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Article ; Online: [Promosing cancer drug, but not available; the complexity of alternative access procedures].

Westgeest, Hans M / Barjesteh van Waalwijk van Doorn-Khosrovani, Sahar

2023 Volume 167

Abstract: It can be a challenge for a healthcare system to facilitate access to novel cancer drugs. This can be due to lack of transparency regarding alternative access pathways before or after authorisation, absence of reimbursement due to uncertainties regarding ...

Abstract	It can be a challenge for a healthcare system to facilitate access to novel cancer drugs. This can be due to lack of transparency regarding alternative access pathways before or after authorisation, absence of reimbursement due to uncertainties regarding clinical value and cost-effectiveness, lengthy price-negotiations and practice variation among hospitals, for instance in conducting molecular diagnostics. Based on three daily practice examples, we discuss the current challenges and complex procedures in providing access through alternative pathways, such as early-access or free-of-charge programmes in the Netherlands. Policymakers, funders, and medical societies need to harmonise procedures, increase transparency regarding treatment and testing options and collaborate more to ensure equal and timely access to valuable cancer therapies. Accurate and responsible communication and reporting regarding the efficacy and availability of novel treatments is crucial to prevent unrealistic expectations, disappointment, and distress among patients and the public.
MeSH term(s)	Humans ; Antineoplastic Agents/therapeutic use ; Netherlands ; Hospitals ; Communication ; Neoplasms/drug therapy
Chemical Substances	Antineoplastic Agents
Language	Dutch
Publishing date	2023-11-22
Publishing country	Netherlands
Document type	English Abstract ; Journal Article
ZDB-ID	82073-8
ISSN	1876-8784 ; 0028-2162
ISSN (online)	1876-8784
ISSN	0028-2162
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Article ; Online: Bronchiolitis after Combination Immunotherapy With Ipilimumab and Nivolumab in a Melanoma Patient.

Basir, Shahir / Bosiers, Jana / Westgeest, Hans M / Yick, David C Y / van Werven, Jochem R / van der Leest, Cor H

Journal of immunotherapy (Hagerstown, Md. : 1997)

2024

Abstract: Therapy with immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of metastatic melanoma but is also associated with various immune-related adverse events (AE), including pulmonary toxicity. Herein, we describe the case of a 60- ... ...

Abstract	Therapy with immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of metastatic melanoma but is also associated with various immune-related adverse events (AE), including pulmonary toxicity. Herein, we describe the case of a 60-year-old female with metastasized melanoma with BRAF mutation under combination immunotherapy with ipilimumab and nivolumab, who presented with a persistent, nonproductive cough for the last two months. Her CT-scan showed de novo bronchial inflammation and wall thickening in all lung fields. Initial treatment with antimicrobial treatment and inhalation corticosteroids did not resolve her symptoms, nor the radiologic abnormalities. Additional testing with transbronchial cryobiopsy showed a histologic picture of diffuse ill-formed granulomas and the presence of moderate chronic active inflammation of the respiratory epithelium, consistent with medication-related bronchiolitis. Bronchiolitis, as present in this case, has rarely been reported as an immune-related AE. A thorough diagnostic workup is mandatory as it remains a diagnosis of exclusion. Management consists of discontinuing ICIs and administering systemic corticosteroids. The addition of immunosuppressive agents (e, infliximab, cyclophosphamide, or mycophenolate mofetil) can be considered in refractory cases. In our case, clinical and radiologic resolution was achieved after discontinuing the ICI and treatment with high-dose prednisone. This case shows that although bronchiolitis is a rare immune-related side effect of ICIs, oncologists, and pulmonologists should always be aware of this relatively easily treatable AE.
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	1064067-8
ISSN	1537-4513 ; 1053-8550 ; 1524-9557
ISSN (online)	1537-4513
ISSN	1053-8550 ; 1524-9557
DOI	10.1097/CJI.0000000000000509
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Zs.A 1778: Show issues

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Article ; Online: Lessons learned from postmarketing withdrawals of expedited approvals for oncology drug indications.

Koole, Simone N / Huisman, Atse H / Timmers, Lonneke / Westgeest, Hans M / van Breugel, Edwin / Sonke, Gabe S / van Waalwijk van Doorn-Khosrovani, Sahar Barjesteh

The Lancet. Oncology

2024 Volume 25, Issue 3, Page(s) e126–e135

Abstract: In the past decade, there have been a record number of oncology therapy approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Besides the EMA's conditional marketing authorisation programme and the FDA's ... ...

Abstract	In the past decade, there have been a record number of oncology therapy approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Besides the EMA's conditional marketing authorisation programme and the FDA's Accelerated Approval Program, we observe a tendency towards fast approval for exploratory studies with non-randomised, uncontrolled designs and surrogate endpoints. This issue raises concerns about the robustness and effectiveness of accepted treatments, leaving patients and health-care professionals in a state of uncertainty. A substantial number of accelerated approvals have recently been withdrawn in the USA, with some still authorised in Europe, emphasising discrepancies in regulatory standards that affect both patients and society as a whole. We highlight examples of drugs, authorised on the basis of surrogate endpoints, that were later withdrawn due to an absence of overall survival benefit. Our findings address the challenges and consequences of accelerated approval pathways in oncology. In conclusion, this Policy Review calls for regulatory bodies to better align their procedures and insist on robust evidence, preferably through unbiased randomised controlled trials. Drug approval processes should prioritise patient benefit, overall survival, and quality of life to minimise risks and uncertainties for patients.
MeSH term(s)	Humans ; Drug Approval ; Europe ; Medical Oncology ; Product Surveillance, Postmarketing ; Safety-Based Drug Withdrawals
Language	English
Publishing date	2024-02-02
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/S1470-2045(23)00592-2
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Zs.A 5696: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Validation of the updated renal graded prognostic assessment (GPA) for patients with renal cancer brain metastases treated with gamma knife radiosurgery.

van Ruitenbeek, Niels J / Ho, Vincent K Y / Westgeest, Hans M / Beerepoot, Laurens V / Hanssens, Patrick E J

Journal of neuro-oncology

2021 Volume 153, Issue 3, Page(s) 527–536

Abstract: Introduction: Prognosis of patients with brain metastasis (BM) from renal cell carcinoma (RCC) is relevant for treatment decisions and can be estimated with the Renal Graded Prognostic Assessment (GPA). The aim of this study is to validate the updated ... ...

Abstract	Introduction: Prognosis of patients with brain metastasis (BM) from renal cell carcinoma (RCC) is relevant for treatment decisions and can be estimated with the Renal Graded Prognostic Assessment (GPA). The aim of this study is to validate the updated version of this instrument in a cohort treated with Gamma Knife radiosurgery (GKRS) without prior local intracerebral therapy. Methods: Between 2007 and 2018, 106 RCC patients with BM were treated with GKRS. They were categorized according to the updated Renal GPA. Overall survival (OS), distant intracranial failure and local failure were estimated using the Kaplan-Meier method and risk factors were identified with Cox proportional hazard regressions. Results: Median OS was 8.6 months. Median OS for GPA categories 0.0-1.0 (15%), 1.5-2.0 (12%), 2.5-3.0 (35%) and 3.5-4.0 (29%) was 2.9, 5.5, 8.1 and 20.4 months, respectively. Karnofsky performance status < 90, serum hemoglobin ≤ 12.5 g/dL, age > 65 years and time from primary diagnosis to brain metastasis < 1 year were significantly related with shorter survival, while presence of extracranial disease, the volume and total number of BM had no significant impact on OS. A total count of > 4 BM was the only predictive factor for distant intracranial failure, while none of the investigated factors predicted local failure. Conclusions: This study confirms the updated Renal GPA in an independent cohort as a valuable instrument to estimate survival in patients with BM from RCC treated with GKRS.
MeSH term(s)	Aged ; Brain Neoplasms/radiotherapy ; Brain Neoplasms/secondary ; Brain Neoplasms/surgery ; Carcinoma, Renal Cell/secondary ; Carcinoma, Renal Cell/surgery ; Humans ; Kidney Neoplasms/surgery ; Prognosis ; Radiosurgery ; Retrospective Studies
Language	English
Publishing date	2021-06-25
Publishing country	United States
Document type	Journal Article ; Validation Study
ZDB-ID	604875-4
ISSN	1573-7373 ; 0167-594X
ISSN (online)	1573-7373
ISSN	0167-594X
DOI	10.1007/s11060-021-03793-9
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Zs.A 1825: Show issues

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Article ; Online: Evidence or Prejudice? Critical Re-Analysis of Randomized Controlled Trials Comparing Overall Survival After Cisplatin Versus Carboplatin-Based Regimens in Advanced Urothelial Carcinoma.

Richters, Anke / Kiemeney, Lambertus A L M / Mehra, Niven / Westgeest, Hans M / Birtle, Alison / Bryan, Richard T / Aben, Katja K H

Clinical genitourinary cancer

2021 Volume 20, Issue 4, Page(s) e346–e352

Abstract: Introduction: For many years EAU guidelines have recommended the use of cisplatin-based regimens over carboplatin for treatment of advanced urothelial cell carcinoma (UCC) in eligible patients. The claim of an overall survival (OS) benefit is based on ( ... ...

Abstract	Introduction: For many years EAU guidelines have recommended the use of cisplatin-based regimens over carboplatin for treatment of advanced urothelial cell carcinoma (UCC) in eligible patients. The claim of an overall survival (OS) benefit is based on (a meta-analysis of) 2 RCTs totalling 190 patients, of which one study has methodological flaws. These studies warrant secondary analysis to substantiate the evidence for an OS benefit of cisplatin- versus carboplatin-based regimens. Patients and methods: Individual patient data (IPD) were reconstructed from the 2 RCTs, assessing OS in both treatment arms. IPD of both studies were then jointly reanalysed to assess an OS estimate with Kaplan-Meier methods, with, and without an alternative censoring scenario to assess the impact of the original biased censoring approach. Kaplan-Meier curves were compared by calculating restricted mean survival time (RMST) differences. Results: In each study individually, and in both studies combined, the survival benefit of cisplatin versus carboplatin was less than 1 month and not significant in a follow-up window of 12 months. This was also the case when an alternative censoring scenario was applied. Conclusion: Careful scrutiny of the data on which guidelines base the recommendation of cisplatin-based chemotherapy for the treatment of advanced UCC does not uphold the finding that cisplatin leads to an OS benefit when compared to carboplatin. This conclusion, combined with higher toxicity in cisplatin-based regimens warrants a reconsideration of this guideline recommendation.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Carboplatin/adverse effects ; Carcinoma, Transitional Cell/drug therapy ; Cisplatin/therapeutic use ; Humans ; Prejudice ; Randomized Controlled Trials as Topic ; Urinary Bladder Neoplasms/drug therapy
Chemical Substances	Carboplatin (BG3F62OND5) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2021-12-27
Publishing country	United States
Document type	Journal Article ; Meta-Analysis
ZDB-ID	2225121-2
ISSN	1938-0682 ; 1558-7673
ISSN (online)	1938-0682
ISSN	1558-7673
DOI	10.1016/j.clgc.2021.12.017
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Zs.A 6168: Show issues

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Article ; Online: Gene-expression-based T-Cell-to-Stroma Enrichment (TSE) score predicts response to immune checkpoint inhibitors in urothelial cancer.

Rijnders, Maud / Nakauma-González, J Alberto / Robbrecht, Debbie G J / Gil-Jimenez, Alberto / Balcioglu, Hayri E / Oostvogels, Astrid A M / Aarts, Maureen J B / Boormans, Joost L / Hamberg, Paul / van der Heijden, Michiel S / Szabados, Bernadett E / van Leenders, Geert J L H / Mehra, Niven / Voortman, Jens / Westgeest, Hans M / de Wit, Ronald / van der Veldt, Astrid A M / Debets, Reno / Lolkema, Martijn P

Nature communications

2024 Volume 15, Issue 1, Page(s) 1349

Abstract: Immune checkpoint inhibitors (ICI) improve overall survival in patients with metastatic urothelial cancer (mUC), but therapeutic success at the individual patient level varies significantly. Here we identify predictive markers of response, based on whole- ...

Abstract	Immune checkpoint inhibitors (ICI) improve overall survival in patients with metastatic urothelial cancer (mUC), but therapeutic success at the individual patient level varies significantly. Here we identify predictive markers of response, based on whole-genome DNA (n = 70) and RNA-sequencing (n = 41) of fresh metastatic biopsy samples, collected prior to treatment with pembrolizumab. We find that PD-L1 combined positivity score does not, whereas tumor mutational burden and APOBEC mutagenesis modestly predict response. In contrast, T cell-to-stroma enrichment (TSE) score, computed from gene expression signature data to capture the relative abundance of T cells and stromal cells, predicts response to immunotherapy with high accuracy. Patients with a positive and negative TSE score show progression free survival rates at 6 months of 67 and 0%, respectively. The abundance of T cells and stromal cells, as reflected by the TSE score is confirmed by immunofluorescence in tumor tissue, and its good performance in two independent ICI-treated cohorts of patients with mUC (IMvigor210) and muscle-invasive UC (ABACUS) validate the predictive power of the TSE score. In conclusion, the TSE score represents a clinically applicable metric that potentially supports the prospective selection of patients with mUC for ICI treatment.
MeSH term(s)	Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Prospective Studies ; T-Lymphocytes ; Carcinoma, Transitional Cell/drug therapy ; Carcinoma, Transitional Cell/genetics ; Urinary Bladder Neoplasms/drug therapy ; Urinary Bladder Neoplasms/genetics ; B7-H1 Antigen
Chemical Substances	Immune Checkpoint Inhibitors ; B7-H1 Antigen
Language	English
Publishing date	2024-02-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45714-0
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Article ; Online: The PRO-RCC study: a long-term PROspective Renal Cell Carcinoma cohort in the Netherlands, providing an infrastructure for 'Trial within Cohorts' study designs.

BMC cancer

2023 Volume 23, Issue 1, Page(s) 648

Abstract: Background: Ongoing research in the field of both localized, locally advanced and metastatic renal cell carcinoma has resulted in the availability of multiple treatment options. Hence, many questions are still unanswered and await further research. A ... ...

Abstract	Background: Ongoing research in the field of both localized, locally advanced and metastatic renal cell carcinoma has resulted in the availability of multiple treatment options. Hence, many questions are still unanswered and await further research. A nationwide collaborative registry allows to collect corresponding data. For this purpose, the Dutch PROspective Renal Cell Carcinoma cohort (PRO-RCC) has been founded, for the prospective collection of long-term clinical data, patient reported outcome measures (PROMs) and patient reported experience measures (PREMs). Methods: PRO-RCC is designed as a multicenter cohort for all Dutch patients with renal cell carcinoma (RCC). Recruitment will start in the Netherlands in 2023. Importantly, participants may also consent to participation in a 'Trial within cohorts' studies (TwiCs). The TwiCs design provides a method to perform (randomized) interventional studies within the registry. The clinical data collection is embedded in the Netherlands Cancer Registry (NCR). Next to the standardly available data on RCC, additional clinical data will be collected. PROMS entail Health-Related Quality of Life (HRQoL), symptom monitoring with optional ecological momentary assessment (EMA) of pain and fatigue, and optional return to work- and/or nutrition questionnaires. PREMS entail satisfaction with care. Both PROMS and PREMS are collected through the PROFILES registry and are accessible for the patient and the treating physician. Trial registration: Ethical board approval has been obtained (2021_218) and the study has been registered at ClinicalTrials.gov (NCT05326620). Discussion: PRO-RCC is a nationwide long-term cohort for the collection of real-world clinical data, PROMS and PREMS. By facilitating an infrastructure for the collection of prospective data on RCC, PRO-RCC will contribute to observational research in a real-world study population and prove effectiveness in daily clinical practice. The infrastructure of this cohort also enables that interventional studies can be conducted with the TwiCs design, without the disadvantages of classic RCTs such as slow patient accrual and risk of dropping out after randomization.
MeSH term(s)	Humans ; Carcinoma, Renal Cell/epidemiology ; Carcinoma, Renal Cell/therapy ; Netherlands/epidemiology ; Prospective Studies ; Quality of Life ; Kidney Neoplasms/epidemiology ; Kidney Neoplasms/therapy
Language	English
Publishing date	2023-07-11
Publishing country	England
Document type	Multicenter Study ; Journal Article
ZDB-ID	2041352-X
ISSN	1471-2407 ; 1471-2407
ISSN (online)	1471-2407
ISSN	1471-2407
DOI	10.1186/s12885-023-11094-9
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Article: Phenotype-guided targeted therapy based on functional signal transduction pathway activity in recurrent ovarian cancer patients: The STAPOVER study protocol.

van der Ploeg, Phyllis / Hendrikse, Cynthia Se / Thijs, Anna Mj / Westgeest, Hans M / Smedts, Huberdina Pm / Vos, M Caroline / Jalving, Mathilde / Lok, Christianne Ar / Boere, Ingrid A / van Ham, Maaike Apc / Ottevanger, Petronella B / Westermann, Anneke M / Mom, Constantijne H / Lalisang, Roy I / Lambrechts, Sandrina / Bekkers, Ruud Lm / Piek, Jurgen Mj

Heliyon

2023 Volume 10, Issue 1, Page(s) e23170

Abstract: Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for ... ...

Abstract	Objective: Ovarian cancer is the fifth cause of cancer-related death among women. The benefit of targeted therapy for ovarian cancer patients is limited even if treatment is stratified by molecular signature. There remains a high unmet need for alternative diagnostics that better predict targeted therapy, as current diagnostics are generally inaccurate predictors. Quantitative assessment of functional signal transduction pathway (STP) activity from mRNA measurements of target genes is an alternative approach. Therefore, we aim to identify aberrantly activated STPs in tumour tissue of patients with recurrent ovarian cancer and start Study design: Patients with recurrent ovarian cancer and either 1) have platinum-resistant disease, 2) refrain from standard therapy or 3) are asymptomatic and not yet eligible for standard therapy will be included in this multi-centre prospective cohort study with multiple stepwise executed treatment arms. Targeted therapy will be available for patients with aberrantly high functional activity of the oestrogen receptor, androgen receptor, phosphoinositide 3-kinase or Hedgehog STP. The primary endpoint of this study is the progression-free survival (PFS) ratio (PFS2/PFS1 ratio) according to RECIST 1.1 determined by the PFS on matched targeted therapy (PFS2) compared to PFS on prior therapy (PFS1). Secondary endpoints include among others best overall response, overall survival, side effects, health-related quality of life and cost-effectiveness. Conclusion: The results of this study will show the clinical applicability of STP activity in selecting recurrent ovarian cancer patients for effective therapies.
Language	English
Publishing date	2023-12-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2023.e23170
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Article ; Online: Influence of Darolutamide on Cabazitaxel Systemic Exposure.

Buck, Stefan A J / Guchelaar, Niels A D / de Bruijn, Peter / Ghobadi Moghaddam-Helmantel, Inge M / Oomen-de Hoop, Esther / Westgeest, Hans M / Hamberg, Paul / Mathijssen-van Stein, Danielle / Lolkema, Martijn P / Koolen, Stijn L W / de Wit, Ronald / Mathijssen, Ron H J

Clinical pharmacokinetics

2022 Volume 61, Issue 10, Page(s) 1471–1473

MeSH term(s)	Androgen Receptor Antagonists ; Humans ; Male ; Prostatic Neoplasms, Castration-Resistant ; Pyrazoles ; Taxoids/adverse effects
Chemical Substances	Androgen Receptor Antagonists ; Pyrazoles ; Taxoids ; darolutamide ; cabazitaxel (51F690397J)
Language	English
Publishing date	2022-07-27
Publishing country	Switzerland
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	197627-8
ISSN	1179-1926 ; 0312-5963
ISSN (online)	1179-1926
ISSN	0312-5963
DOI	10.1007/s40262-022-01159-6
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Article ; Online: Genome-wide aneuploidy detected by mFast-SeqS in circulating cell-free DNA is associated with poor response to pembrolizumab in patients with advanced urothelial cancer.

Mendelaar, Pauline A J / Robbrecht, Debbie G J / Rijnders, Maud / de Wit, Ronald / de Weerd, Vanja / Deger, Teoman / Westgeest, Hans M / Aarts, Maureen J B / Voortman, Jens / Martens, John W M / van der Veldt, Astrid A M / Nakauma-González, José Alberto / Wilting, Saskia M / Lolkema, Martijn

Molecular oncology

2022 Volume 16, Issue 10, Page(s) 2086–2097

Abstract: Second-line treatment with immune checkpoint inhibition in patients with metastatic urothelial cancer (mUC) has a low success rate (~ 20%). Circulating tumour-derived DNA (ctDNA) levels may guide patient stratification, provided that an affordable and ... ...

Abstract	Second-line treatment with immune checkpoint inhibition in patients with metastatic urothelial cancer (mUC) has a low success rate (~ 20%). Circulating tumour-derived DNA (ctDNA) levels may guide patient stratification, provided that an affordable and robust assay is available. Here, we investigate whether the modified fast aneuploidy screening test-sequencing system (mFast-SeqS) may provide such an assay. To this end, mFast-SeqS was performed on cell-free DNA (cfDNA) from 74 patients with mUC prior to treatment with pembrolizumab. Results were associated with corresponding tissue-based profiles, plasma-based variant allele frequencies (VAFs) and clinical response. We found that plasma-derived mFast-SeqS-based aneuploidy scores significantly correlated with those observed in the corresponding tumour tissue as well as with the ctDNA level in the plasma. In multivariate logistic regression analysis, a high aneuploidy score was independently associated with lack of clinical benefit from treatment with pembrolizumab. In conclusion, mFast-SeqS provides a patient-friendly, high-throughput and affordable method to estimate ctDNA level. Following independent validation, this test could be used to stratify mUC patients for response prior to the initiation of treatment with pembrolizumab.
MeSH term(s)	Aneuploidy ; Antibodies, Monoclonal, Humanized ; Biomarkers, Tumor/genetics ; Cell-Free Nucleic Acids/genetics ; Circulating Tumor DNA/genetics ; Humans ; Neoplasms
Chemical Substances	Antibodies, Monoclonal, Humanized ; Biomarkers, Tumor ; Cell-Free Nucleic Acids ; Circulating Tumor DNA ; pembrolizumab (DPT0O3T46P)
Language	English
Publishing date	2022-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13196
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