Abstract Background Patients with metastatic clear cell renal cell carcinoma (ccRCC) have a dismal prognosis. Therefore, new and less toxic treatments are needed. Objective We determined the maximum ...tolerated dose (MTD) and potential therapeutic efficacy of multiple infusions of lutetium 177 (177 Lu)-girentuximab (cG250) on various dose levels in a phase 1 trial in patients with progressive metastasized ccRCC. Design, setting, and participants In this uncontrolled case series in 23 patients with progressive ccRCC metastases, cG250 accumulation was verified by diagnostic indium 111-cG250 imaging. Patients then received a high-activity dose of177 Lu-cG250. Intervention Groups of three patients received177 Lu-cG250, starting at a dose level of 1110 MBq/m2177 Lu-cG250, with dose increments of 370 MBq/m2 per group. In the absence of persistent toxicity, progressive disease, and accelerated blood clearance, patients were eligible for retreatment after 3 mo with 75% of the previous activity dose. Patients could receive a total of three treatment cycles. Outcome measurements and statistical analysis Determination of the MTD was the primary and therapeutic efficacy was the secondary outcome measurement of the study. Results and limitations The MTD was 2405 MBq/m2 because higher doses resulted in dose-limiting myelotoxicity. Some patients received second (13 of 23 56%) and third (4 of 23 17%) treatment cycles. Most patients (17 of 23 74%) demonstrated stable disease 3 mo after the first treatment, and one patient showed a partial response that lasted for 9 mo. Mean growth of target tumor lesions was reduced from 40.4% (95% confidence interval CI, ±17.0) during the last 3 mo before study entry to 5.5% (95% CI, ±5.3; p < 0.001) at 3 mo after the first treatment cycle. No major nonhematologic side effects were observed. Conclusions177 Lu-cG250 radioimmunotherapy in metastatic ccRCC patients is well tolerated at an activity dose level as high as 2405 MBq/m2 (MTD). Radioimmunotherapy with177 Lu-cG250 may stabilize previously progressive metastatic ccRCC.
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.
Abstract
Introduction
The optimal treatment plan for patients with cancer is discussed in multidisciplinary team meetings (MDTMs). Effective meetings require all participants to have collaboration ...and communication competences. Participating residents (defined as qualified doctors in training to become a specialist) are expected to develop these competences by observing their supervisors. However, the current generation of medical specialists is not trained to work in multidisciplinary teams; currently, training mainly focuses on medical competences. This study aims to identify barriers and facilitators among residents with respect to learning how to participate competently in MDTMs, and to identify additional training needs regarding their future role in MDTMs, as perceived by residents and specialists.
Methods
Semi-structured interviews were conducted with Dutch residents and medical specialists participating in oncological MDTMs. Purposive sampling was used to maximise variation in participants’ demographic and professional characteristics (e.g. sex, specialty, training duration, type and location of affiliated hospital). Interview data were systematically analysed according to the principles of thematic content analysis.
Results
Nineteen residents and 16 specialists were interviewed. Three themes emerged: 1) awareness of the educational function of MDTMs among specialists and residents; 2) characteristics of MDTMs (e.g. time constraints, MDTM regulations) and 3) team dynamics and behaviour. Learning to participate in MDTMs is facilitated by: specialists and residents acknowledging the educational function of MDTMs beyond their medical content, and supervisors fulfilling their teaching role and setting conditions that enable residents to take a participative role (e.g. being well prepared, sitting in the inner circle, having assigned responsibilities). Barriers to residents’ MDTM participation were insufficient guidance by their supervisors, time constraints, regulations hindering their active participation, a hierarchical structure of relations, unfamiliarity with the team and personal characteristics of residents (e.g. lack of confidence and shyness). Interviewees indicated a need for additional training (e.g. simulations) for residents, especially to enhance behavioural and communication skills.
Conclusion
Current practice with regard to preparing residents for their future role in MDTMs is hampered by a variety of factors. Most importantly, more awareness of the educational purposes of MDTMs among both residents and medical specialists would allow residents to participate in and learn from oncological MDTMs. Future studies should focus on collaboration competences.
Aims
Patients with metastatic gastrointestinal stromal tumours (GIST) are treated in first line with the oral tyrosine kinase inhibitor, imatinib, until progressive disease. With this fixed dosing ...regimen, only approximately 40% of patients reach adequate plasma levels within the therapeutic index. Therapeutic drug monitoring (TDM) is a solution to reach plasma levels within the therapeutic index. However, introducing TDM will also increase costs, due to prolonged imatinib use and laboratory costs. The aim of this study was to evaluate the cost‐effectiveness of TDM in patients with metastatic/unresectable GIST treated with imatinib as a first line treatment, compared with fixed dosing.
Methods
A survival model was created to simulate progression, mortality and treatment costs over a 5‐year time horizon, comparing fixed dosing vs TDM‐guided dosing. The outcomes measured were treatments costs, life‐years and quality‐adjusted life‐years.
Results
Total costs over the 5‐year time horizon were estimated to be €106 994.85 and €150 477.08 for fixed dosing vs TDM‐guided dosing, respectively. A quality‐adjusted life year gain of 0.74 (95% confidence interval 0.66–0.90) was estimated with TDM‐guided dosing compared to fixed dosing. An average incremental cost‐effectiveness ratio of €58 785.70 per quality‐adjusted life year gained was found, mainly caused by longer use and higher dosages of imatinib.
Conclusion
Based on the currently available data, this analysis suggests that TDM‐guided dosing may be a cost‐effective intervention for patients with metastatic/unresectable GIST treated with imatinib which will be improved when imatinib losses its patency.
In part A, the aim was to define the maximum tolerated dose (MTD) of the hydrogen sulfate (Hyd-Sulfate) oral capsule formulation of the mitogen-activated protein kinase kinase inhibitor AZD6244 ...(ARRY-142886). In part B, the aim was to compare the pharmacokinetic profile of the new Hyd-Sulfate capsule with the initial AZD6244 free-base suspension and further characterize the pharmacodynamic profile and efficacy of the new formulation.
In part A, 30 patients received escalating doses of AZD6244 Hyd-Sulfate twice daily. In part B, 29 patients were randomized to a single dose of the Hyd-Sulfate capsule or free-base suspension, followed by a washout, then a single dose of the alternative formulation. Patients received the Hyd-Sulfate capsule twice daily at MTD of part A thereafter.
The MTD of the Hyd-Sulfate capsule was 75 mg twice daily. Dose limiting toxicities were Common Terminology Criteria for Adverse Events grade 3 acneiform rash and pleural effusion. Fatigue (65.7%) and acneiform dermatitis (60.0%) were the most frequent adverse events at the MTD. Based on area under curve(0-24), exposure of the 75 mg Hyd-Sulfate capsule relative to the 100 mg free-base suspension was 197% (90% confidence interval, 161-242%). Pharmacodynamic analysis showed that inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced extracellular signal-regulated kinase phosphorylation in peripheral blood lymphocytes was related to plasma concentrations of AZD6244, with an estimated IC(50) of 352 ng/mL and maximum inhibition (E(max)) of approximately 91%, showing target inhibition. A patient with metastatic melanoma bearing a V600E BRAF mutation achieved a complete response persisting after 15 months of therapy.
The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials.
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 (
= 29), multifocal disease (
= 5), lymph node metastasis (
= 8) and/or distant metastasis (
= 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- (
= 4), intermediate- (
= 15) and high- (
= 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.
Tyrosine kinase inhibitors (TKIs) as sorafenib are known to reduce the number of immunosuppressive regulatory T cells (Tregs) in the peripheral blood and thereby shifting the immune balance to a more ...stimulating setting. The effect of sorafenib on intratumoural Tregs is unclear but important for future combinations of TKIs and immunotherapy. We, therefore, evaluated the accumulation of regulatory T cells (Tregs, defined as, CD4+FoxP3+CD25highCD127low‐cells) in blood, ascites, metastases and primary tumours of patients with renal cell carcinoma (RCC), and we explored the effect of neoadjuvant treatment with sorafenib 400 mg bid on intratumoural Tregs in 11 patients with RCC in comparison to 15 nontreated RCC patients. We found that immunosuppressive Tregs specifically accumulate in primary tumour, metastases and ascites of RCC‐patients. Tumour infiltrating Tregs were functional. Neoadjuvant sorafenib treatment significantly reduced the percentage of tumour‐infiltrating Tregs (mean 17.3% vs. 28.1%, p = 0.046). Diminished Treg accumulation at the tumour site adds to explain the clinical effectiveness of sorafenib treatment. This observation may have important implications for the use of sorafenib in combination with immunotherapy in patients with RCC, since the depletion of Tregs has been associated with enhanced responses on vaccine mediated immunotherapy.
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.
Co‐treatment with gastric acid suppressants (GAS) in patients taking anticancer drugs that exhibit pH‐dependant absorption may lead to decreased drug exposure and may hamper drug efficacy. In our ...study, we investigated whether a 1‐hour time interval between subsequent intake of pazopanib and GAS could mitigate this negative effect on drug exposure. We performed an observational study in which we collected the first steady‐state pazopanib trough concentration (Cmin) levels from patients treated with pazopanib 800 mg once daily (OD) taken fasted or pazopanib 600 mg OD taken with food. All patients were advised to take GAS 1 hour after pazopanib. Patients were grouped based on the use of GAS and the geometric (GM) Cmin levels were compared between groups for each dose regimen. Additionally, the percentage of patients with exposure below the target threshold of 20.5 mg/L and the effect of the type of PPI was explored. The GM Cmin levels were lower in GAS users vs non‐GAS users for both the 800 and 600 mg cohorts (23.7 mg/L 95% confidence interval CI: 21.1‐26.7 vs 28.2 mg/L 95% CI: 25.9‐30.5, P = .015 and 26.0 mg/L 95% CI: 22.4‐30.3 vs 33.5 mg/L 95% CI: 30.3‐37.1, P = .006). Subtherapeutic exposure was more prevalent in GAS users vs non‐GAS users (33.3% vs 19.5% and 29.6% vs 14%). Sub‐analysis showed lower GM pazopanib Cmin in patients who received omeprazole, while minimal difference was observed in those receiving pantoprazole compared to non‐users. Our research showed that a 1‐hour time interval between intake of pazopanib and GAS did not mitigate the negative effect of GAS on pazopanib exposure and may hamper pazopanib efficacy.
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