adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Drs. M. te Lintel Hekkert, Junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Drs. S van Duijn, Junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Drs. A. van Hoeven, Junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- D.P. Gutierrez, projectsecretaresse, 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.
Achternaam werkgroeplid |
Hoofdfunctie |
Nevenwerkzaamheden |
Persoonlijke financiële belangen |
Persoonlijke relaties |
Extern gefinancierd onderzoek |
Intellectuele belangen en reputatie |
Overige belangen |
De Man (vz.) |
Hoogleraar Hepatologie, Erasmus MC Rotterdam |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
Haj Mohammad |
Internist-oncoloog, Universitair Medisch Centrum Utrecht |
Penningmeester Dutch Upper GI Cancer (DUCG), onbetaald |
Geen |
Geen |
Geen |
Lid wetenschappelijke raad Dutch Hepato and Cholangio Carcinoma Group(DHCG) |
Geen |
Burgmans |
Sectiehoofd interventie radiologie LUMC |
Voorzitter Nederlandse Vereniging Interventieradiologie |
Geen |
Geen |
PROMETHEUS studie, subsidie KWF, project leider |
Geen |
Geen |
Lam |
Nucleair geneeskundige, UMC Utrecht |
Geen |
Geen |
Geen |
Terumo, Quirem Medical en Boston scientific leveren financiële steun aan wetenschappelijke projecten |
Geen |
Het UMC Utrecht ontvangt royalties en milestone payments van Terumo/Quirem Medical |
Franken |
Verpleegkundig Specialist Levertumoren |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
Verheij |
Hoogleraar hepatopancreatobiliaire Pathologie aan de Universiteit van Amsterdam |
lid medische adviesraad NLV (onbezoldigd) |
Geen |
Geen |
Geen |
Geen |
Geen |
Sprengers |
MDL-arts Erasmus MC |
Geen |
Geen |
Geen |
Ik doe translationeel onderzoek met als doel behandeling van patiënten met een HCC te verbeteren. Daarbij wordt soms samengewerkt met famaceutische partijen die producten ontwikkelen die hieraan bij kunnen dragen. Te allen tijde betreft dit objectief wetenschappelijk onderzoek zonder winstoogmerk. |
Geen |
Geen |
Van Vilsteren |
MDL-arts UMCG 0,9 fte |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
Takkenberg |
Maag- Darm Leverarts met specifiek aandachtsgebied leverziekten. Sinds 1-4-2015 in deinst van het Amsterdam UMC, locatie AMC. |
Geen |
Betaald adviesschap: |
Geen |
Ik ben PI van de PEARL studie. Dit is een dubbelblind gerandomiseerde studie bij patiënten die een transjugulaire intrahepatische portosysthemische shunt (TIPS) krijgen. Patiënten worden gerandomiseerd tussen profylactisch lactulose en rifaximin versus lactulose en placebo. Doel is het voorkomen van post-TIPS hepatische encafalopathie (EudraCT-nummer 2018-004323-37). Deze studie wordt gefinancierd door ZonMW en ondersteund door Norgine. Zij leveren de rifaximin en placebo tabletten. |
Secretaris Dutch Hepatocellular and cholangiocarcinoma Group (DHCG) |
Geen |
Van Erpecum |
MDL-arts UMC Utrecht |
Associate Editor European Journal of Internal Medicine (onbetaald) |
Geen |
Geen |
Geen |
Geen |
Geen |
Willemssen |
Abdominaal Radioloog |
Bestuurslid abdominale sectie NVvR (onbetaald) |
Geen |
Geen |
Geen |
Geen |
Geen |
Méndez Romero |
Staflid afdeling radiotherapie in het Erasmus MC |
Als staflid in ee adademisch ziekenhuis ben ik in loondienst van het ErasmusMC |
Geen |
Geen |
Geen |
Geen |
Geen |
Tjwa |
MDL arts / hepatoloog |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
Braat |
chirurg |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
Nijkamp |
Chirurg Universitair Medisch Centrum Groningen |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
Willemse |
Directeur Nederlandse Leverpatiënten Vereniging |
* Bestuurslid Liver Patients International (onbetaald) |
Geen |
Geen |
Geen |
Geen |
Geen |
IJzermans |
Hoofd HPB & Transplantatiechirurgie Erasmus MC |
- |
Niet van toepassing |
Nee |
Niet van toepassing |
Niet van toepassing |
Nee |
Vos, de - Geelen |
* Internist - Medisch Oncoloog Maastricht UMC+ |
Has served as a constultant for Amgen, AstraZeneca, MSD, Pierre Fabre and Servier and has received institutional research funding from Servier |
Has served as a constultant for Amgen, AstraZeneca, MSD, Pierre Fabre and Servier and has received institutional research funding from Servier. Geen directe financiële belangen in een farmaceutisch bedrijf |
Geen |
* Servier: Microbioomonderzoek - Projectleider |
Geen |
Geen |
Hoek, van |
* Hoogleraar Hepatologie, Universiteit Leiden |
* Norgine Pharma - patient voorlichtingsmateriaal maken, onder andere podcast - betaald |
Geen |
Nee |
* Roche - Piranga Studie (hepatitis B) - Projectleider |
Geen |
Nee |
Delden, van |
Radioloog, Amsterdam UMC |
Voorzitter DHCG |
Geen |
Geen |
Geen |
Geen |
Geen |
Doukas |
Universitair Medisch Specialist, Patholoog, Afdeling Pathologie Erasmus MC, Rotterdam |
Geen |
Niet van toepassing |
Niet van toepassing |
Niet van toepassing |
Niet van toepassing |
Niet van toepassing |
Coenraad |
Associate professor, MDL arts Leids Universitair Medisch Centrum (1.0 fte) |
Nevenfuncties: |
Niet van toepassing |
Niet van toepassing |
* Horizon2020 - EU Project id 945096. Title ‘Novel treatment of acute-on-chronic liver failure using synergistic action of G-CSF and TAK-242 - Geen projectleider |
Niet van toepassing |
Niet van toepassing |
Erdmann |
Chirurg AUMC |
geen |
geen |
geen |
AGEM - perfusie onderzoek (50K), rol als projectleider |
geen |
geen |
Inbreng patiëntenperspectief
Er werd aandacht besteed aan het patiëntenperspectief door deelname van de afgevaardigde patiëntenvereniging Nederlandse Leverpatiëntenvereniging in de werkgroep. De afgevaardigde heeft meebeslist bij het opstellen van de uitgangsvragen, de keuze voor de uitkomstmaten en bij het opstellen van de overwegingen. De conceptrichtlijn is tevens voor commentaar voorgelegd aan de Nederlandse Leverpatiëntenvereniging en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.
Wkkgz & Kwalitatieve raming van mogelijke substantiële financiële gevolgen
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 geen substantiële financiële gevolgen zijn voor deze richtlijn, gezien het aantal patiënten kleiner is dan 5000.
Werkwijze
AGREE
Deze richtlijnmodule is opgesteld conform de eisen vermeld in het rapport Medisch Specialistische Richtlijnen 2.0 van de adviescommissie Richtlijnen van de Raad Kwaliteit. Dit rapport is gebaseerd op het AGREE II instrument (Appraisal of Guidelines for Research & Evaluation II; Brouwers, 2010).
Knelpuntenanalyse en uitgangsvragen
Tijdens de voorbereidende fase inventariseerde de werkgroep de knelpunten in de zorg voor patiënten met Hepatocellulaircarcinoom. De werkgroep beoordeelde de aanbeveling(en) uit de eerdere richtlijn Hepatocellulaircarcinoom op noodzaak tot revisie. Tevens zijn er knelpunten aangedragen door de deelnemende WV-en, de V&VN en de Nederlandse Leverpatiëntenvereniging.
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 |
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Redelijk |
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Laag |
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Zeer laag |
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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 |
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Sterke aanbeveling |
Zwakke (conditionele) aanbeveling |
Voor patiënten |
De meeste patiënten zouden de aanbevolen interventie of aanpak kiezen en slechts een klein aantal niet. |
Een aanzienlijk deel van de patiënten zouden de aanbevolen interventie of aanpak kiezen, maar veel patiënten ook niet. |
Voor behandelaars |
De meeste patiënten zouden de aanbevolen interventie of aanpak moeten ontvangen. |
Er zijn meerdere geschikte interventies of aanpakken. De patiënt moet worden ondersteund bij de keuze voor de interventie of aanpak die het beste aansluit bij zijn of haar waarden en voorkeuren. |
Voor beleidsmakers |
De aanbevolen interventie of aanpak kan worden gezien als standaardbeleid. |
Beleidsbepaling vereist uitvoerige discussie met betrokkenheid van veel stakeholders. Er is een grotere kans op lokale beleidsverschillen. |
Organisatie van zorg
In de knelpuntenanalyse en bij de ontwikkeling van de richtlijnmodule is expliciet aandacht geweest voor de organisatie van zorg: alle aspecten die randvoorwaardelijk zijn voor het verlenen van zorg (zoals coördinatie, communicatie, (financiële) middelen, mankracht en infrastructuur). Randvoorwaarden die relevant zijn voor het beantwoorden van deze specifieke uitgangsvraag zijn genoemd bij de overwegingen. Meer algemene, overkoepelende, of bijkomende aspecten van de organisatie van zorg worden behandeld in de module Organisatie van zorg.
Commentaar- en autorisatiefase
De conceptrichtlijnmodule werd aan de betrokken (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd ter commentaar. De commentaren werden verzameld en besproken met de werkgroep. Naar aanleiding van de commentaren werd de conceptrichtlijnmodule aangepast en definitief vastgesteld door de werkgroep. De definitieve richtlijnmodule werd aan de deelnemende (wetenschappelijke) verenigingen en (patiënt) organisaties voorgelegd voor autorisatie en door hen geautoriseerd dan wel geaccordeerd.
Literatuur
Agoritsas T, Merglen A, Heen AF, Kristiansen A, Neumann I, Brito JP, Brignardello-Petersen R, Alexander PE, Rind DM, Vandvik PO, Guyatt GH. UpToDate adherence to GRADE criteria for strong recommendations: an analytical survey. BMJ Open. 2017 Nov 16;7(11):e018593. doi: 10.1136/bmjopen-2017-018593. PubMed PMID: 29150475; PubMed Central PMCID: PMC5701989.
Alonso-Coello P, Schünemann HJ, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Rada G, Rosenbaum S, Morelli A, Guyatt GH, Oxman AD; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 1: Introduction. BMJ. 2016 Jun 28;353:i2016. doi: 10.1136/bmj.i2016. PubMed PMID: 27353417.
Alonso-Coello P, Oxman AD, Moberg J, Brignardello-Petersen R, Akl EA, Davoli M, Treweek S, Mustafa RA, Vandvik PO, Meerpohl J, Guyatt GH, Schünemann HJ; GRADE Working Group. GRADE Evidence to Decision (EtD) frameworks: a systematic and transparent approach to making well informed healthcare choices. 2: Clinical practice guidelines. BMJ. 2016 Jun 30;353:i2089. doi: 10.1136/bmj.i2089. PubMed PMID: 27365494.
Brouwers MC, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna SE, Littlejohns P, Makarski J, Zitzelsberger L; AGREE Next Steps Consortium. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ. 2010 Dec 14;182(18):E839-42. doi: 10.1503/cmaj.090449. Epub 2010 Jul 5. Review. PubMed PMID: 20603348; PubMed Central PMCID: PMC3001530.
Hultcrantz M, Rind D, Akl EA, Treweek S, Mustafa RA, Iorio A, Alper BS, Meerpohl JJ, Murad MH, Ansari MT, Katikireddi SV, Östlund P, Tranæus S, Christensen R, Gartlehner G, Brozek J, Izcovich A, Schünemann H, Guyatt G. The GRADE Working Group clarifies the construct of certainty of evidence. J Clin Epidemiol. 2017 Jul;87:4-13. doi: 10.1016/j.jclinepi.2017.05.006. Epub 2017 May 18. PubMed PMID: 28529184; PubMed Central PMCID: PMC6542664.
Medisch Specialistische Richtlijnen 2.0 (2012). Adviescommissie Richtlijnen van de Raad Kwalitieit. 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.