Publications by authors named "Maureen J B Aarts"

35 Publications

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 May 18. Epub 2021 May 18.

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
May 2021

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

Cancer Immunol Immunother 2021 Mar 27. 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
March 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 Mar 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 Mar 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 Feb 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

Healthcare Costs of Metastatic Cutaneous Melanoma in the Era of Immunotherapeutic and Targeted Drugs.

Cancers (Basel) 2020 Apr 18;12(4). Epub 2020 Apr 18.

Department of Health Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, Burgemeester Oudlaan 50, 3062 PA Rotterdam, The Netherlands.

Immunotherapeutic and targeted drugs improved survival of patients with metastatic melanoma. There is, however, a lack of evidence regarding their healthcare costs in clinical practice. The aim of our study was to provide insight into real-world healthcare costs of patients with metastatic cutaneous melanoma. Data were obtained from the Dutch Melanoma Treatment Registry for patients who were registered between July 2012 and December 2018. Mean total/monthly costs per patient were reported for all patients, patients who did not receive systemic therapy, and patients who received systemic therapy. Furthermore, mean episode/monthly costs per line of therapy and drug were reported for patients who received systemic therapy. Mean total/monthly costs were € 89,240/€ 6809: € 7988/€ 2483 for patients who did not receive systemic therapy ( = 784) and € 105,078/€ 7652 for patients who received systemic therapy ( = 4022). Mean episode/monthly costs were the highest for nivolumab plus ipilimumab (€ 79,675/€ 16,976), ipilimumab monotherapy (€ 79,110/€ 17,252), and dabrafenib plus trametinib (€ 77,053/€ 12,015). Dacarbazine yielded the lowest mean episode/monthly costs (€ 6564/€ 2027). Our study showed that immunotherapeutic and targeted drugs had a large impact on real-world healthcare costs. As new drugs continue entering the treatment landscape for (metastatic) melanoma, it remains crucial to monitor whether the benefits of these drugs outweigh their costs.
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http://dx.doi.org/10.3390/cancers12041003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225943PMC
April 2020

Association of Anti-TNF with Decreased Survival in Steroid Refractory Ipilimumab and Anti-PD1-Treated Patients in the Dutch Melanoma Treatment Registry.

Clin Cancer Res 2020 05 27;26(9):2268-2274. Epub 2020 Jan 27.

Department of Medical Oncology, University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands.

Purpose: Unleashing the immune system by PD-1 and/or CTLA-4 blockade can cause severe immune-related toxicity necessitating immunosuppressive treatment. Whether immunosuppression for toxicity impacts survival is largely unknown.

Experimental Design: Using data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR), we analyzed the association between severe toxicity and overall survival (OS) in 1,250 patients with advanced melanoma who were treated with immune checkpoint inhibitors (ICI) in first line between 2012 and 2017. Furthermore, we analyzed whether toxicity management affected survival in these patients.

Results: A total of 1,250 patients were included, of whom 589 received anti-PD1 monotherapy, 576 ipilimumab, and 85 combination therapy. A total of 312 patients (25%) developed severe (grade ≥3) toxicity. Patients experiencing severe ICI toxicity had a significantly prolonged survival with a median OS of 23 months compared with 15 months for patients without severe toxicity [hazard ratio (HR) = 0.77; 95% confidence interval (CI), 0.63-0.93]. Among patients experiencing severe toxicity, survival was significantly decreased in patients who received anti-TNF ± steroids for steroid-refractory toxicity compared with patients who were managed with steroids only (HR = 1.61; 95% CI, 1.03-2.51), with a median OS of 17 and 27 months, respectively.

Conclusions: Patients experiencing severe ICI toxicity have a prolonged OS. However, this survival advantage is abrogated when anti-TNF is administered for steroid-refractory toxicity. Further prospective studies are needed to assess the effect of different immunosuppressive regimens on checkpoint inhibitor efficacy..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3322DOI Listing
May 2020

Molecular testing in metastatic basal cell carcinoma.

J Am Acad Dermatol 2019 Dec 21. Epub 2019 Dec 21.

Department of Dermatology, Maastricht University Medical Center, Maastricht, the Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: Metastatic basal cell carcinoma (mBCC) is a very rare entity, and diagnosis can be challenging. Therapeutic options are limited, and response to targeted therapy is poor.

Objective: To demonstrate a clonal relationship between BCCs and their metastases and to explore which hedgehog pathway-related mutations are involved in mBCC.

Methods: Genetic analysis was conducted in 10 primary BCCs and their metastases. Genes relevant for BCC development were analyzed in tumor and metastasis material with small molecule molecular inversion probes (smMIPs) for PTCH1, PTCH2, SMO, SUFU, GLI2, and TP53 or with targeted next generation sequencing of the same genes and CDKN2A, CDKN2B, CIC, DAXX, DDX3X, FUBP1, NF1, NF2, PTEN, SETD2, TRAF7, and the TERT promoter.

Results: In 8 of 10 patients, identical gene mutations could be demonstrated in the primary tumors and their metastases. A broad spectrum of mutations was found. Four patients had SMO mutations in their tumor or metastasis, or both. All SMO mutations found were known to cause resistance to targeted therapy with vismodegib.

Limitations: In 2 patients there was insufficient qualitative DNA available for genetic analysis.

Conclusions: Molecular testing can help to identify the origin of a BCC metastasis and may be of prognostic and therapeutic value.
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http://dx.doi.org/10.1016/j.jaad.2019.12.026DOI Listing
December 2019

Cancer-related cognitive problems at work: experiences of survivors and professionals.

J Cancer Surviv 2020 04 25;14(2):168-178. Epub 2019 Nov 25.

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

Purpose: Cancer-related cognitive problems (cancer-related cognitive problems) in working cancer survivors are found to affect work outcomes. We aimed to generate in-depth information regarding cancer-related cognitive problems in working cancer survivors, strategies used to cope with cancer-related cognitive problems at work, and needs of cancer survivors and professionals regarding cancer-related cognitive problems at work.

Methods: Five focus groups were formed, amongst which three focus groups with cancer survivors (n = 8, n = 7, and n = 8) and two focus groups with professionals (n = 7, n = 8). Thematic analysis of the transcripts was performed to create concepts.

Results: Both cancer survivors and professionals confirmed that cancer-related cognitive problems, which occurred in several domains of neurocognitive functioning, affect work functioning. Cancer survivors used several strategies (e.g., applying practical adjustments, re-organization of work, and accepting limitations) to cope with cancer-related cognitive problems at work, as did professionals in their attempt at supporting cancer survivors facing these problems. Various needs of cancer survivors (e.g., supportive care options, acknowledgment by others) and professionals (e.g., improvement of expertise, clarity about referral pathways) regarding cancer-related cognitive problems at work were mentioned.

Conclusions: Due to the growing number of working cancer survivors dealing with cancer-related cognitive problems, it is essential to sustain their employability. Therefore, cognitive rehabilitation interventions should be developed, taking functioning at work into account. Knowledge amongst professionals regarding cancer-related cognitive problems, as well as coordination of care for cancer-related cognitive problems, should be improved. Ensuring professional education regarding cancer-related cognitive problems, within both the healthcare and occupational setting, is of utmost importance.

Implications For Cancer Survivors: Support for working cancer survivors who experience cancer-related cognitive problems might increase their employability in the longer term.
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http://dx.doi.org/10.1007/s11764-019-00830-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182611PMC
April 2020

Platinum exposure and cause-specific mortality among patients with testicular cancer.

Cancer 2020 02 15;126(3):628-639. Epub 2019 Nov 15.

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

Background: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era.

Methods: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis.

Results: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m platinum dose administered (P  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure.

Conclusions: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.
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http://dx.doi.org/10.1002/cncr.32538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004069PMC
February 2020

Melanoma in older patients: declining gap in survival between younger and older patients with melanoma.

Acta Oncol 2020 Jan 26;59(1):4-12. Epub 2019 Jul 26.

Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, The Netherlands.

Older people have the highest incidence of melanoma and the population in most Western countries is ageing. We evaluated how the gap in incidence and survival between younger and older patients has developed during the past decades. All patients diagnosed with cutaneous melanoma between 1989 and 2015 ( = 84,827) were identified from the Netherlands Cancer Registry. Elderly were defined as aged ≥70 years. Differences in patient and tumor characteristics were described, age-specific incidence rates were calculated, and relative survival (RS) and multivariable analyses estimating the Relative Excess Rate of dying (RER) were conducted In older men, the melanoma age-standardized incidence increased from 18 to 103/100,000 person-years (py) between 1989 and 2015 and in older women from 23 to 70/100,000 py. In younger men and women, it increased from 8 to 21 and from 13 to 28/100,000 py, respectively. Median Breslow thickness declined from 1.8 to 1.1 mm and from 1.6 to 1.1 mm in older men and women (2003 versus 2015), and from 1.1 to 0.9 mm and 0.9 to 0.8 mm in younger men and women. In older men, 5-year RS increased from 67% (95% CI: 63%-72%) in 1989-1997 to 85% (95% CI: 83%-87%) in 2007-2015 and in older women from 81% (95% CI: 78%-85%) to 89% (95% CI: 87%-91%). In younger men and women, RS increased from 82% (95% CI: 81%-83%) to 90% (95% CI: 90%-91%) and from 92% (95% CI: 92%-93%) to 96% (95% CI: 95%-96%). After case-mix correction , older men and women no longer showed an improved survival over time (RER 2010-2015 2003-2009: 0.97; 95% CI: 0.81-1.16 and 0.95; 95% CI: 0.79-1.16). Whereas in younger men and women survival remained improved (RER 0.75; 95% CI: 0.67-0.83 and 0.77; 95%CI: 0.67-0.89). The gap in melanoma incidence between younger and older people is increasing due to a strong increase in incidence in older adults. Disparities in survival are declining, related to a narrowing gap in Breslow thickness.
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http://dx.doi.org/10.1080/0284186X.2019.1643914DOI Listing
January 2020

Real-world use, safety, and survival of ipilimumab in metastatic cutaneous melanoma in The Netherlands.

Anticancer Drugs 2018 07;29(6):572-578

Dutch Institute for Clinical Auditing, Leiden.

Phase III trials with ipilimumab showed an improved survival in patients with metastatic melanoma. We evaluated the use and safety of ipilimumab, and the survival of all patients with metastatic cutaneous melanoma (N=807) receiving ipilimumab in real-world clinical practice in The Netherlands using data from the Dutch Melanoma Treatment Registry. Patients who were registered between July 2012 and July 2015 were included and analyzed according to their treatment status: treatment-naive (N=344) versus previously-treated (N=463). Overall, 70% of treatment-naive patients and 62% of previously-treated patients received all four planned doses of ipilimumab. Grade 3 and 4 immune-related adverse events occurred in 29% of treatment-naive patients and 21% of previously-treated patients. No treatment-related deaths occurred. Median time to first event was 5.4 months [95% confidence interval (CI): 4.7-6.5 months] in treatment-naive patients and 4.4 months (95% CI: 4.0-4.7 months) in previously-treated patients. Median overall survival was 14.3 months (95% CI: 11.6-16.7 months) in treatment-naive patients and 8.7 months (95% CI: 7.6-9.6 months) in previously-treated patients. In both patient groups, an elevated lactate dehydrogenase level (hazard ratio: 2.25 and 1.70 in treatment-naive and previously-treated patients, respectively) and American Joint Committee on Cancer M1c-stage disease (hazard ratio: 1.81 and 1.83, respectively) were negatively associated with overall survival. These real-world outcomes of ipilimumab slightly differed from outcomes in phase III trials. Although phase III trials are crucial for establishing efficacy, real-world data are of great added value enhancing the generalizability of outcomes of ipilimumab in clinical practice.
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http://dx.doi.org/10.1097/CAD.0000000000000629DOI Listing
July 2018

Real-world healthcare costs of ipilimumab in patients with advanced cutaneous melanoma in The Netherlands.

Anticancer Drugs 2018 07;29(6):579-588

Institute for Medical Technology Assessment.

There is limited evidence on the costs associated with ipilimumab. We investigated healthcare costs of all Dutch patients with advanced cutaneous melanoma who were treated with ipilimumab. Data were retrieved from the nation-wide Dutch Melanoma Treatment Registry. Costs were determined by applying unit costs to individual patient resource use. A total of 807 patients who were diagnosed between July 2012 and July 2015 received ipilimumab in Dutch practice. The mean (median) episode duration was 6.27 (4.61) months (computed from the start of ipilimumab until the start of a next treatment, death, or the last date of follow-up). The average total healthcare costs amounted to &OV0556;81 484, but varied widely (range: &OV0556;18 131-&OV0556;160 002). Ipilimumab was by far the most important cost driver (&OV0556;73 739). Other costs were related to hospital admissions (&OV0556;3323), hospital visits (&OV0556;1791), diagnostics and imaging (&OV0556;1505), radiotherapy (&OV0556;828), and surgery (&OV0556;297). Monthly costs for resource use other than ipilimumab were &OV0556;1997 (SD: &OV0556;2629). Treatment-naive patients (n=344) had higher total costs compared with previously-treated patients (n=463; &OV0556;85 081 vs. &OV0556;78 811). Although patients with colitis (n=106) had higher costs for resource use other than ipilimumab (&OV0556;11 426) compared with patients with other types of immune-related adverse events (n=90; &OV0556;9850) and patients with no immune-related adverse event (n=611; &OV0556;6796), they had lower total costs (&OV0556;76 075 vs. &OV0556;87 882 and &OV0556;81 480, respectively). In conclusion, this nation-wide study provides valuable insights into the healthcare costs of advanced cutaneous melanoma patients who were treated with ipilimumab in clinical practice. Most of the costs were attributable to ipilimumab, but the costs and its distribution varied considerably across subgroups.
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http://dx.doi.org/10.1097/CAD.0000000000000628DOI Listing
July 2018

Axillary staging in breast cancer patients treated with neoadjuvant chemotherapy in two Dutch phase III studies.

Oncotarget 2017 Jul;8(28):46557-46564

Department of Medical Oncology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: Primary aim of our study was to assess the impact of timing of sentinel node procedure, pre- versus post-neoadjuvant chemotherapy, on final pathologic node-negative rate (pN0) in patients with clinically node-negative (cN0) breast cancer. Secondary endpoint was the usability of the sentinel node procedure in patients with clinically node-positive disease that converted to cN0 after neoadjuvant chemotherapy.

Patients And Methods: Patients were enrolled in two sequentially conducted Dutch phase III trials, studying the impact of two neoadjuvant chemotherapy schedules and use of zoledronic acid on complete pathologic response rate. For the present analyses, patients were excluded if they had not undergone surgical axillary staging.

Results: In total 439 patients were included, of whom 230 (52%) had pre-treatment cN0. In this group, pN0 status was seen in 58% (N = 23) of patients with a sentinel node biopsy post-neoadjuvant chemotherapy compared to 51% (N = 83) pre-neoadjuvant chemotherapy, including the axillary lymph node dissection whenever performed. In multivariable analysis, timing of sentinel node procedure (pre- versus post- neoadjuvant chemotherapy) was, however, not significantly associated with final pN0/pN0(i+) status, with an odds ratio of 1.18 (95% CI 0.64 - 2.18) after correction for age, clinical tumor status, histology, grade, hormone- and HER2 receptor. Of patients with clinically node-positive disease only 15% had a final pN0 status, with a false-negative rate of the sentinel node of 30%.

Conclusion: In breast cancer patients with cN0 disease, sentinel node procedure performed post-neoadjuvant chemotherapy led to nodal down staging, although not statistically significant after multivariate correction for patient and tumor characteristics.
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http://dx.doi.org/10.18632/oncotarget.15101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542292PMC
July 2017
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