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Patients with gastro‐intestinal stromal tumors (GISTs) undergoing tyrosine kinase inhibitor therapy are monitored with regular computed tomography (CT) scans, exposing patients to cumulative radiation. This exploratory study aimed to evaluate circulating tumor DNA (ctDNA) testing to monitor treatment response and compare changes in ctDNA levels with RECIST 1.1 and total tumor volume measurements. Between 2014 and 2021, six patients with KIT proto‐oncogene, receptor tyrosine kinase (KIT) exon‐11‐mutated GIST from whom long‐term plasma samples were collected prospectively were included in the study. ctDNA levels of relevant plasma samples were determined using the KIT exon 11 digital droplet PCR drop‐off assay. Tumor volume measurements were performed using a semi‐automated approach. In total, 94 of 130 clinically relevant ctDNA samples were analyzed. Upon successful treatment response, ctDNA became undetectable in all patients. At progressive disease, ctDNA was detectable in five out of six patients. Higher levels of ctDNA correlated with larger tumor volumes. Undetectable ctDNA at the time of progressive disease on imaging was consistent with lower tumor volumes compared to those with detectable ctDNA. In summary, ctDNA levels seem to correlate with total tumor volume at the time of progressive disease. Our exploratory study shows promise for including ctDNA testing in treatment follow‐up.

Abstract Neoadjuvant immune checkpoint blockade (ICB) has shown unprecedented activity in mismatch repair deficient (MMRd) colorectal cancers, but its effectiveness in MMRd endometrial cancer (EC) remains unknown. In this investigator-driven, phase I, feasibility study (NCT04262089), 10 women with MMRd EC of any grade, planned for primary surgery, received two cycles of neoadjuvant pembrolizumab (200 mg IV) every three weeks. A pathologic response (primary objective) was observed in 5/10 patients, with 2 patients showing a major pathologic response. No patient achieved a complete pathologic response. A partial radiologic response (secondary objective) was observed in 3/10 patients, 5/10 patients had stable disease and 2/10 patients were non-evaluable on magnetic resonance imaging. All patients completed treatment without severe toxicity (exploratory objective). At median duration of follow-up of 22.5 months, two non-responders experienced disease recurrence. In-depth analysis of the loco-regional and systemic immune response (predefined exploratory objective) showed that monoclonal T cell expansion significantly correlated with treatment response. Tumour-draining lymph nodes displayed clonal overlap with intra-tumoural T cell expansion. All pre-specified endpoints, efficacy in terms of pathologic response as primary endpoint, radiologic response as secondary outcome and safety and tolerability as exploratory endpoint, were reached. Neoadjuvant ICB with pembrolizumab proved safe and induced pathologic, radiologic, and immunologic responses in MMRd EC, warranting further exploration of extended neoadjuvant treatment.

Introduction: Basal cell carcinoma (BCC) is treated with local surgery or noninvasive treatment modalities. If a BCC remains untreated, it can develop into a locally advanced BCC or a metastatic BCC. Case Presentation: Here we report in detail the management of three complex advanced BCC (aBCC) after treatment failure with vismodegib. On all tumors, next generation DNA sequencing in the Center for Personalized Cancer Treatment-02 (CPCT-02) study was performed; subsequently, patients were included in the Drug Rediscovery Protocol (DRUP) trial, in which treatment was started with commercially available targeted anticancer drugs based on the molecular tumor profile. All patients showed partial response or stable disease following treatment with second line PD-1 inhibitors with an average duration of response of 12.3 months. Discussion/Conclusion: Immunotherapy can be a treatment option for aBCC resistant to hedgehog pathway inhibitor treatment. However, despite the high tumor mutational burden of aBCCs, immunotherapy does not always lead to a long response. Rechallenge or combining treatment of hedgehog inhibitors and PD-1 inhibitors by parallel or alternating cycles may be a strategy to lengthen the treatment response.

Abstract Background Patient safety is crucial for quality of care. Preventable adverse events (AEs) occur in 1 of 20 patients in the hospital, but it is unknown whether this is different for patients with a condition relevant for palliative care. The majority of the limited available research on this topic is only focused on patients already receiving palliative care, and do not make comparisons with other patients at the end-of-life. We identified and compared the prevalence, preventability, nature and causes of AEs in patients with and without a condition relevant for palliative care. Methods A nationwide retrospective record review study was performed in 20 Dutch hospitals. A total of 2,998 records of patients who died in hospital in 2019 was included. Records were reviewed for AEs. We identified two subgroups: patients with (n = 2,370) or without (n = 248) a condition relevant for palliative care through the selection method of Etkind (2017). Descriptive analyses were performed to calculate prevalence, nature, causes and prevention strategies. T-tests were performed to calculate differences between subgroups. Results We found no significant differences between subgroups regarding AE prevalence, this was 15.3% in patients with a condition relevant for palliative care, versus 12.0% in patients without a condition relevant for palliative care (p = 0.148). Potentially preventable AE prevalence was 4.3% versus 4.4% (p = 0.975). Potentially preventable death prevalence in both groups was 3.2% (p = 0.938). There were differences in the nature of AEs: in patients with a condition relevant for palliative care this was mostly related to medication (33.1%), and in patients without a condition relevant for palliative care to surgery (50.8%). In both subgroups in the majority of AEs a patient related cause was identified. For the potentially preventable AEs in both subgroups the two most important prevention strategies as suggested by the medical reviewers were reflection and evaluation and quality assurance. Discussion Patient safety risks appeared to be equally prevalent in both subgroups. The nature of AEs does differ between subgroups: medication- versus surgery-related, indicating that tailored safety measures are needed. Recommendations for practice are to focus on reflecting on AEs, complemented with case evaluations.

Introduction: Imatinib has led to a phenomenal progress in the treatment of GIST. A rare and lesser-known side effect of imatinib is pneumonitis, an uncommon multicausal interstitial lung disease. Methods: Patients registered within the Dutch GIST Registry (DGR) were reviewed. For the patients identified with an imatinib-induced pneumonitis we reported the time on imatinib to develop pneumonitis, how the pneumonitis was diagnosed, graded and managed, and how the GIST treatment was managed. Cases: Of the 1934 patients registered in the DGR, 1161 patients received imatinib at some point, of which nine patients (0.8 %) were identified with an imatinib-induced pneumonitis. At time of the pneumonitis, patients received a daily imatinib dose of 200–400 mg for a mean duration of 486 days. One patient was able to continue imatinib in a lower dose, in the other eight patients imatinib was interrupted, and six of these patients started prednisolone treatment. After management of the imatinib-induced pneumonitis, four patients stopped imatinib permanently, two patients were rechallenged with imatinib, and two patients started treatment with second-line sunitinib. Conclusion: Imatinib-induced pneumonitis is a rare side effect, which may affect GIST management considerably. After the management of imatinib-induced pneumonitis, clinicians are left with difficult treatment dilemmas.

Abstract Background Quality of care at the end of life in hospitals is often perceived to be lower compared to the care that is provided to people who die in their own home. Documenting and measuring indicators of common end-of-life symptoms could help improve end-of-life care in hospitals. This study provided insight into quality indicators for the end-of-life care of patients who died in a Dutch hospital, and assessed differences between deceased patients who were admitted for palliative/terminal care versus patients admitted for other reasons. Methods In a retrospective record review study, trained nurses reviewed electronic health records (EHRs) of patients who died in 2019 (n = 2998), in a stratified sample of 20 Dutch hospitals. The nurses registered whether data was found in de EHRs about quality indicators for end-of-life care. This concerned: symptoms (pain, shortness of breath, anxiety, depressive symptoms), spiritual and psychological support and advance care planning. Multilevel regression analyses were performed to assess differences between patients who had been admitted for palliative/terminal care and patients admitted for other reasons. Results Common end-of-life symptoms were rarely measured using a standardized method (e.g. Numeric Rating Scale, Visual Analogue Scale or Utrecht Symptom Diary). The symptom burden of pain was measured using a standardized method more often (63.3%) than the symptom burden of shortness of breath (2.2%), anxiety (0.5%) and depressive symptoms (0.3%). Similarly, little information was documented in the EHRs regarding wish to involve a spiritual counsellor, psychologist or social worker. Life expectancy was documented in 66%. The preferred place of death was documented less often (20%). The documentation of some quality indicators differed between patients who were admitted for palliative/terminal care compared to other patients. Conclusion Except for the burden of pain, symptoms are rarely measured with standardized methods in patients who died in Dutch Hospitals. This study underlines the importance of documenting information about symptom burden and aspects related to advance care planning, and spiritual and psychological support to improve the quality of end-of-life care for patients in hospitals. Furthermore, uniformity in measuring methods improves the possibility to compare results between patient groups and settings.

Background: This study compares the characteristics, referral and treatment patterns and overall survival (OS) of gastrointestinal stromal tumor (GIST) patients treated in reference and non-reference centers in the Netherlands. Patients and methods: This retrospective cohort study on patients diagnosed between 2016 and 2019, utilises data from the Netherlands Cancer Registry and the Dutch Nationwide Pathology Database. Patients were categorized into two groups: patients diagnosed in or referred to reference centers and patients diagnosed in non-reference centers without referral. Results: This study included 1,550 GIST patients with a median age of 67.0 in reference and 68.0 years in non-reference centers. Eighty-seven per cent of patients were diagnosed in non-reference centers, of which 36.5% (493/1,352) were referred to a reference center. Referral rates were higher for high-risk (62.2% [74/119]) and metastatic patients (67.2% [90/134]). Mutation analysis was performed in 96.9% and 87.6% of these cases in reference and in non-reference centers (p < 0.01), respectively. Systemic therapy was given in reference centers versus non-reference in 89.5% versus 82.0% (p < 0.01) of high-risk and in 94.1% versus 65.9% (p < 0.01) of metastatic patients, respectively. The proportion of positive resection margins and tumor rupture did not differ between reference and non-reference centers. Median OS was not reached. Conclusion: A substantial amount of metastatic GIST patients in non-reference centers did not receive systemic treatment. This might be due to valid reasons. However, optimisation of the referral strategy of GIST patients in the Netherlands could benefit patients. Further research is needed to explore reasons for not starting systemic treatment in metastatic GIST patients.

Abstract Although patients with advanced cancer often experience multiple symptoms simultaneously, clinicians usually focus on symptoms that are volunteered by patients during regular history-taking. We aimed to evaluate the feasibility of a Bayesian network (BN) model to predict the presence of simultaneous symptoms, based on the presence of other symptoms. Our goal is to help clinicians prioritize which symptoms to assess. Patient-reported severity of 11 symptoms (scale 0–10) was measured using an adapted Edmonton Symptom Assessment Scale (ESAS) in a national cross-sectional survey among advanced cancer patients. Scores were dichotomized ( 10% difference was considered inaccurate. Symptom scores of 532 patients were collected. A symptom score ≥ 4 was most prevalent for fatigue (64.7%). AUCs varied between 0.60 and 0.78, with satisfactory AUCs for 8/11 symptoms. Calibration was accurate for 101/110 predicted conditional probabilities. Whether a patient experienced fatigue was directly associated with experiencing 7 other symptoms. For example, in the absence or presence of fatigue, the model predicted a 8.6% and 33.1% probability of experiencing anxiety, respectively. It is feasible to use BN development for prioritizing symptom assessment. Fatigue seems most eligble to serve as a starting symptom for predicting the probability of experiencing simultaneous symptoms.

Abstract Background Acquired resistance to approved tyrosine kinase inhibitors limits their clinical use in patients with gastrointestinal stromal tumor (GIST). This study investigated the safety, tolerability and efficacy of alpelisib, a phosphatidylinositol 3-kinase inhibitor, used in combination with imatinib in patients with advanced GIST who had failed prior therapy with both imatinib and sunitinib. Methods This phase 1b, multicenter, open-label study consisted of 2 phases: dose escalation and dose expansion. Dose escalation involved 200 mg once daily (QD) alpelisib, initially, followed by 250 and 350 mg. These were combined with 400 mg QD imatinib until maximum tolerated dose (MTD) and/or a recommended phase 2 dose (RP2D) of alpelisib in combination with imatinib was determined. This MTD/RP2D dose was tested to evaluate the clinical activity of this combination in dose expansion. Results Fifty-six patients were enrolled, 21 and 35 in the dose escalation and expansion phases, respectively. The MTD of alpelisib given with imatinib was determined as 350 mg QD. Combination treatment showed partial response in 1 (2.9%) and stable disease in 15 (42.9%) patients. Median progression-free survival was 2 months (95% CI 1.8–4.6). Overall, 92.9% patients had adverse events (AEs) while 46.4% had grade 3/4 AEs, hyperglycemia being the most common (23.2%). Conclusions The MTD of alpelisib was estimated as 350 mg QD when used in combination with imatinib 400 mg QD after oral administration in patients with advanced GIST. The safety and tolerability profile of this combination was acceptable; however, the combination did not demonstrate sufficient clinical activity to justify additional clinical testing. Trial registration ClinicalTrials.gov NCT01735968 (date of initial registration 28/11/2012).

Abstract Background A high percentage of people dying at home, and a low percentage of people being admitted to hospital and dying there are regarded as indicators of appropriate care at the end of life. However, performance standards for these quality indicators are often lacking, which makes it difficult to state whether an indicator score falls between the ranges of good or poor quality care. The aim of this study was to assess quality indicators concerning place of death and hospital care utilization in people with diseases relevant for palliative care, and to establish best practice performance standards based on indicator scores in 31 regions in the Netherlands. Methods A retrospective nationwide population-based observational study was conducted, using routinely collected administrative data concerning persons who died in 2017 in the Netherlands with underlying causes relevant for palliative care (N = 109,707). Data from four registries were linked for analysis. Scores on eight quality indicators concerning place of death and hospital care utilization were calculated, and compared across 31 healthcare insurance regions to establish relative benchmarks. Results On average, 36.4% of the study population died at home (range between regions 30.5%-42.6%) and 20.4% in hospital (range 16.6%-25.5%). Roughly half of the population who received hospital care at any time in the last year of life were found to (also) receive hospital care in the last month of life. In the last month, 32.0% of the study population were admitted to hospital (range 29.4-36.4%), 5.3% to an Intensive Care Unit (range 3.2-6.9%) and 23.9% visited an Emergency Department (range 21.0-27.4%). In the same time period, less than 1% of the study population was resuscitated in hospital or received tube or intravenous feeding in hospital. Conclusions The variation between regions points towards opportunities for practice improvement. The best practice performance standards as set in this study serve as ambitious but attainable targets for those regions that currently do not meet the standards. Policymakers, healthcare providers and researchers can use the suggested performance standards to further analyze causes of variance between regions and develop and test interventions that can improve practice.

Abstract Background Effective systemic treatments have revolutionized the management of patients with metastatic melanoma, including those with brain metastases. The extent to which these treatments influence disease trajectories close to death is unknown. Therefore, this study aimed to gain insight into provided treatments and healthcare consumption during the last 3 months of life in patients with melanoma brain metastases. Methods Retrospective, single-center study, including consecutive patients with melanoma brain metastases diagnosed between June-2015 and June-2018, referred to the medical oncologist, and died before November-2019. Patient and tumor characteristics, anti-tumor treatments, healthcare consumption, presence of neurological symptoms, and do-not-resuscitate status were extracted from medical charts. Results 100 patients were included. A BRAF-mutation was present in 66 patients. Systemic anti-tumor therapy was given to 72% of patients during the last 3 months of life, 34% in the last month, and 6% in the last week. Patients with a BRAF-mutation more frequently received systemic treatment during the last 3 (85% vs. 47%) and last month (42% vs. 18%) of life than patients without a BRAF-mutation. Furthermore, patients receiving systemic treatment were more likely to visit the emergency room (ER, 75% vs. 36%) and be hospitalized (75% vs. 36%) than those who did not. Conclusion The majority of patients with melanoma brain metastases received anti-tumor treatment during the last 3 months of life. ER visits and hospitalizations occurred more often in patients on anti-tumor treatment. Further research is warranted to examine the impact of anti-tumor treatments close to death on symptom burden and care satisfaction.