Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology - an analysis of the closed cohorts of a multicentre prospective study.

BACKGROUND: Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS: We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS: For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS: Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.

Levels of circulating tumor DNA correlate with tumor volume in gastro-intestinal stromal tumors: an exploratory long-term follow-up study.

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.

Financial difficulties experienced by patients with gastrointestinal stromal tumours (GIST) in the Netherlands: data from a cross-sectional multicentre study.

PURPOSE: This study aims to (1) explore the prevalence of patient-reported financial difficulties among GIST patients, differentiating between those currently undergoing tyrosine kinase inhibitor (TKI) treatment and those who are not; (2) investigate associations between financial difficulties and sociodemographic and clinical characteristics, work, cancer-related concerns, anxiety and depression and (3) study the impact of financial difficulties on health-related quality of life. METHODS: A cross-sectional study was conducted among Dutch GIST patients diagnosed between 2008 and 2018, who were invited to complete a one-time survey between September 2020 and June 2021. Patients completed nine items of the EORTC item bank regarding financial difficulties, seven work-related questions, the Hospital Anxiety and Depression Scale, Cancer Worry Scale and EORTC QLQ-C30. RESULTS: In total, 328 GIST patients participated (response rate 63.0%), of which 110 (33.8%) were on TKI treatment. Patients currently treated with TKIs reported significantly more financial difficulties compared to patients not on TKIs (17.3% vs 8.7%, p = 0.03). The odds of experiencing financial difficulties was 18.9 (95% CI 1.7-214.7, p = 0.02) times higher in patients who were less able to work due to their GIST diagnosis. Patients who experienced financial difficulties had significantly lower global quality of life and functioning, and more frequently reported psychological symptoms as compared to patients who did not report financial difficulties. CONCLUSION: Even in a country where the costs of TKIs and follow-up care are covered by health insurance, financial difficulties can be present in GIST patients, especially in patients on TKI treatment, and may negatively influence the quality of life.

Fear, anxiety and depression in gastrointestinal stromal tumor (GIST) patients in the Netherlands: Data from a cross-sectional multicenter study / Miedo, ansiedad y depresión en pacientes con tumores del estroma gastrointestinal (GIST) en los Países Bajos: datos de un estudio multicéntrico transversal

Background: This study aims to (1) investigate the prevalence of anxiety, depression and severe fear of cancer recurrence or progression in gastrointestinal stromal tumor (GIST) patients treated in a curative or palliative setting, (2) compare their prevalence with a norm population, (3) identify factors associated with anxiety, depression and severe fear, and (4) study the impact of these psychological symptoms on health-related quality of life (HRQoL). Methods: In a cross-sectional study, GIST patients completed the Hospital Anxiety and Depression Scale, Cancer Worry Scale, and EORTC QLQ-C30. Results: Of the 328 patients, 15% reported anxiety, 13% depression, and 43% had severe fear. Anxiety and depression levels were comparable between the norm population and patients in the curative setting, but significantly higher for patients in the palliative setting. Having other psychological symptoms was associated with anxiety, while current TKI treatment and anxiety were associated with depression. Severe fear was associated with age, female sex, palliative treatment setting, anxiety, and GIST-related concerns. Conclusion: GIST patients treated in a palliative setting are more prone to experience psychological symptoms, which can significantly impair their HRQoL. These symptoms deserve more attention in clinical practice, in which regular screening can be helpful, and appropriate interventions should be offered.(AU)

Referral patterns of GIST patients: data from a nationwide study.

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.

Fear, anxiety and depression in gastrointestinal stromal tumor (GIST) patients in the Netherlands: Data from a cross-sectional multicenter study.

Background: This study aims to (1) investigate the prevalence of anxiety, depression and severe fear of cancer recurrence or progression in gastrointestinal stromal tumor (GIST) patients treated in a curative or palliative setting, (2) compare their prevalence with a norm population, (3) identify factors associated with anxiety, depression and severe fear, and (4) study the impact of these psychological symptoms on health-related quality of life (HRQoL). Methods: In a cross-sectional study, GIST patients completed the Hospital Anxiety and Depression Scale, Cancer Worry Scale, and EORTC QLQ-C30. Results: Of the 328 patients, 15% reported anxiety, 13% depression, and 43% had severe fear. Anxiety and depression levels were comparable between the norm population and patients in the curative setting, but significantly higher for patients in the palliative setting. Having other psychological symptoms was associated with anxiety, while current TKI treatment and anxiety were associated with depression. Severe fear was associated with age, female sex, palliative treatment setting, anxiety, and GIST-related concerns. Conclusion: GIST patients treated in a palliative setting are more prone to experience psychological symptoms, which can significantly impair their HRQoL. These symptoms deserve more attention in clinical practice, in which regular screening can be helpful, and appropriate interventions should be offered.

Cost Savings and Waste Reduction Through Redispensing Unused Oral Anticancer Drugs: The ROAD Study.

Importance: New strategies targeting waste are required to improve financial and ecologic sustainability of expensive therapies, such as oral anticancer drugs, that frequently remain unused by patients. Redispensing unused oral anticancer drugs seems to be a promising strategy when drug quality is guaranteed. Objectives: To determine the waste reduction and net cost savings attained by redispensing oral anticancer drugs that go unused by patients compared with the standard practice of disposal. Design, Settings, and Participants: The ROAD study was a prospective single-group intervention conducted in the outpatient pharmacies of 4 hospitals in the Netherlands from February 1, 2021, to February 1, 2023, with 12-month follow-up of each patient. Patients with cancer and who had a prescription for an oral anticancer drug that could be stored at room temperature were included. Of 2426 eligible patients, 602 did not consent and 601 did not respond. Data analyses were performed from August 25, 2022, to April 19, 2023. Intervention: Participants received oral anticancer drugs for use at home in special packaging (ie, sealed packaging with time-temperature indicator), to be returned to the pharmacy should these remain unused. The pharmacy ensured quality of returned drugs based on authenticity, appearance, remaining shelf life and adequate storage temperature. Drugs fulfilling quality requirements were redispensed to other patients. Main Outcome and Measure: Total waste reduction and mean net annual cost savings per patient compared with the standard practice of disposal. Optimization of cost savings was explored by introducing variations in the quality assurance procedure and patient population. All analyses used the average exchange rate for 2021 €1 = US $1.18. Results: Of 1223 patients with cancer who consented, 1071 participated (median [IQR] age, 70 [62-75] years; 622 [58.1%] were male). In all, 171 patients (16.0%; 95% CI, 13.8%-18.3%) returned 335 unused oral anticancer drug packages. Of the returned drugs, 228 packages were redispensed, which reduced waste by 68.1% (95% CI, 67.7%-68.5%) compared with the standard practice (disposal). Redispensing unused oral anticancer drugs comprised 2.4% (95% CI, 2.2%-2.5%) of total drug costs, providing mean net annual cost savings of US $680 (95% CI, $524-$837) up to $1591 (95% CI, $1226-$2002) per participant. Conclusions and Relevance: The findings of this multicenter intervention study indicate that redispensing unused oral anticancer drugs is associated with waste reduction and cost savings, which in turn may improve the affordability and sustainability of cancer treatment. Trial Registration: World Health Organization International Clinical Trials Registry Platform Identifier: NL9208.

Effect of Aprepitant on Etoposide Pharmacokinetics in Patients with Testicular Cancer: A Pharmacokinetic Study to Determine the Absence of a Clinically Relevant Interaction.

All patients treated with anticancer agents should receive the most effective anti-emetic regimen. Anti-emetic guidelines provide recommendations but do not take into account possible drug-drug interactions between anti-emetics and anticancer drugs. This study determines the clinical relevance of the potential drug-drug interaction of the neurokinin-1 receptor antagonist, aprepitant, on the pharmacokinetics of etoposide. Aprepitant is a moderate CYP3A4 inhibitor and may increase the systemic exposure of etoposide which is partly metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). In this prospective observational study, the pharmacokinetics of etoposide with and without concomitant use of aprepitant was determined in 12 patients receiving first-line chemotherapy for testicular cancer. The geometric mean (95% confidence interval (CI)) area under the plasma concentration-time curve 0-24 hour (AUC0-24h ) of etoposide with aprepitant was 86.2 (79.7-93.2) mg/L*hour vs. 83.7 (75.8-92.4) mg/L*hour without aprepitant. Geometric mean ratios (90% CIs) of AUC0-24h and maximum plasma concentration (Cmax ) for etoposide with and without aprepitant were 1.03 (0.96-1.10) and 0.96 (0.89-1.03), respectively. This study confirms the absence of a clinically relevant interaction between etoposide and aprepitant. Both drugs can be safely combined without affecting etoposide exposure.

Results of the first international quality control programme for oral targeted oncolytics.

AIMS: With the rising number of oral targeted oncolytics and growing awareness of the benefits of therapeutic drug monitoring (TDM) within the field of oncology, it is expected that the requests for quantifying concentrations of these drugs will increase. It is important to (cross-)validate available assays and ensure its quality, as results may lead to altered dosing recommendations. Therefore, we aimed to evaluate the performance of laboratories measuring concentrations of targeted oral oncolytics in a one-time international quality control (QC) programme. METHODS: Participating laboratories received a set of plasma samples containing low, medium and high concentrations of imatinib, sunitinib, desethylsunitinib, pazopanib, cabozantinib, olaparib, enzalutamide, desmethylenzalutamide and abiraterone, with the request to report their results back within five weeks after shipment. Accuracy was defined acceptable if measurements where within 85%-115% from the weighed-in reference concentrations. Besides descriptive statistics, an exploratory ANOVA was performed. RESULTS: Seventeen laboratories from six countries reported 243 results. Overall, 80.7% of all measurements were within the predefined range of acceptable accuracy. Laboratories performed best in quantifying imatinib and poorest in quantifying desethylsunitinib (median absolute inaccuracy respectively 4.0% (interquartile range (IQR) 1.8%-6.5%) and 15.5% (IQR 8.8%-34.9%)). The poorest performance of desethylsunitinib might be caused by using the stable-isotope-labelled sunitinib instead of desethylsunitinib as an internal standard, or due to the light-induced cis(Z)/trans(E) isomerization of (desethyl)sunitinib. Overall, drug substance and performing laboratory seemed to influence the absolute inaccuracy (F = 16.4; p < 0.001 and F = 35.5; p < 0.001, respectively). CONCLUSION: Considering this is the first evaluation of an international QC programme for oral targeted oncolytics, an impressive high percentage of measurements were within the predefined range of accuracy. Cross-validation of assays that are used for dose optimization of oncolytics will secure the performance and will protect patients from incorrect advices.

Individualized Dosing Patterns in the Treatment of Older Patients with Gastrointestinal Stromal Tumors: Results of a Registry-Based Observational National Cohort Study Including 871 Patients.

BACKGROUND: While the effectiveness of tyrosine kinase inhibitors (TKIs) seems similar in older patients with gastrointestinal stromal tumors (GIST) compared with younger patients, toxicities in older patients treated with TKIs more often lead to discontinuation of treatment. OBJECTIVE: To better understand the age-related pharmacology and pharmacodynamic differences in patients with GIST treated with TKIs, the primary aim of this study was to evaluate TKI dosing patterns in older patients with GIST, while the secondary aims were to evaluate differences in imatinib trough plasma concentrations between age groups and to compare the overall survival (OS) in patients with and without dose reductions in all treatment lines in a palliative setting. METHODS: Patients (18 years of age or older) with histologically proven GIST diagnosed between January 2009 and June 2021 and treated with one or more lines of TKIs were selected from the Dutch GIST Registry (DGR) database. Age groups were divided into younger patients (age <70 years) and older patients (age ≥70 years). All imatinib trough plasma concentrations of blood withdrawals taken from initiation of imatinib until a maximum of 1 year of treatment with imatinib were collected. Reasons for first adjustment of treatment were classified as adverse event, dose modification, progressive disease and other reasons. The next treatment steps after first adjustment of treatment were defined as dose escalation, dose reduction, dose interruption, or end of treatment. The association of dose reduction and OS was analyzed using the landmark approach. RESULTS: Overall, 871 patients were included in this study, including 577 younger patients and 294 older patients. Older patients more often had an adverse event as the reason for first adjustment of treatment with both imatinib (45.6%; p < 0.001) and sunitinib (58.6%; p = 0.224) compared with younger patients (19.5% and 42.7%, respectively). Adjustment of imatinib and sunitinib after starting on a standard dose because of an adverse event most often resulted in dose reduction in both age groups. Median trough plasma concentrations of all samples taken within the first year after initiation of imatinib were higher in older patients (1228 ng/mL, interquartile range [IQR] 959-1687) compared with younger patients (1035 ng/mL [IQR 773-1377]; p < 0.001). No significant differences were seen between OS in patients with or without dose reduction in all treatment lines (imatinib: p = 0.270; sunitinib: p = 0.547; and regorafenib: p = 0.784). CONCLUSION: Older patients showed higher imatinib trough plasma concentrations compared with younger patients and also had earlier and more often adverse events as the reason for first adjustment of treatment with imatinib followed by dose reduction. However, in a landmark analysis, patients with imatinib dose reductions had no poorer outcomes compared with patients not requiring a dose reduction.

Therapeutic drug monitoring to personalize dosing of imatinib, sunitinib, and pazopanib: A mixed methods study on barriers and facilitators.

BACKGROUND: Personalized dosing based on measurement of individual drug levels and adjusting the dose accordingly can improve efficacy and decrease unnecessary toxicity of oncological treatment. For imatinib, sunitinib, and pazopanib, this therapeutic drug monitoring (TDM)-guided dosing is, however, not routinely used, despite accumulating evidence favoring individualized dosing. Therefore, we aimed to identify and quantify (potential) barriers and facilitators in TDM-guided dosing for imatinib, sunitinib, and pazopanib. METHODS: We performed a mixed methods study among all stakeholders involved: patients, healthcare professionals (HCPs), pharmaceutical companies, and health insurance companies. During the first qualitative part of this study, we performed semi-structured individual interviews and one focus group interview to identify all (potential) barriers and facilitators, and during the second quantitative part of this study, we used a web-based survey to quantify these findings. The interviews addressed the six domains of the implementation of change model of Grol and Wensing: (1) the innovation itself; (2) the HCP; (3) the patient; (4) social context; (5) organizational context; and (6) finances, law, and governance. RESULTS: In the qualitative study, we interviewed 20 patients, 18 HCPs and 10 representatives of pharmaceutical and health insurance companies and identified 72 barriers and 90 facilitators. In the quantitative study, the survey was responded by 66 HCPs and 58 patients. Important barriers were on the domain of the HCP, such as a lack of experience with TDM (36.4%), on the domain of the patient, such as lack of awareness of TDM (39.7%), and the processing time for measurement and interpretation of the TDM result (40.9%) (organizational domain). Important facilitators were education of HCPs (95.5%), education of patients (87.9%) and facilitating an overview of when and where TDM measurements are being performed (86.4%). CONCLUSION: We identified and quantified important barriers and facilitators for the implementation of TDM-guided dosing for imatinib, sunitinib, and pazopanib. Based on our results, the implementation strategy should mainly focus on educating both HCPs and patients and on the organizational aspect of TDM.

The association of having a monitoring or blunting coping style with psychological distress, health-related quality of life and satisfaction with healthcare in gastrointestinal stromal tumour (GIST) patients.

BACKGROUND: There are two main coping styles regarding information seeking under medical threat; monitoring (information-seeking) and blunting (information-avoiding). The aim of this study is to (1) determine factors associated with a monitoring or blunting coping style in gastro-intestinal stromal tumour (GIST) patients and (2) investigate its association with psychological distress, cancer-related concerns, health-related quality of life and satisfaction with healthcare. METHODS: In a cross-sectional study, Dutch GIST patients completed the shortened version of the Threatening Medical Situations Inventory to determine their coping style, the Hospital Anxiety and Depression Scale, Cancer Worry Scale, EORTC QLQ-C30 and part of the EORTC QLQ-INFO25. RESULTS: A total of 307 patients were classified as blunters (n = 175, 57%) or monitors (n = 132, 43%). Coping style was not associated with tumour or treatment variables, but being a female (OR 2.5; 95%CI 1.5-4.1; p= <.001) and higher educated (OR 5.5; 95%CI 2.5-11.9, p= <.001) were associated with higher odds of being a monitor. Monitors scored significantly lower on emotional functioning (mean = 86.8 vs mean = 90.9, p=.044), which is considered a trivial difference, more often experienced severe fear of cancer recurrence or progression (53.0% vs 37.7%, p=.007), and had more concerns about dying from GIST in the future (60.6% vs 47.4%, p=.025). Compared to blunters, monitors were less satisfied with the received healthcare and information, and would have liked to receive more information. CONCLUSION: GIST patients with a monitoring coping style experience a higher emotional burden. Additionally, monitors exhibit a greater need for information. Although this need for information could potentially result in fears and concerns, recognising it may also create an opening for tailored communication and information.

Personalized Therapy of Sarcomas.

Sarcomas are a group of rare malignant mesenchymal tumors [...].

Prognostic Factors in Epithelioid Hemangioendothelioma: Analysis of a Nationwide Molecularly/Immunohistochemically Confirmed Cohort of 57 Cases.

Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular sarcoma with variable aggressive clinical behavior. In this retrospective study, we aimed to investigate prognostic factors based on clinicopathologic findings in a molecularly/immunohistochemically confirmed nationwide multicenter cohort of 57 EHE cases. Patients had unifocal disease (n = 29), multifocal disease (n = 5), lymph node metastasis (n = 8) and/or distant metastasis (n = 15) at the time of diagnosis. The overall survival rate was 71.4% at 1 year and 50.7% at 5 years. Survival did not correlate with sex, age or histopathological parameters. No survival differences were observed between multifocal and metastatic disease, suggesting that multifocality represents early metastases and treatment options are limited in comparison to unifocal disease. In unifocal tumors, survival could be predicted using the risk stratification model of Shibayama et al., dividing the cases into low- (n = 4), intermediate- (n = 15) and high- (n = 3) risk groups. No clinical or histopathological parameters were associated with progressive unifocal disease course. Lymph node metastases at the time of diagnosis occurred in 14.0% of the cases and were mainly associated with tumor localization in the head and neck area, proposing lymph node dissection. In conclusion, our results demonstrate the aggressive behavior of EHE, emphasize the prognostic value of a previously described risk stratification model and may provide new insights regarding tumor focality, therapeutic strategies and prognosis.

The Prognostic Relevance of MRI Characteristics in Myxofibrosarcoma Patients Treated with Neoadjuvant Radiotherapy.

To improve local control, neoadjuvant radiotherapy (nRT) followed by surgery is the standard of care in myxofibrosarcoma (MFS) because of its infiltrative growth pattern. Nevertheless, local recurrence rates are high. Data on prognostic factors for poor clinical outcomes are lacking. This retrospective study thus investigates the prognostic relevance of magnetic resonance imaging (MRI) characteristics before and after nRT in 40 MFS patients, as well as their association with disease-free survival (DFS) and overall survival (OS). A vascular pedicle, defined as extra-tumoral vessels at the tumor periphery, was observed in 12 patients (30.0%) pre-nRT and remained present post-nRT in all cases. Patients with a vascular pedicle had worse DFS (HR 5.85; 95% CI 1.56-21.90; p = 0.009) and OS (HR 9.58; 95% CI 1.91-48.00; p = 0.006). An infiltrative growth pattern, referred to as a tail sign, was observed in 22 patients (55.0%) pre-nRT and in 19 patients (47.5%) post-nRT, and was associated with worse DFS post-nRT (HR 6.99; 95% CI 1.39-35.35; p = 0.019). The percentage of tumor necrosis estimated by MRI was increased post-nRT, but was not associated with survival outcomes. The presence of a tail sign or vascular pedicle on MRI could support the identification of patients at risk for poor clinical outcomes after nRT.

Measuring Tumour Imatinib Concentrations in Gastrointestinal Stromal Tumours: Relevant or Redundant?

Imatinib plasma trough concentrations are associated with efficacy for patients treated for advanced or metastatic KIT-positive gastrointestinal stromal tumours (GISTs). This relationship has not been studied for patients treated in the neoadjuvant setting, let alone its correlation with tumour drug concentrations. In this exploratory study we aimed to determine the correlation between plasma and tumour imatinib concentrations in the neoadjuvant setting, investigate tumour imatinib distribution patterns within GISTs, and analyse its correlation with pathological response. Imatinib concentrations were measured in both plasma and in three regions of the resected primary tumour: the core, middle part, and periphery. Twenty-four tumour samples derived from the primary tumours of eight patients were included in the analyses. Imatinib tumour concentrations were higher compared to plasma concentrations. No correlation was observed between plasma and tumour concentrations. Interpatient variability in tumour concentrations was high compared to interindividual variability in plasma concentrations. Although imatinib accumulates in tumour tissue, no distribution pattern of imatinib in tumour tissue could be identified. There was no correlation between imatinib concentrations in tumour tissue and pathological treatment response.

Pros and cons of streamlining and use of computerised clinical decision support systems to future-proof oncological multidisciplinary team meetings.

Introduction: Nowadays nearly every patient with cancer is discussed in a multidisciplinary team meeting (MDTM) to determine an optimal treatment plan. The growth in the number of patients to be discussed is unsustainable. Streamlining and use of computerised clinical decision support systems (CCDSSs) are two major ways to restructure MDTMs. Streamlining is the process of selecting the patients who need to be discussed and in which type of MDTM. Using CCDSSs, patient data is automatically loaded into the minutes and a guideline-based treatment proposal is generated. We aimed to identify the pros and cons of streamlining and CCDSSs. Methods: Semi-structured interviews were conducted with Dutch MDTM participants. With purposive sampling we maximised variation in participants' characteristics. Interview data were thematically analysed. Results: Thirty-five interviews were analysed. All interviewees agreed on the need to change the current MDTM workflow. Streamlining suggestions were thematised based on standard and complex cases and the location of the MDTM (i.e. local, regional or nationwide). Interviewees suggested easing the pressure on MDTMs by discussing standard cases briefly, not at all, or outside the MDTM with only two to three specialists. Complex cases should be discussed in tumour-type-specific regional MDTMs and highly complex cases by regional/nationwide expert teams. Categorizing patients as standard or complex was found to be the greatest challenge of streamlining. CCDSSs were recognised as promising, although none of the interviewees had made use of them. The assumed advantage was their capacity to generate protocolised treatment proposals based on automatically uploaded patient data, to unify treatment proposals and to facilitate research. However, they were thought to limit the freedom to deviate from the treatment advice. Conclusion: To make oncological MDTMs sustainable, methods of streamlining should be developed and introduced. Physicians still have doubts about the value of CCDSSs.

Local treatment in metastatic GIST patients: A multicentre analysis from the Dutch GIST Registry.

BACKGROUND: The added value of local treatment in selected metastatic GIST patients is unclear. This study aims to provide insight into the usefulness of local treatment in metastatic GIST by use of a survey study and retrospective analyses in a clinical database. METHODS: A survey study was conducted among clinical specialists to select most relevant characteristics of metastatic GIST patients considered for local treatment, defined as elective surgery or ablation. Patients were selected from the Dutch GIST Registry. A multivariate Cox-regression model for overall survival since time of diagnosis of metastatic disease was estimated with local treatment as a time-dependent variable. An additional model was estimated to assess prognostic factors since local treatment. RESULTS: The survey's response rate was 14/16. Performance status, response to TKIs, location of active disease, number of lesions, mutation status, and time between primary diagnosis and metastases, were regarded the 6 most important characteristics. Of 457 included patients, 123 underwent local treatment, which was associated with better survival after diagnosis of metastases (HR = 0.558, 95%CI = 0.336-0.928). Progressive disease during systemic treatment (HR = 3.885, 95%CI = 1.195-12.627) and disease confined to the liver (HR = 0.269, 95%CI = 0.082-0.880) were associated with worse and better survival after local treatment, respectively. CONCLUSION: Local treatment is associated with better survival in selected patients with metastatic GIST. Locally treated patients with response to TKIs and disease confined to the liver have good clinical outcome. These results might be considered for tailoring treatment, but should be interpreted with care because only specific patients are provided with local treatment in this retrospective study.

Improved Efficacy of First-Line Imatinib in Advanced Gastrointestinal Stromal Tumors (GIST): The Dutch GIST Registry Data.

BACKGROUND: Patients with unresectable and metastasized gastrointestinal stromal tumor (GIST) experienced a remarkable improvement of progression-free survival (PFS) and overall survival (OS) after the introduction of imatinib. Our hypothesis is that the outcomes of treatment with imatinib are even better nowadays compared with the registration trials that were performed two decades ago. To study this, we used real-life data from a contemporary registry. METHODS: A multicenter, retrospective study was performed by exploring clinical data from a prospective real-life clinical database, the Dutch GIST Registry (DGR). Patients with advanced GIST treated with first-line imatinib were included and PFS (primary outcome) and OS (secondary outcome) were analyzed. Results of our study were compared with published results of the European Organisation for Research and Treatment of Cancer (EORTC) 62005 trial, which marked the first era of imatinib in the treatment of GIST. RESULTS: Overall, 420 of the 435 patients treated with imatinib in the DGR had recorded response evaluation and were included in the analysis. During a median follow-up of 35.0 months (range 2.0-136.0), progression of GIST was eventually observed in 217 patients (51.2%). The DGR cohort showed a longer median PFS (33.0 months, 95% confidence interval [CI] 28.4-37.6) compared with the EORTC 62005 trial (an estimated PFS of 19.5 months). Additionally, the median OS of 68.0 months (95% CI 56.1-80.0) was longer than the exposed median OS (46.8 months) published in the long-term follow-up results of the EORTC 62005 trial (median follow-up duration 10.9 years). CONCLUSION: This study provides an update on outcomes of imatinib in the treatment of advanced GIST patients and demonstrates improved clinical outcomes since the first randomized studies of imatinib 2 decades ago. Furthermore, these results represent outcomes in real-world clinical practice and can serve as a reference when evaluating effectiveness of imatinib in patients with advanced GIST.