Publications by authors named "Maureen J Aarts"

64 Publications

Cytoreductive nephrectomy and exposure to sunitinib - a post hoc analysis of the Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) trial.

BJU Int 2021 Oct 27. Epub 2021 Oct 27.

Royal Free London NHS Foundation Trust and UCL Division of Surgery and Interventional Science, London, UK.

Objective: To analyse if exposure to sunitinib in the Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) trial, which investigated opposite sequences of cytoreductive nephrectomy (CN) and systemic therapy, is associated with the overall survival (OS) benefit observed in the deferred CN arm.

Patients And Methods: A post hoc analysis of SURTIME trial data. Variables analysed included number of patients receiving sunitinib, time from randomisation to start sunitinib, overall response rate by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and duration of drug exposure and dose in the intention-to-treat population of the immediate and deferred arm. Descriptive methods and 95% confidence-intervals (CI) were used.

Results: In the deferred arm, 97.7% (95% CI 89.3-99.6%; n = 48) received sunitinib vs 80% (95% CI 66.9-88.7%, n = 40) in the immediate arm. Following immediate CN, 19.6% progressed 4 weeks after CN and the median time to start sunitinib was 39.5 vs 4.5 days in the deferred arm. At week 16, 46.0% had progressed at metastatic sites in the immediate CN arm vs 32.7% in the deferred arm. Sunitinib dose reductions, escalations and interruptions were not statistically significantly different between arms. Among patients who received sunitinib in the immediate or deferred arm the median total sunitinib treatment duration was 172.5 vs 248 days. Reduction of target lesions was more profound in the deferred arm.

Conclusions: In comparison to the deferred CN approach, immediate CN impairs administration, onset, and duration of sunitinib. Starting with systemic therapy leads to early and more profound disease control and identification of progression prior to planned CN, which may have contributed to the observed OS benefit.
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http://dx.doi.org/10.1111/bju.15625DOI Listing
October 2021

Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment.

Int J Mol Sci 2021 Oct 18;22(20). Epub 2021 Oct 18.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, 6229 ER Maastricht, The Netherlands.

Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10-50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (>90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs.
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http://dx.doi.org/10.3390/ijms222011199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8540269PMC
October 2021

Hospital Variation in Cancer Treatments and Survival OutComes of Advanced Melanoma Patients: Nationwide Quality Assurance in The Netherlands.

Cancers (Basel) 2021 Oct 11;13(20). Epub 2021 Oct 11.

Dutch Institute for Clinical Auditing, Rijnsburgerweg 10, 2333 AA Leiden, The Netherlands.

Background: To assure a high quality of care for patients treated in Dutch melanoma centers, hospital variation in treatment patterns and outcomes is evaluated in the Dutch Melanoma Treatment Registry. The aim of this study was to assess center variation in treatments and 2-year survival probabilities of patients diagnosed between 2013 and 2017 in the Netherlands.

Methods: We selected patients diagnosed between 2013 and 2017 with unresectable IIIC or stage IV melanoma, registered in the Dutch Melanoma Treatment Registry. Centers' performance on 2-year survival was evaluated using Empirical Bayes estimates calculated in a random effects model. Treatment patterns of the centers with the lowest and highest estimates for 2-year survival were compared.

Results: For patients diagnosed between 2014 and 2015, significant center variation in 2-year survival probabilities was observed even after correcting for case-mix and treatment with new systemic therapies. The different use of new systemic therapies partially explained the observed variation. From 2016 onwards, no significant difference in 2-year survival was observed between centers.

Conclusion: Our data suggest that between 2014 and 2015, after correcting for patient case-mix, significant variation in 2-year survival probabilities between Dutch melanoma centers existed. The use of new systemic therapies could partially explain this variation. In 2013 and between 2016 and 2017, no significant variation between centers existed.
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http://dx.doi.org/10.3390/cancers13205077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533953PMC
October 2021

Anti-PD-1 Efficacy in Patients with Metastatic Urothelial Cancer Associates with Intratumoral Juxtaposition of T Helper-Type 1 and CD8 T cells.

Clin Cancer Res 2021 Oct 6. Epub 2021 Oct 6.

Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands.

Purpose: PD-1 inhibition results in durable antitumor responses in a proportion of patients with metastatic urothelial cancer (mUC). The majority of patients, however, do not experience clinical benefit. In this study, we aimed to identify early changes in T-cell subsets that underlie anti-PD-1 efficacy in patients with mUC.

Experimental Design: Paired samples were collected from peripheral blood, plasma, and metastatic lesions of 56 patients with mUC at baseline and weeks 6 and 12 after initiating pembrolizumab treatment (200 mg intravenously, every 3 weeks). Samples were analyzed using multiplex flow cytometry, ELISA, and stainings, including cellular network analysis. Treatment response was evaluated as best overall response according to RECIST v1.1, and patients were classified as responder (complete or partial response) or nonresponder (progressive disease).

Results: In responders, baseline fractions of CD4 T cells expressing cosignaling receptors were higher compared with nonresponders. The fraction of circulating PD-1 CD4 T cells decreased at weeks 6 and 12, whereas the fraction of 4-1BB CD28 CD4 T cells increased at week 12. In metastatic lesions of responders, the baseline density of T helper-type 1 (Th1) cells, defined as T-bet CD4 T cells, was higher as compared to non-responders. Upon treatment, Th1 cells became localized in close proximity to CD8 T cells, CD11b myeloid cells, and tumor cells.

Conclusions: A decrease in the fraction of circulating PD-1 CD4 T cells, and juxtaposition of Th1, CD8, and myeloid cells was associated with response to anti-PD-1 treatment in patients with mUC.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3319DOI Listing
October 2021

The unfavorable effects of COVID-19 on Dutch advanced melanoma care.

Int J Cancer 2021 Oct 3. Epub 2021 Oct 3.

Scientific Bureau, Dutch Institute for Clinical Auditing, Leiden, The Netherlands.

The COVID-19 pandemic had a severe impact on medical care. Our study aims to investigate the impact of COVID-19 on advanced melanoma care in the Netherlands. We selected patients diagnosed with irresectable stage IIIc and IV melanoma during the first and second COVID-19 wave and compared them with patients diagnosed within the same time frame in 2018 and 2019. Patients were divided into three geographical regions. We investigated baseline characteristics, time from diagnosis until start of systemic therapy and postponement of anti-PD-1 courses. During both waves, fewer patients were diagnosed compared to the control groups. During the first wave, time between diagnosis and start of treatment was significantly longer in the southern region compared to other regions (33 vs 9 and 15 days, P-value <.05). Anti-PD-1 courses were postponed in 20.0% vs 3.0% of patients in the first wave compared to the control period. Significantly more patients had courses postponed in the south during the first wave compared to other regions (34.8% vs 11.5% vs 22.3%, P-value <.001). Significantly more patients diagnosed during the second wave had brain metastases and worse performance status compared to the control period. In conclusion, advanced melanoma care in the Netherlands was severely affected by the COVID-19 pandemic. In the south, the start of systemic treatment for advanced melanoma was more often delayed, and treatment courses were more frequently postponed. During the second wave, patients were diagnosed with poorer patient and tumor characteristics. Longer follow-up is needed to establish the impact on patient outcomes.
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http://dx.doi.org/10.1002/ijc.33833DOI Listing
October 2021

Adjuvant treatment for melanoma in clinical practice - Trial versus reality.

Eur J Cancer 2021 11 29;158:234-245. Epub 2021 Sep 29.

Department of Biomedical Data Sciences, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333ZA, the Netherlands; Department of Surgical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, the Netherlands; Scientific Bureau, Dutch Institute for Clinical Auditing, Rijnsburgerweg 10, Leiden, 2333AA, the Netherlands.

Background: Little is known about outcomes of adjuvant-treated melanoma patients beyond the clinical trial setting. Since 2019, adjuvant-treated melanoma patients have been registered in the DMTR, a population-based registry to monitor the quality and safety of melanoma care in the Netherlands. This study aims to describe treatment patterns, relapse, and toxicity rates of adjuvant-treated melanoma patients beyond the clinical trial setting.

Methods: Analyses were performed on adjuvant-treated melanoma patients included in the DMTR. Descriptive statistics were used to analyse patient-, and treatment characteristics. A baseline registration completeness analysis was performed, and an analysis on trial eligibility in clinical practice patients. Recurrence-free survival (RFS) at 12-months was estimated with the Kaplan-Meier method.

Results: A total of 641 patients were treated with adjuvant anti-PD-1 therapy. RFS at 12-months was 70.6% (95% CI, 66.9-74.6) with a median follow-up of 12.8 months. Sex, stage of disease and Breslow thickness were associated with a higher hazard for RFS. Eighteen per cent of the anti-PD-1-treated patients developed grade ≥3 toxicity. Sixty-one per cent of patients prematurely discontinued anti-PD-1 therapy.

Conclusion: Adjuvant anti-PD-1 treatment of resected stage III/IV melanoma in daily practice showed slightly higher toxicity rates and more frequent premature discontinuation but similar RFS rates compared to trials.
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http://dx.doi.org/10.1016/j.ejca.2021.08.044DOI Listing
November 2021

Sex-Based Differences in Treatment with Immune Checkpoint Inhibition and Targeted Therapy for Advanced Melanoma: A Nationwide Cohort Study.

Cancers (Basel) 2021 Sep 16;13(18). Epub 2021 Sep 16.

Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Recent meta-analyses show conflicting data on sex-dependent benefit following systemic treatment for advanced melanoma patients. We examined the nationwide Dutch Melanoma Treatment Registry (July 2013-July 2018), assessing sex-dependent differences in advanced melanoma patients (stage IIIC/IV) with respect to clinical characteristics, mutational profiles, treatments initiated, grade 3-4 adverse events (AEs), treatment responses, and mortality. We included 3985 patients, 2363 men (59%) and showed that although men and women with advanced melanoma differ in clinical and tumor characteristics, the safety profile of immune checkpoint inhibition (ICI) is comparable. The data suggest a 10% survival advantage for women, mainly seen in patients ≥60 years of age and patients with BRAF V600 mutant melanoma. Following ICI there was no survival difference.
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http://dx.doi.org/10.3390/cancers13184639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465427PMC
September 2021

Discontinuation of anti-PD-1 monotherapy in advanced melanoma-Outcomes of daily clinical practice.

Int J Cancer 2022 Jan 2;150(2):317-326. Epub 2021 Oct 2.

Divisions of Medical Oncology and Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

There is no consensus on the optimal treatment duration of anti-PD-1 for advanced melanoma. The aim of our study was to gain insight into the outcomes of anti-PD-1 discontinuation, the association of treatment duration with progression and anti-PD-1 re-treatment in relapsing patients. Analyses were performed on advanced melanoma patients in the Netherlands who discontinued first-line anti-PD-1 monotherapy in the absence of progressive disease (n = 324). Survival was estimated after anti-PD-1 discontinuation and with a Cox model the association of treatment duration with progression was assessed. At the time of anti-PD-1 discontinuation, 90 (28%) patients had a complete response (CR), 190 (59%) a partial response (PR) and 44 (14%) stable disease (SD). Median treatment duration for patients with CR, PR and SD was 11.2, 11.5 and 7.2 months, respectively. The 24-month progression-free survival and overall survival probabilities for patients with a CR, PR and SD were, respectively, 64% and 88%, 53% and 82%, 31% and 64%. Survival outcomes of patients with a PR and CR were similar when anti-PD-1 discontinuation was not due to adverse events. Having a PR at anti-PD-1 discontinuation and longer time to first response were associated with progression [hazard ratio (HR) = 1.81 (95% confidence interval, CI = 1.11-2.97) and HR = 1.10 (95% CI = 1.02-1.19; per month increase)]. In 17 of the 27 anti-PD-1 re-treated patients (63%), a response was observed. Advanced melanoma patients can have durable remissions after (elective) anti-PD-1 discontinuation.
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http://dx.doi.org/10.1002/ijc.33800DOI Listing
January 2022

Nivolumab exposure in a hemodialysis patient with metastatic melanoma.

Melanoma Res 2021 Dec;31(6):579-581

Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center.

The effect of intermittent hemodialysis (IHD) on nivolumab serum concentrations in patients with severe renal impairment is largely unknown. Here, we present a 79-year-old patient with metastatic melanoma and end-stage renal disease on IHD three times a week, treated with 480 mg nivolumab every 4 weeks. A serum trough concentration of nivolumab was determined before the start of the third cycle, and two samples were taken immediately before and after a hemodialysis session during this cycle. All nivolumab serum concentrations were within a similar range as those previously measured among patients without renal insufficiency, after a comparable duration of nivolumab treatment. Therefore, we conclude that IHD does not influence nivolumab exposure. Furthermore, nivolumab treatment was continued without complications and appears to be well tolerated for patients on IHD.
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http://dx.doi.org/10.1097/CMR.0000000000000775DOI Listing
December 2021

Toxicity, Response and Survival in Older Patients with Metastatic Melanoma Treated with Checkpoint Inhibitors.

Cancers (Basel) 2021 Jun 5;13(11). Epub 2021 Jun 5.

Department of Medical Oncology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Background: Previous trials suggest no differences in immunotherapy treatment between older and younger patients, but mainly young patients with a good performance status were included. The aim of this study was to describe the treatment patterns and outcomes of "real-world" older patients with metastatic melanoma and to identify predictors of outcome.

Methods: We included patients aged ≥65 years with metastatic melanoma from the Dutch Melanoma Treatment Registry. We described the reasons for hospital admissions and treatment discontinuation. Additionally, we assessed predictors of toxicity and response using logistic regression models and survival using Cox regression models.

Results: We included 2216 patients. Grade ≥3 toxicity was not associated with age, comorbidities or WHO status. Patients aged ≥75 discontinued treatment due to toxicity more often, resulting in fewer treatment cycles. Response rates were similar to previous trials (40.3% and 43.6% in patients aged 65-75 and ≥75, respectively, for anti-PD1 treatment) and did not decrease with age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity.

Conclusion: Response rates and toxicity outcomes of checkpoint inhibitors did not change with increasing age or comorbidity. However, the impact of grade I-II toxicity on quality of life deserves further study as older patients discontinue treatment more frequently.
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http://dx.doi.org/10.3390/cancers13112826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201158PMC
June 2021

Tyrosine Kinase Inhibitor Sunitinib Delays Platelet-Induced Coagulation: Additive Effects of Aspirin.

Thromb Haemost 2021 Jun 15. Epub 2021 Jun 15.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.

Background:  Sunitinib is a multitarget tyrosine kinase inhibitor (TKI) used for cancer treatment. In platelets, sunitinib affects collagen-induced activation under noncoagulating conditions. We investigated (1) the effects of sunitinib on thrombus formation induced by other TK-dependent receptors, and (2) the effects under coagulating conditions. Cardiovascular disease is a comorbidity in cancer patients, resulting in possible aspirin treatment. Sunitinib and aspirin are associated with increased bleeding risk, and therefore we also investigated (3) the synergistic effects of these compounds on thrombus and fibrin formation.

Methods:  Blood or isolated platelets from healthy volunteers or cancer patients were incubated with sunitinib and/or aspirin or vehicle. Platelet activation was determined by TK phosphorylation, flow cytometry, changes in [Ca], aggregometry, and whole blood perfusion over multiple surfaces, including collagen with(out) tissue factor (TF) was performed.

Results:  Sunitinib reduced thrombus formation and phosphatidylserine (PS) exposure under flow on collagen type I and III. Also, sunitinib inhibited glycoprotein VI-induced TK phosphorylation and Ca elevation. Upon TF-triggered coagulation, sunitinib decreased PS exposure and fibrin formation. In blood from cancer patients more pronounced effects of sunitinib were observed in lung and pancreatic as compared to neuroglioblastoma and other cancer types. Compared to sunitinib alone, sunitinib plus aspirin further reduced platelet aggregation, thrombus formation, and PS exposure on collagen under flow with(out) coagulation.

Conclusion:  Sunitinib suppresses collagen-induced procoagulant activity and delays fibrin formation, which was aggravated by aspirin. Therefore, we urge for awareness of the combined antiplatelet effects of TKIs with aspirin, as this may result in increased risk of bleeding.
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http://dx.doi.org/10.1055/s-0041-1730312DOI Listing
June 2021

Outcomes for systemic therapy in older patients with metastatic melanoma: Results from the Dutch Melanoma Treatment Registry.

J Geriatr Oncol 2021 09 19;12(7):1031-1038. Epub 2021 May 19.

Department of Surgical Oncology, Netherlands Cancer Institute- Antoni van Leeuwenhoek hospital, Amsterdam, the Netherlands; Scientific bureau, Dutch Institute for Clinical Auditing, Leiden, the Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.

Background: The incidence of metastatic melanoma is increasing in all ages. Multiple trials with targeted drugs and immune checkpoint inhibitors showed improved survival in metastatic melanoma. However, patients aged ≥75 years are often under-represented in clinical trials, therefore raising questions on safety and efficacy of treatment.

Patients And Methods: We analyzed a real-world cohort of 3054 patients with metastatic melanoma stratified for age (≤65 years, 66-74 years and ≥ 75 years), and BRAF status, providing data on treatment strategies, toxicity, and survival. Kaplan Meier curves and Cox Proportional Hazard Models were used to present overall survival (OS) and Melanoma Specific Survival (MSS).

Results: Overall, 52.2% of patients were ≤ 65 years and 18.4% of patients ≥75 years. BRAF mutated tumors were found less often in patients ≥75 years: 34.5% versus 65% in patients ≤65 years. Patients ≥75 years received systemic therapy less frequently compared to their younger counterparts independent of the BRAF status. When receiving treatment, no statistical significant difference in grade 3 or 4 toxicity was observed. Three year Overall Survival rate was 13.7% (9.1-19.3) in patients ≥75 years versus 26.7% (23.1-30.4) in patients ≤65 years, with a Hazard Ratio (HR) of 1.71 (95%CI 1.50-1.95), p < 0.001. Three year Melanoma Specific Survival was 30.4% (22.0-39.2) versus 34.0% (29.7-38.2), HR 1.26 (95% CI 1.07-1.49), p = 0.005 with an adjusted HR of 1.21 (1.00-1.47), p = 0.049.

Conclusion: Patients with metastatic melanoma ≥75 years are less frequently treated, but when treated there is no statistical significant increase in toxicity and only a borderline statistical significant difference in Melanoma Specific Survival was seen, compared to younger patients.
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http://dx.doi.org/10.1016/j.jgo.2021.04.006DOI Listing
September 2021

Clinical outcome of patients with metastatic melanoma of unknown primary in the era of novel therapy.

Cancer Immunol Immunother 2021 Nov 27;70(11):3123-3135. Epub 2021 Mar 27.

Departments of Medical Oncology and Radiology and Nuclear Medicine, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Melanoma of unknown primary (MUP) is considered different from melanoma of known primary (MKP), and it is unclear whether these patients benefit equally from novel therapies. In the current study, characteristics and overall survival (OS) of patients with advanced and metastatic MUP and MKP were compared in the era of novel therapy. Patients were selected from the prospective nation-wide Dutch Melanoma Treatment Registry (DMTR). The following criteria were applied: diagnosis of stage IIIc unresectable or IV cutaneous MKP (cMKP) or MUP between July 2012 and July 2017 and treatment with immune checkpoint inhibition and/or targeted therapy. OS was estimated using the Kaplan-Meier method. The stratified multivariable Cox regression model was used for adjusted analysis. A total of 2706 patients were eligible including 2321 (85.8%) patients with cMKP and 385 (14.2%) with MUP. In comparative analysis, MUP patients more often presented with advanced and metastatic disease at primary diagnosis with poorer performance status, higher LDH, and central nervous system metastases. In crude analysis, median OS of cMKP or MUP patients was 12 months (interquartile range [IQR] 5 - 44) and 14 months (IQR 5 - not reached), respectively (P = 0.278). In adjusted analysis, OS in MUP patients was superior (hazard rate 0.70, 95% confidence interval 0.58-0.85; P < 0.001). As compared to patients with advanced and metastatic cMKP, MUP patients have superior survival in adjusted analysis, but usually present with poorer prognostic characteristics. In crude analysis, OS was comparable indicating that patients with MUP benefit at least equally from treatment with novel therapies.
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http://dx.doi.org/10.1007/s00262-021-02871-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8505371PMC
November 2021

Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients.

Hepatol Int 2021 Apr 25;15(2):510-519. Epub 2021 Feb 25.

Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort.

Methods: Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3-4 hepatitis and outcome.

Results: 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44).

Conclusion: Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.
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http://dx.doi.org/10.1007/s12072-021-10151-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144142PMC
April 2021

Safety and Efficacy of Checkpoint Inhibition in Patients With Melanoma and Preexisting Autoimmune Disease : A Cohort Study.

Ann Intern Med 2021 05 16;174(5):641-648. Epub 2021 Feb 16.

Leiden University Medical Center, Leiden, the Netherlands (M.K.V., O.M.D., E.K.).

Background: Because immune checkpoint inhibition (ICI) can cause immune-related adverse events (irAEs) mimicking immunologic diseases, patients with preexisting autoimmune disease (AID) have been excluded from clinical trials.

Objective: To evaluate the safety and efficacy of ICI in patients with advanced melanoma with and without AID.

Design: Nationwide cohort study.

Setting: The Netherlands.

Patients: 4367 patients with advanced melanoma enrolled in the Dutch Melanoma Treatment Registry (DMTR) between July 2013 and July 2018 and followed through February 2019.

Measurements: Patient, clinical, and treatment characteristics; irAEs of grade 3 or higher; treatment response; and survival.

Results: A total of 415 patients (9.5%) had AID, categorized as rheumatologic AID ( = 227), endocrine AID ( = 143), inflammatory bowel disease (IBD) ( = 55), or "other" ( = 8). Of these, 228 patients (55%) were treated with ICI (vs. 2546 [58%] without AID); 87 were treated with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4), 187 with anti-programmed cell death 1 (PD-1), and 34 with the combination. The incidences of irAEs of grade 3 or higher in patients with AID were 30% (95% CI, 21% to 41%) with anti-CTLA-4, 17% (CI, 12% to 23%) with anti-PD-1, and 44% (CI, 27% to 62%) with combination therapy; for patients without AID, the incidences were 30% (CI, 27% to 33%) ( = 916), 13% (CI, 12% to 15%) ( = 1540), and 48% (CI, 43% to 53%) ( = 388), respectively. Patients with AID more often discontinued anti-PD-1 treatment because of toxicity than patients without AID (17% [CI, 12% to 23%] vs. 9% [CI, 8% to 11%]). Patients with IBD were more prone to anti-PD-1-induced colitis (6/31 = 19% [CI, 7% to 37%]) than patients with other AIDs (3% [CI, 0% to 6%]) and patients without AID (2% [CI, 2% to 3%]).The objective response rate was similar in patients with versus without AID who were treated with anti-CTLA-4 (10% [CI, 5% to 19%] vs. 16% [CI, 14% to 19%]), anti-PD-1 (40% [CI, 33% to 47%] vs. 44% [CI, 41% to 46%]), or the combination (39% [CI, 20% to 59%] vs. 43% [CI, 38% to 49%]). Survival did not differ between patients with and those without AID (median, 13 months [CI, 10 to 16 months] vs. 14 months [CI, 13 to 15 months]).

Limitation: Information was limited on AID severity and immunosuppressive treatment.

Conclusion: Response to ICI with anti-CTLA-4, anti-PD-1, or their combination for advanced melanoma and overall incidence of any irAEs of grade 3 or higher were similar in patients with and without preexisting AID. However, severe colitis and toxicity requiring early discontinuation of treatment occurred more frequently among patients with preexisting IBD, warranting close follow-up.

Primary Funding Source: The Netherlands Organization for Health Research and Development.
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http://dx.doi.org/10.7326/M20-3419DOI Listing
May 2021

First-line BRAF/MEK inhibitors versus anti-PD-1 monotherapy in BRAF-mutant advanced melanoma patients: a propensity-matched survival analysis.

Br J Cancer 2021 03 26;124(7):1222-1230. Epub 2021 Jan 26.

Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, De Boelelaan 1118, Amsterdam, 1081HZ, The Netherlands.

Background: Anti-PD-1 antibodies and BRAF/MEK inhibitors are the two main groups of systemic therapy in the treatment of BRAF-mutant advanced melanoma. Until now, data are inconclusive on which therapy to use as first-line treatment. The aim of this study was to use propensity score matching to compare first-line anti-PD-1 monotherapy vs. BRAF/MEK inhibitors in advanced BRAF-mutant melanoma patients.

Methods: We selected patients diagnosed between 2014 and 2017 with advanced melanoma and a known BRAF-mutation treated with first-line BRAF/MEK inhibitors or anti-PD-1 antibodies, registered in the Dutch Melanoma Treatment Registry. Patients were matched based on their propensity scores using the nearest neighbour and the optimal matching method.

Results: Between 2014 and 2017, a total of 330 and 254 advanced melanoma patients received BRAF/MEK inhibitors and anti-PD-1 monotherapy as first-line systemic therapy. In the matched cohort, patients receiving anti-PD-1 antibodies as a first-line treatment had a higher median and 2-year overall survival compared to patients treated with first-line BRAF/MEK inhibitors, 42.3 months (95% CI: 37.3-NE) vs. 19.8 months (95% CI: 16.7-24.3) and 65.4% (95% CI: 58.1-73.6) vs. 41.7% (95% CI: 34.2-51.0).

Conclusions: Our data suggest that in the matched BRAF-mutant advanced melanoma patients, anti-PD-1 monotherapy is the preferred first-line treatment in patients with relatively favourable patient and tumour characteristics.
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http://dx.doi.org/10.1038/s41416-020-01229-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007796PMC
March 2021

Eight years of experience with vismodegib for advanced and multiple basal cell carcinoma patients in the Netherlands: a retrospective cohort study.

Br J Cancer 2021 03 19;124(7):1199-1206. Epub 2021 Jan 19.

Department of Dermatology, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Vismodegib has been used for the treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC (mBCC) since 2011. Most efficacy and safety data are provided by clinical trials. This study evaluates the effectiveness of vismodegib for the treatment of laBCC, mBCC and basal cell nevus syndrome (BCNS) patients, and the tumour characteristics associated with a higher probability of achieving a complete response in the Netherlands.

Methods: A retrospective cohort study that included all patients ≥18 years with histologically proven basal cell carcinoma that received ≥1 dose of vismodegib between July 2011 and September 2019 in the Netherlands.

Results: In total, 48 laBCC, 11 mBCC and 19 BCNS patients were included. Median progression-free survival was 10.3 months (95% confidence interval (CI), 7.5-22.6) for laBCC, 11.7 (95% CI, 5.2-17.5) for mBCC and 19.1 (95% CI, 7.4-20.2) for BCNS. Larger laBCCs were associated with a lower probability of complete response (hazard ratio (HR) 0.77 per increase in cm, p = 0.02). Of all BCNS patients, 63% received ≥2 treatment sequences with vismodegib; all achieved partial responses.

Conclusions: Half of the aBCC patients progress within 1 year after the start of vismodegib treatment. More research is needed to investigate other treatment strategies after vismodegib progression and to evaluate long-term effects of repetitive vismodegib treatment.
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http://dx.doi.org/10.1038/s41416-020-01220-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007568PMC
March 2021

Postapproval trials versus patient registries: comparability of advanced melanoma patients with brain metastases.

Melanoma Res 2021 02;31(1):58-66

Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, University of Utrecht, Heidelberglaan.

Postapproval trials and patient registries have their pros and cons in the generation of postapproval data. No direct comparison between clinical outcomes of these data sources currently exists for advanced melanoma patients. We aimed to investigate whether a patient registry can complement or even replace postapproval trials. Postapproval single-arm clinical trial data from the Medicines Evaluation Board and real-world data from the Dutch Melanoma Treatment Registry were used. The study population consisted of advanced melanoma patients with brain metastases treated with targeted therapies (BRAF- or BRAF-MEK inhibitors) in the first line. A Cox hazard regression model and a propensity score matching (PSM) model were used to compare the two patient populations. Compared to patients treated in postapproval trials (n = 467), real-world patients (n = 602) had significantly higher age, higher ECOG performance status, more often ≥3 organ involvement and more symptomatic brain metastases. Lactate dehydrogenase levels were similar between both groups. The unadjusted median overall survival (mOS) in postapproval clinical trial patients was 8.7 (95% CI, 8.1-10.4) months compared to 7.2 (95% CI, 6.5-7.7) months (P < 0.01) in real-world patients. With the Cox hazard regression model, survival was adjusted for prognostic factors, which led to a statistically insignificant difference in mOS for trial and real-world patients of 8.7 (95% CI, 7.9-10.4) months compared to 7.3 (95% CI, 6.3-7.9) months, respectively. The PSM model resulted in 310 matched patients with similar survival (P = 0.9). Clinical outcomes of both data sources were similar. Registries could be a complementary data source to postapproval clinical trials to establish information on clinical outcomes in specific subpopulations.
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http://dx.doi.org/10.1097/CMR.0000000000000707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757745PMC
February 2021

Nationwide Outcomes of Advanced Melanoma According to BRAFV600 Status.

Am J Clin Oncol 2021 02;44(2):82-89

Department of Medical Oncology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam.

Objective: The aim of this study was to evaluate treatment patterns and overall survival (OS) of patients with BRAFV600 wild-type and BRAFV600-mutant advanced melanoma in the Netherlands.

Methods: We selected patients of 18 years and over, diagnosed between 2016 and 2017 with unresectable stage IIIC or IV melanoma, registered in the Dutch Melanoma Treatment Registry. To assess the association of BRAFV600-mutation status with OS we used the Cox proportional-hazards model.

Results: A total of 642 BRAFV600 wild-type and 853 mutant patients were included in the analysis. Median OS did not differ significantly between both groups, 15.2 months (95% confidence interval [CI]: 13.2-19.2) versus 20.6 months (95% CI: 18.3-25.0). Survival rates at 6 and 12 months were significantly lower for BRAFV600 wild-type patients compared with BRAFV600-mutant patients, 72.0% (95% CI: 68.6-75.6) and 56.0% (95% CI: 52.2-60.0) versus 83.4% (95% CI: 80.9-85.9) and 65.7% (95% CI: 62.6-69.0). Two-year survival was not significantly different between both groups, 41.1% (95% CI: 37.2-45.3) versus 47.0% (95% CI: 43.6-60.6). Between 0 and 10 months, BRAFV600 wild-type patients had a decreased survival with a hazard ratio for OS of 2.00 (95% CI: 1.62-2.46) but this effect disappeared after 10 months. At 12 months, BRAFV600-mutant patients had started with second-line systemic treatment more often compared with BRAFV600 wild-type patients (50% vs. 19%).

Conclusion: These results suggest that advanced BRAFV600 wild-type melanoma patients have worse survival than BRAFV600-mutated patients during the first 10 months after diagnosis because of less available treatment options.
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http://dx.doi.org/10.1097/COC.0000000000000786DOI Listing
February 2021

Real-world Data of Nivolumab for Patients With Advanced Renal Cell Carcinoma in the Netherlands: An Analysis of Toxicity, Efficacy, and Predictive Markers.

Clin Genitourin Cancer 2021 06 14;19(3):274.e1-274.e16. Epub 2020 Oct 14.

Specialist Centre for Kidney Cancer, Royal Free London NHS Foundation Trust, London, United Kingdom.

Background: Nivolumab, a programmed death 1 inhibitor, has been approved as second-line treatment for advanced renal cell carcinoma (RCC) in Europe since 2016. We investigated the toxicity and efficacy of nivolumab as well as potential predictive biomarkers in the Dutch population.

Patients And Methods: This was a retrospective, multicenter study of the Dutch national registry of nivolumab for the treatment of advanced RCC. The main outcome parameters included toxicity, objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and time to treatment failure (TTF). In addition, potential predictive and prognostic biomarkers for outcomes were evaluated.

Results: Data on 264 patients were available, of whom 42% were International Metastatic RCC Database Consortium (IMDC) poor risk at start of nivolumab, 16% had ≥ 3 lines of previous therapy, 7% had non-clear-cell RCC, 11% had brain metastases, and 20% were previously treated with everolimus. Grade 3/4 immune-related adverse events occurred in 15% of patients. The median OS was 18.7 months (95% confidence interval, 13.7-23.7 months). Progression occurred in 170 (64.4%) of 264 patients, with a 6-and 12-months TTP of 49.8% and 31.1%, respectively. The ORR was 18.6% (49 of 264; 95% confidence interval, 14%-23%). Elevated baseline lymphocytes were associated with improved PFS (P = .038) and elevated baseline lactate dehydrogenase with poor OS, PFS, and TTF (P = .000). On-treatment increase in eosinophils by week 8 predicted improved OS (P = .003), PFS (P = .000), and TTF (P = .014), whereas a decrease of neutrophils was associated with significantly better TTF (P = .023).

Conclusions: The toxicity and efficacy of nivolumab for metastatic RCC after previous lines of therapy are comparable with the results in the pivotal phase III trial and other real-world data. On-treatment increase in eosinophil count is a potential biomarker for efficacy and warrants further investigation.
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http://dx.doi.org/10.1016/j.clgc.2020.10.003DOI Listing
June 2021

Lower risk of severe checkpoint inhibitor toxicity in more advanced disease.

ESMO Open 2020 11;5(6):e000945

Department of Medical Oncology, UMC Utrecht, Utrecht, The Netherlands. Electronic address:

Background: Immune checkpoint inhibitor (ICI) can cause severe and sometimes fatal immune-related adverse events (irAEs). Since these irAEs mimick immunological disease, a female predominance has been speculated on. Nevertheless, no demographic or tumour-related factors associated with an increased risk of irAEs have been identified until now.

Methods: Risk ratios of severe (grade ≥3) irAEs for age, sex, WHO performance status, number of comorbidities, stage of disease, number of metastases and serum lactate dehydrogenases (LDH) were estimated using data from anti-PD1-treated patients with advanced melanoma in the prospective nationwide Dutch Melanoma Treatment Registry.

Results: 111 (11%) out of 819 anti-programmed cell death 1 treated patients experienced severe irAEs. Patients with non-lung visceral metastases (stage IV M1c or higher) less often experienced severe irAEs (11%) compared with patients with only lung and/or lymph node/soft tissue involvement (stage IV M1b or lower; 19%; adjusted risk ratio (RR) 0.63; 95% CI 0.41 to 0.94). Patients with LDH of more than two times upper limit of normal had a non-significantly lower risk of developing severe irAEs than those with normal LDH (RR 0.65; 95% CI 0.20 to 2.13). None of the other variables were associated with severe irAEs.

Conclusion: In patients with melanoma, more advanced disease is associated with a lower rate of severe irAEs. No association with sex was found.
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http://dx.doi.org/10.1136/esmoopen-2020-000945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670947PMC
November 2020

Dose-Dependent Effect of Platinum-Based Chemotherapy on the Risk of Metachronous Contralateral Testicular Cancer.

J Clin Oncol 2021 02 29;39(4):319-327. Epub 2020 Oct 29.

Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Purpose: Patients with testicular germ cell tumor (TGCT) are at increased risk of developing a contralateral TGCT (CTGCT). Although some studies suggest that prior treatment with platinum-based chemotherapy affects CTGCT risk, a relationship between CTGCT risk and platinum dose has not previously been assessed. We analyzed the association between the number of platinum-based chemotherapy cycles and CTGCT risk.

Patients And Methods: The risk of developing a metachronous CTGCT was evaluated in a nationwide cohort of 4,755 patients diagnosed with primary TGCT in the Netherlands between 1989 and 2007. Standardized incidence ratios were computed to compare CTGCT incidence with expected TGCT on the basis of TGCT incidence in the general population. The cumulative incidence of CTGCT was estimated in the presence of death as competing risk. The effect of treatment with platinum-based chemotherapy on CTGCT risk was assessed using multivariable Cox proportional hazards regression models.

Results: CTGCT was diagnosed in 136 patients (standardized incidence ratio, 14.6; 95% CI, 12.2 to 17.2). The cumulative incidence increased up to 20 years after primary diagnosis, reaching 3.4% (95% CI, 2.8% to 4.0%) after 20 years of follow up. The risk of developing a CTGCT decreased with age (hazard ratio [HR], 0.93; 95% CI, 0.90 to 0.96), was lower after nonseminomatous germ cell tumor (HR, 0.58; 95% CI, 0.35 to 0.96) and decreased with every additional cycle of chemotherapy (HR, 0.74; 95% CI, 0.64 to 0.85).

Conclusion: Approximately one in every 30 survivors of TGCT will develop a CTGCT, with CTGCT incidence increasing up to 20 years after a primary TGCT. Treatment with platinum-based chemotherapy shows a dose-dependent inverse association with CTGCT risk.
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http://dx.doi.org/10.1200/JCO.20.02352DOI Listing
February 2021

Avelumab for advanced Merkel cell carcinoma in the Netherlands: a real-world cohort.

J Immunother Cancer 2020 09;8(2)

Department of Medical Oncology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: Merkel cell carcinoma (MCC) is associated with high recurrence rates and poor survival when metastatic disease is present. The immune checkpoint inhibitor avelumab has shown high response rates (RRs) and durable responses in patients with advanced MCC (aMCC) in clinical trials. To date, only results from clinical trials, patients treated in an expanded access program and very small numbers of patients have been reported. In this study, detailed real-world efficacy and toxicity data of avelumab in patients with aMCC are reported.

Methods: Patients with aMCC treated in four dedicated referral centers in the Netherlands were analyzed from February 2017 until December 2019. Patients were included if they had received at least one administration of avelumab, regardless of previous lines of therapy. Patient data were collected retrospectively from patient records. Primary endpoints were response rate (RR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.

Results: Fifty-four patients received avelumab. Eight (15%) patients had locally advanced disease (laMCC). In 40 (74%) patients, avelumab was first-line treatment, these included all patients with laMCC. The median follow-up was 8.9 (range 0.5-35.9) months. RR was 57% (n=31) with 24% (n=13) of patients achieving a complete response. The median DOR was 8.4 (range 1.3-22.1) months and 23 (43%) patients had an ongoing response at the end of the study. The median PFS was 8.6 (95% CI 1.6-15.5) months, and the median OS was 25.8 (95% CI 9.1-42.4) months. Six (11%) patients experienced grade 3 toxicity. No grade 4-5 toxicity was seen.

Conclusions: In this real-world cohort, clinical efficacy and toxicity outcomes in clinical practice were in line with results from clinical trials and showed relatively high RRs and durable responses in patients with aMCC.
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http://dx.doi.org/10.1136/jitc-2020-001076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511642PMC
September 2020

Real-world Outcomes of First-line Anti-PD-1 Therapy for Advanced Melanoma: A Nationwide Population-based Study.

J Immunother 2020 10;43(8):256-264

Department of Medical Oncology, Amsterdam UMC-location VUmc, Cancer Center Amsterdam, Amsterdam.

The efficacy of anti-programmed death-1 (PD-1) monotherapy for advanced melanoma has been established, but it is unknown to what extent patients benefit in the real world. In this observational study with nationwide population-based data from the Dutch Melanoma Treatment Registry, we analyzed real-world outcomes of first-line anti-PD-1 monotherapy in advanced melanoma patients diagnosed in 2015 to 2016. Overall survival (OS) was estimated with the Kaplan-Meier method. Competing risks analysis was used to estimate probabilities for second-line treatment, with death as competing risk. With a Cox model, the association of factors with OS was estimated. Patients who received anti-PD-1 monotherapy (n=550) had a median age of 65 years and 502 (95%) patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, 383 (70%) had normal lactate dehydrogenase (LDH), 370 (67%) had stage IV-M1c disease, and in 441 (81%), brain metastases were absent. The median OS was 24 months [95% confidence interval (CI): 20-30 mo]. The median OS of patients normally eligible for phase III trial participation was 31 months (95% CI: 23-not estimable). The BRAF mutation was associated with superior OS. ECOG PS of ≥1, symptomatic brain metastases, and liver metastases were associated with inferior OS and, together with elevated LDH, with death before second-line treatment. Patients with a complete response had a 2-year OS probability from first reported complete response of 92% (95% CI: 86%-99%). Real-world advanced melanoma patients in the Netherlands have benefitted from anti-PD-1 monotherapy. ECOG PS ≥1, symptomatic brain metastasis, liver metastasis, and elevated LDH are important prognostic factors for survival. The additional information that this study provides could help to improve more effective use in the real world.
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http://dx.doi.org/10.1097/CJI.0000000000000334DOI Listing
October 2020

Survival outcomes of patients with advanced mucosal melanoma diagnosed from 2013 to 2017 in the Netherlands - A nationwide population-based study.

Eur J Cancer 2020 09 4;137:127-135. Epub 2020 Aug 4.

Divisions of Medical Oncology and Molecular Oncology & Immunology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066CX, the Netherlands. Electronic address:

Background: Mucosal melanoma (MM) is rare and has a poor prognosis. Since 2011, new effective treatments are available for advanced melanoma. It is unclear whether patients with mucosal melanoma equally benefit from these new treatments compared with patients with cutaneous melanoma (CM).

Methods: Patients with advanced MM and CM diagnosed between 2013 and 2017 were included from a nationwide population-based registry - the Dutch Melanoma Treatment Registry. Overall survival (OS) was estimated with the Kaplan-Meier method (also for a propensity score-matched cohort). A Cox model was used to analyse the association of possible prognostic factors with OS.

Results: In total, 120 patients with MM and 2960 patients with CM were included. Median OS was 8.7 months and 14.5 months, respectively. Patients with MM were older (median age 70 versus 65 years) and more often female (60% versus 41%), compared with CM. In total, 77% and 2% of the MM patients were treated with first-line immunotherapy and targeted therapy, respectively, compared with 49% and 33% of the CM patients. In contrast to CM, OS for MM did not improve for patients diagnosed in 2015-2017, compared with 2013-2014. ECOG performance score ≥1 (HR = 1.99 [1.26-3.15; p = 0.003]) and elevated LDH level (HR = 1.63 [0.96-2.76]; p = 0.069) in MM were associated with worse survival.

Conclusions: Within the era of immune and targeted therapies, prognosis for patients with advanced MM has not improved as much as for CM. Collaboration is necessary to enlarge sample size for research to improve immunotherapeutic strategies and identify targetable mutations.
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http://dx.doi.org/10.1016/j.ejca.2020.05.021DOI Listing
September 2020

Age Does Matter in Adolescents and Young Adults versus Older Adults with Advanced Melanoma; A National Cohort Study Comparing Tumor Characteristics, Treatment Pattern, Toxicity and Response.

Cancers (Basel) 2020 Jul 27;12(8). Epub 2020 Jul 27.

Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, PO box 9600, 2300 RC Leiden, The Netherlands.

Cutaneous melanoma is a common type of cancer in Adolescents and Young Adults (AYAs, 15-39 years of age). However, AYAs are underrepresented in clinical trials investigating new therapies and the outcomes from these therapies for AYAs are therefore unclear. Using prospectively collected nation-wide data from the Dutch Melanoma Treatment Registry (DMTR), we compared baseline characteristics, mutational profiles, treatment strategies, grade 3-4 adverse events (AEs), responses and outcomes in AYAs ( = 210) and older adults ( = 3775) who were diagnosed with advanced melanoma between July 2013 and July 2018. Compared to older adults, AYAs were more frequently female (51% versus 40%, = 0.001), and had a better Eastern Cooperative Oncology Group performance status (ECOG 0 in 54% versus 45%, = 0.004). BRAF and NRAS mutations were age dependent, with more BRAF V600 mutations in AYAs (68% versus 46%) and more NRAS mutations in older adults (13% versus 21%), < 0.001. This finding translated in distinct first-line treatment patterns, where AYAs received more initial targeted therapy. Overall, grade 3-4 AE percentages following first-line systemic treatment were similar for AYAs and older adults; anti-PD-1 (7% versus 14%, = 0.25), anti-CTLA-4 (16% versus 33%, = 0.12), anti-PD-1 + anti-CTLA-4 (67% versus 56%, = 0.34) and BRAF/MEK-inhibition (14% versus 23%, = 0.06). Following anti-CTLA-4 treatment, no AYAs experienced a grade 3-4 colitis, while 17% of the older adults did ( = 0.046). There was no difference in response to treatment between AYAs and older adults. The longer overall survival observed in AYAs (hazard ratio (HR) 0.7; 95% CI 0.6-0.8) was explained by the increased cumulative incidence of non-melanoma related deaths in older adults (sub-distribution HR 2.8; 95% CI 1.5-4.9), calculated by competing risk analysis. The results of our national cohort study show that baseline characteristics and mutational profiles differ between AYAs and older adults with advanced melanoma, leading to different treatment choices made in daily practice. Once treatment is initiated, AYAs and older adults show similar tumor responses and melanoma-specific survival.
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http://dx.doi.org/10.3390/cancers12082072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464956PMC
July 2020

Internet-based cognitive rehabilitation for WORking Cancer survivors (i-WORC): study protocol of a randomized controlled trial.

Trials 2020 Jul 20;21(1):664. Epub 2020 Jul 20.

Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: Cognitive problems are common in non-central nervous system cancer survivors. These problems are perceived as an important contributor to decline in work performance and work ability. Various interventions for cognitive problems have been proposed, but effectiveness regarding work-related outcomes has not yet been established. Effective treatment options to alleviate the adverse influence of cognitive problems on work performance are needed for working cancer survivors. In this paper, we will describe the design of a randomized, controlled, multicenter trial that evaluates the (cost-)effectiveness of an Internet-based cognitive rehabilitation program for occupationally active cancer survivors confronted with cognitive problems.

Methods/ Design: A three-armed randomized controlled trial will be conducted, including two intervention groups (i.e., basic and extensive cognitive rehabilitation program) and one waitlist control group. In total, 261 cancer survivors (18-65 years) who have returned to work and who experience cognitive problems will be recruited. Patients with and without cognitive impairment as established in a neuropsychological assessment will be eligible; stratification will take place based on the presence of this cognitive impairment. The extensive intervention arm will contain a comprehensive training program (including psycho-education, fatigue management, and cognitive strategy training) with individual guidance (blended intervention). The basic intervention arm will contain a brief cognitive training program (including psycho-education and fatigue management) without individual guidance. The primary outcome will be accomplishment of an individually defined work-related treatment goal. Secondary outcomes include, among others, subjective cognitive functioning, work functioning, and quality of life. Primary and secondary outcomes will be measured at baseline (T0) and at 12 weeks (T1) and 26 weeks (T2) post-randomization.

Discussion: About 40-50% of the cancer patients worldwide are of working age at time of diagnosis. Many of the occupationally active cancer survivors experience cognitive problems. Both from an individual and a societal perspective, it is important to sustain cancer survivors' employability. An effective treatment to alleviate the impact of cognitive decline and to improve work ability might help cancer survivors to sustain employability.

Trial Registration: ClinicalTrials.gov NCT03900806 . Registered on 03 April 2019 (current status: ongoing).
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http://dx.doi.org/10.1186/s13063-020-04570-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372808PMC
July 2020

Real-world outcomes of advanced melanoma patients not represented in phase III trials.

Int J Cancer 2020 12 4;147(12):3461-3470. Epub 2020 Jul 4.

Scientific department, Dutch Institute for Clinical Auditing, Leiden, The Netherlands.

The aim was to provide evidence on systemically treated patients with advanced melanoma not represented in phase III trials to support clinical decision-making. Analysis were performed on advanced melanoma patients diagnosed between 2014 and 2017 in the Netherlands, treated with immune- or targeted therapy, who met ≥1 trial exclusion criteria. These criteria were derived from the KEYNOTE-006 and CHECKMATE-067/-066 phase III trials. Prognostic importance of factors associated with overall survival (OS) was assessed with the Kaplan-Meier method, Cox models, predicted OS probabilities of prognostic subgroups and a conditional inference survival tree (CIST). A nationwide population-based registry was used as data source. Of 2536 systemically treated patients with advanced melanoma, 1004 (40%) patients were ineligible for phase IIII trials. Ineligible patients had a poorer median OS (mOS) compared to eligible patients (8.8 vs 23 months). Eligibility criteria strongly associated with OS in systemically treated ineligible patients were Eastern Cooperative Oncology Group Performance Score (ECOG PS) ≥2, brain metastases (BM) and lactate dehydrogenase (LDH) of >500 U/L. Patients with ECOG PS of ≥2 with or without symptomatic BM had a predicted mOS of 6.5 and 11.3 months and a 3-year survival probability of 9.3% and 23.6%, respectively. The CIST showed the strongest prognostic covariate for survival was LDH, followed by ECOG PS. The prognosis of patients with LDH of >500 U/L is poor, but long-term survival is possible. The prognosis of ineligible patients with advanced melanoma in real-world was very heterogeneous and highly dependent on LDH value, ECOG PS and symptomatic BM.
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http://dx.doi.org/10.1002/ijc.33162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689762PMC
December 2020

Surgery for Unresectable Stage IIIC and IV Melanoma in the Era of New Systemic Therapy.

Cancers (Basel) 2020 May 7;12(5). Epub 2020 May 7.

Department of Surgical Oncology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

Opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapeutics over the past decade. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage IIIC and IV melanoma, who have previously been treated with immunotherapy or targeted therapy. Data was extracted from the Dutch Melanoma Treatment Registry (DMTR) on 154 patients obtaining disease control to systemic therapy and undergoing subsequent surgery. Disease control was defined as a complete response (CR), which was seen in 3.2% of patients; a partial response (PR), seen in 46.1% of patients; or stable disease (SD), seen in 44.2% of patients. At a median follow-up of 10.0 months (interquartile range 4-22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression-free survival (PFS) was 9.0 months (95% CI 6.3-11.7). A CR or PR at first follow-up after surgery was associated with both a better OS and PFS compared to stable or progressive disease ( < 0.001). We conclude that selected patients can benefit from surgery after achieving disease control with systemic therapy.
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http://dx.doi.org/10.3390/cancers12051176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281176PMC
May 2020
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