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.</p

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.</p

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= &lt;.001) and higher educated (OR 5.5; 95%CI 2.5–11.9, p= &lt;.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.</p

Feasibility of therapeutic drug monitoring of sorafenib in patients with liver or thyroid cancer

Introduction: Sorafenib is a tyrosine-kinase inhibitor approved for the treatment of renal cell carcinoma, hepatocellular carcinoma, thyroid carcinoma, and desmoid fibromatosis. As high inter-individual variability exists in exposure, there is a scientific rationale to pursue therapeutic drug monitoring (TDM). We investigated the feasibility of TDM in patients on sorafenib and tried to identify sub-groups in whom pharmacokinetically (PK) guided-dosing might be of added value. Methods: We included patients who started on sorafenib (between October 2017 and June 2020) at the recommended dose of 400 mg BID or with a step-up dosing schedule. Plasma trough levels (Ctrough) were measured at pre-specified time-points. Increasing the dose was advised if Ctrough was below the target of 3750 ng/mL and toxicity was manageable. Results: A total of 150 samples from 36 patients were collected. Thirty patients (83 %) had a Ctrough below the prespecified target concentration at a certain time point during treatment. Toxicity from sorafenib hampered dosing according to target Ctrough in almost half of the patients. In 11 patients, dosing was adjusted based on Ctrough. In three patients, this resulted in an adequate Ctrough without additional toxicity four weeks after the dose increase. In the remaining eight patients, dose adjustment based on Ctrough did not result in a Ctrough above the target or caused excessive toxicity. Conclusions: TDM for sorafenib is not of added value in daily clinical practice. In most cases, toxicity restricts the possibility of dose escalations.</p

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.</p

Non-cytotoxic systemic treatment in malignant peripheral nerve sheath tumors (MPNST) : A systematic review from bench to bedside

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Once metastasized, prognosis is poor despite regular treatment with conventional cytotoxic drugs. This study reviews the preclinical and clinical results of non-cytotoxic systemic therapy in MPNST. Methods: A systematic search was performed in PubMed and Embase databases according to the PRISMA guidelines. Search terms related to ‘MPNST’, ‘targeted therapy’, ‘immunotherapy’, and ‘viral therapy’ were used. Only in vivo studies and clinical trials were included. Clinicaltrials.gov was also searched for any ongoing trials including MPNST patients. Qualitative synthesis was performed on all studies stratifying per target: membrane, cytoplasmic, nuclear, immunotherapy and oncolytic viruses, and other. In vivo studies were assessed for treatment effect on tumor growth (low/intermediate/high), survival, and metastases. Clinical trials were assessed on response rate, progression-free survival, and overall survival. Results: After full-text screening, 60 in vivo studies and 19 clinical trials were included. A total of 13 trials are ongoing and unpublished. The included trials displayed relatively poor response rates thus far, with patients achieving stable disease at best. Inhibiting cytoplasmic targets most commonly yielded high treatment effect, predominantly after mTOR inhibition. Oncolytic viruses and angiogenesis inhibition also demonstrate intermediate to high effect. Therapies including a combination of drugs were most effective in controlling tumor growth. Several ongoing trials investigate potentially promising pathways, while others have yet to be established. Conclusion: Targeting the PI3K/Akt/mTOR pathway seems most promising in the treatment of MPNSTs. Oncolytic viruses and angiogenesis inhibition represent emerging therapies that require further study. Combinations of targeted therapies are most likely key to maximize treatment effect

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 &lt; 0.01), respectively. Systemic therapy was given in reference centers versus non-reference in 89.5% versus 82.0% (p &lt; 0.01) of high-risk and in 94.1% versus 65.9% (p &lt; 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.</p

Treatment dilemmas in patients with gastrointestinal stromal tumors (GIST) who experienced imatinib-induced pneumonitis:A case series

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.</p

Treatment dilemmas in patients with gastrointestinal stromal tumors (GIST) who experienced imatinib-induced pneumonitis:A case series

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.</p