{"id":10069,"date":"2026-04-08T15:11:05","date_gmt":"2026-04-08T15:11:05","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/rawa-ismail\/"},"modified":"2026-04-23T07:45:27","modified_gmt":"2026-04-23T07:45:27","slug":"rawa-ismail","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/rawa-ismail\/","title":{"rendered":"Rawa Ismail"},"content":{"rendered":"","protected":false},"excerpt":{"rendered":"","protected":false},"author":8,"featured_media":12912,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-10069","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"Real-world data in cancer treatment","samenvatting":"Deel I: het gebruik van kwaliteitsregistraties om echte-wereld data te genereren\nIn het eerste deel van dit proefschrift wordt er gefocust op de kwaliteitsregistraties en nieuwe methodes om RWD uit bestaande databronnen te verzamelen, zonder dat daar een extra registratielast bij komt kijken. In hoofdstuk 2 wordt de start van het DICA Geneesmiddelen programma en de eerste resultaten hieruit beschreven. Dit programma gebruikt verschillende bestaande echte-wereld databronnen die waardevolle inzichten kunnen geven in de behandeling van kanker, zonder dat er extra registratielast ontstaat.\n\nHoofdstuk 3 beschrijft de start en de eerste resultaten van de Dutch Lung Cancer Audit for Lung Oncology (DLCA-L), de longkanker kwaliteitsregistratie. De DLCA-L is in 2016 gestart met het verzamelen van echte-wereld data van alle pati\u00ebnten met longkanker in Nederland, met een focus op de diagnose en behandeling van deze pati\u00ebnten. Er zijn kwaliteitsindicatoren ontwikkeld, die leiden tot een verbetering in de kankerzorg in het ziekenhuis. Een voorbeeld hiervan is de kwaliteitsindicator die gaat over beeldvorming van de hersenen bij diagnose van pati\u00ebnten met stadium III niet-kleincellig longcarcinoom (NSCLC). Dit percentage was 80% in 2017 en is toegenomen tot 90% in 2019. Daarbij is tevens de praktijkvariatie tussen Nederlandse ziekenhuizen gereduceerd. De DLCA-L is ook waardevol gebleken in het monitoren van de immunotherapiebehandeling in Nederland.\n\nDeel II: Methodes om de echte-wereld en klinische studies resultaten te vergelijken\nIn deel II worden verschillende methodes bediscussieerd die de verschillen tussen de pati\u00ebnten in de echte-wereld en in de klinische studies onderzoeken. Hoofdstuk 4 beschrijft een studie waarin is onderzocht of data van een kwaliteitsregistratie dezelfde resultaten geeft als data uit klinische studies die worden gedaan na toelating op de markt (post-autorisatie klinische studies). Voor pati\u00ebnten met gemetastaseerd melanoom, was er geen directe vergelijking tussen echte-wereld en trial pati\u00ebnten. Derhalve is er een onderzoek verricht waarbij er gekeken is naar pati\u00ebnten met gemetastaseerd melanoom die ook hersenmetastases hadden, en die behandeld werden met BRAF-MEK remmers. We hebben data uit de Dutch Melanoma Treatment Registry (DMTR) gebruikt voor de echte-wereld populatie. Vanuit de database van het College ter Beoordeling van Geneesmiddelen (CBG) zijn de data uit vier post-autorisatie klinische studies verkregen, over een vergelijkbare groep pati\u00ebnten. Twee methodes zijn gebruikt om de twee groepen en hun uitkomsten te vergelijken: een Cox hazard regressie model en propensity score matching. Beide methodes toonden geen verschil aan tussen de twee groepen, wanneer pati\u00ebnten uit de groepen werden gematcht of als er gecorrigeerd werd voor de pati\u00ebnt- en tumorkarakteristieken. Deze studie toonde aan dat registraties een complementaire databron zijn aan post-autorisatie klinische studies om data over klinische uitkomsten van specifieke subpopulaties te verkrijgen. In hoofdstuk 5 hebben we onderzocht wat de toegevoegde waarde van individuele pati\u00ebntdata uit klinische studies is in het vergelijken van trial- en echte-wereldpati\u00ebnten. Hierbij werd er gefocust op de nivolumab behandeling van pati\u00ebnten met stadium IV NSCLC. In eerder onderzoek werd er gebruik gemaakt van de gepubliceerde gegevens van de klinische studies, maar verschillen die geobserveerd werden konden beperkt worden onderzocht en verklaard, omdat de individuele pati\u00ebntdata van de trialpati\u00ebnten niet beschikbaar waren. Deze studie toonde aan dat het analyseren van individuele pati\u00ebntdata van de echte-wereld en trialpati\u00ebnten samen betere inzichten geeft in de potenti\u00eble factoren die verantwoordelijk zijn voor de verschillen tussen deze twee settings.\n\nDeel III: Verschillen in uitkomsten tussen echte-wereld- en trialpati\u00ebnten met melanoom.\nHet is belangrijk om de verschillen in uitkomsten tussen de echte-wereld populatie en de populatie die behandeld is in de fase III klinische studies te kwantificeren en te begrijpen, om uiteindelijk klinische keuzes op basis van echte-wereld data te verbeteren. Hoofdstuk 6 richt zich op de klinische uitkomsten van gemetastaseerde melanoompati\u00ebnten die niet in aanmerking zouden komen voor de fase III klinische studies (ineligible pati\u00ebnten). Ineligible pati\u00ebnten werden gedefinieerd als pati\u00ebnten die karakteristieken hadden die overeenkwamen met \u00e9\u00e9n of meerdere exclusiecriteria van de fase III klinische studies voor gemetastaseerd melanoom. Aangezien ineligible pati\u00ebnten ge\u00ebxcludeerd worden uit de fase III klinische studies, is informatie over uitkomsten van deze pati\u00ebnten relevant voor de klinische praktijk. Veertig procent van de systemisch behandelde pati\u00ebnten met gemetastaseerd melanoom zou ineligible zijn voor de fase III klinische studies. Deze ineligible pati\u00ebnten hadden een slechtere mediane overleving (mOS) vergeleken met pati\u00ebnten die wel in aanmerking zouden komen voor de studies (8,8 versus 23 maanden), maar de 3-jaars overleving was alsnog 22% in ineligible pati\u00ebnten. Deze studie concludeerde dat de prognose van de ineligible pati\u00ebnten met gemetastaseerd melanoom in de echte-wereld zeer heterogeen is en sterk afhangt van een aantal factoren. Dat zijn de lactaatdehydrogenase (LDH) waarde, de Eastern Cooperative Oncology Group Performance Score (ECOG PS), en de aanwezigheid van symptomatische hersenmetastasen.\n\nHoofdstuk 7 rapporteert de echte-wereld uitkomsten van pati\u00ebnten met stadium III\/IV melanoom die adjuvant behandeld zijn. Deze studie toont de behandelpatronen, de terugval, en toxiciteit aan die we buiten de klinische trial setting zien. De ziektevrije overleving (RFS) op 12 maanden was 70.6% (95% CI 66.9-74.6). Dit is vergelijkbaar met de RFS percentages in de klinische studie. In de dagelijkse praktijk wordt er wel enigszins meer toxiciteit gezien (18% versus 14%) vergeleken met de trials. Een ander belangrijk verschil is dat de anti-PD-1 adjuvante behandeling in 61% van de pati\u00ebnten vroegtijdig werd gestopt in de klinische praktijk.","summary":"The treatment landscape for patients with certain types of cancer (advanced melanoma, lung cancer, and advanced breast cancer) has dramatically changed in recent years with the important breakthrough in medical treatments[1,2]. Randomized controlled trials (RCTs) are considered the golden standard to determine the efficacy of new treatments[3,4]. The different aspects of a RCT and the processes used (randomization, blinding, and long follow-up) minimize the risk of confounding and information- and selection bias that could influence the results. This improves the internal validity of clinical trials, enabling the estimation of new treatments\u2019 valid treatment effects. The strict in- and exclusion criteria used in a RCT cause a significant difference between patients enrolled in RCTs and the heterogeneous patient population treated in routine clinical practice, which lowers the external validity of RCTs[5,6]. To treat patients in daily clinical practice effectively and to be able to give patients realistic treatment expectations, it is necessary to estimate the real-world effectiveness of therapies based on patients\u2019 characteristics.\n\nAn issue in the field of cancer is the rising health care costs[7]. Novel treatments are often expensive[8]. Reimbursement of systemic therapies is usually based on the trial data collected for market approval. Since a broader population in clinical practice will be treated with these therapies, information on the real-world effectiveness of treatments is necessary for daily clinical practice, health technology assessment bodies (HTA\u2019s), and insurers.\n\nIn recent years, real-world data (RWD) has gained the interest of different stakeholders in cancer care. The RWD used in this thesis are data collected in a non-experimental setting. The rapid changes in treatment options for patients with cancer and the rising healthcare costs cause a need for RWD. The studies in this thesis aimed to investigate how the real-world population of patients with cancer differs from the trial population and how real-world data can be used in daily clinical practice to improve cancer care.\n\nPart I: The use of quality registries to generate real-world data\nIn part I, we focused on quality registries and new methods to collect RWD from existing data sources without causing an extra registration burden. In chapter 2, we describe the initiation of the DICA Medicines program and present the first RWD results. This program uses multiple existing real-world data sources to provide valuable insights into cancer care without causing an extra registration burden.\n\nChapter 3 describes the initiation and first results of the Dutch Lung Cancer Audit for Lung Oncology (DLCA-L). The DLCA-L started in 2016, collecting RWD on all lung cancer patients diagnoses and systemic treatment in the Netherlands. Quality indicators were developed, which led to improvement in in-hospital cancer care. An example of a quality indicator is brain imaging at diagnosis of stage III NSCLC patients, which increased from 80% in 2017 to 90% in 2019, and thus hospital variation was reduced. The DLCA-L has also been very valuable in monitoring immunotherapy use in the Netherlands[9].\n\nPart II: Methods to compare real-world and clinical trial outcomes\nIn part II, we discuss appropriate methods to investigate the differences between real-world and clinical trial patients. Chapter 4 described whether data from a quality registry could provide comparable data as post-approval clinical trials. For advanced melanoma patients, no direct comparisons between real-world and trial patients existed. We, therefore, conducted a study on advanced melanoma patients with brain metastases that were treated with BRAF-MEK inhibitors. We used data from the Dutch Melanoma Treatment Registry (DMTR) for the real-world population and data from four post-approval clinical trials derived from the Medicines Evaluation Board. Two methods were used to compare the two groups: a Cox hazard regression model and propensity score matching. Both methods showed no difference between the groups when matching on or adjusting for patient- and tumor characteristics. This study showed that registries could be a complementary data source to post-approval clinical trials to establish information on clinical outcomes in specific subpopulations[10]. In chapter 5 we aimed to explore the additional benefit of a comparison from pivotal trial data with patient-level data (PLD), focusing on nivolumab treatment in stage IV NSCLC patients. Previous studies used reported outcomes from pivotal trials, but any observed differences could only be limitedly explored further for causation because of the unavailability of patient-level data from trial participants[11]. This study showed that analyzing PLD from both real-world and trial patients together can lead to better insight in potential factors responsible for a gap in outcomes between these two settings.\n\nPart III: Differences in outcomes between real-world and trial patients with melanoma\nIt is important to quantify and understand the differences in real-world population outcomes and the outcomes presented in phase III clinical trials to improve clinical decisions based on RWD. Chapter 6 focuses on ineligible advanced melanoma patients and their real-world outcomes. Ineligible patients were defined as patients who met one or multiple exclusion criteria of the phase III clinical trials. Since ineligible patients are excluded from phase III trials, this real-world information is significant for clinical practice. A total of 40% of the systemically treated advanced melanoma patients would have been considered ineligible for phase III clinical trials. Ineligible patients had a poorer median overall survival (mOS) compared to eligible patients (8.8 versus 23 months), but the 3-year OS probability was still 22%. This study concluded that the prognosis of ineligible patients with advanced melanoma in real-world was very heterogeneous and highly dependent on lactate dehydrogenase (LDH) value, Eastern Cooperative Oncology Group Performance Score (ECOG PS), and symptomatic brain metastases[12].\n\nChapter 7 reports the real-world outcomes of adjuvant-treated resected stage III\/IV melanoma patients. This study shows treatment patterns, relapse, and toxicity rates beyond the clinical trial setting. The recurrence-free survival (RFS) at 12 months was 70.6% (95% CI, 66.9-74.6), similar to the trial RFS rates. However, adjuvant anti-PD-1 treatment in daily practice showed slightly higher toxicity rates (18% versus 14%) compared to trials. Sixty-one percent of patients prematurely discontinued anti-PD-1 therapy[13].\n\nIn chapter 8, we investigated the real-world survival of advanced melanoma patients treated with BRAF-MEK inhibitors and identified characteristics of long-term survivors with advanced melanoma. Recently, 5-year survival outcomes of advanced melanoma patients treated with BRAF-MEK therapies in RCTs were published[14\u201316]. These results are favourable, but the real-world results remained unknown. The median progression-free survival (mPFS) and mOS of real-world patients were respectively 8.0 (95% CI, 6.8-9.4) and 11.7 (95% CI, 10.3-13.5) months. Two-year survival was reached by 28% of the patients, 22% reached 3-year survival, and 19% reached 4-year survival. Long-term survival of real-world patients treated with first-line BRAF-MEK inhibitors is significantly lower than that of trial patients, which is probably explained by poorer baseline characteristics of patients treated in daily practice.\n\nPart IV: The value of real-world data in clinical practice\nIn part IV, two studies are described in which RWD were used to create valuable evidence that can be used in clinical practice. Chapter 9 focuses on a different patient population, patients with advanced breast cancer treated with palbociclib. This study aimed to provide insights into the real-world use of palbociclib, dose reductions, and drug effectiveness in (older) patients with advanced breast cancer. Dose reductions occurred in 33% of all patients (n=598), which is similar to the PALOMA-3 trial[17]. Patients with dose reductions had no poorer outcomes compared to patients not requiring a dose reduction. Older patients treated with palbociclib had more frequent dose reductions, but this did not appear to affect OS (20.7 vs. 26.7 months, p=0.051)[18].\n\nAnother value of quality registries is the availability of RWD in extraordinary settings. To investigate the effects of the SARS-COV-2 pandemic on regular lung cancer care in the Netherlands, we studied in chapter 10 every patient with lung cancer registered in the DLCA-L. We observed a major decline in the number of non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) patients diagnosed during the first wave of the COVID-19 pandemic compared to the same period in 2018 and 2019. Furthermore, NSCLC patients diagnosed during the first wave of the pandemic presented with significantly worse ECOG PS \u22652 (26% vs. 20%, p-value < 0.001), and more patients presented with metastatic disease compared to the control period (49% vs. 43%, p-value <0.001)[19]. We fear that the impact of the COVID pandemic on lung cancer care will remain visible in upcoming years and that delayed lung cancer diagnosis may lead to a different victim group of COVID-19.\n\nIn chapter 11 a general discussion on the studies in this thesis is presented. The main findings, relevant literature, the relevance of our findings, limitations of the studies and future perspectives are discussed.","auteur":"Rawa Ismail","auteur_slug":"rawa-ismail","publicatiedatum":"18 mei 2022","taal":"EN","url_flipbook":"https:\/\/ebook.proefschriftmaken.nl\/ebook\/rawaismail?iframe=true","url_download_pdf":"","url_epub":"","ordernummer":"FTP-202604081507","isbn":"9789464238075","doi_nummer":"","naam_universiteit":"Universiteit Utrecht","afbeeldingen":12912,"naam_student:":"","binnenwerk":"","universiteit":"Universiteit Utrecht","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/10069","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio"}],"about":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/types\/us_portfolio"}],"author":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/users\/8"}],"replies":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/comments?post=10069"}],"version-history":[{"count":1,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/10069\/revisions"}],"predecessor-version":[{"id":10072,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/10069\/revisions\/10072"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/12912"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=10069"}],"wp:term":[{"taxonomy":"us_portfolio_category","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio_category?post=10069"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}