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 Renal cell cancer (RCC) is considered to be an immunogenic cancer with high numbers of infiltrating lymphocytes and reports of modest responses to immunostimulatory cytokines such as interleukin-2 (IL-2) and interferon-a (IFN-a).
Dose optimization proved an effective tool to reach adequate trough levels in patients treated with imatinib, sunitinib and pazopanib. The percentage of patients with adequate trough levels increased from 38 to 64%. Therapeutic drug monitoring may add to the improvement of efficacy and reduction of toxicity and costs of these treatments.
In order to explore the potential of immune checkpoint blockade in sarcoma, we investigated expression and clinical relevance of programmed cell death-1 (PD-1), programmed death ligand-1 (PD-L1) and CD8 in tumors of 208 sarcoma patients. Primary untreated osteosarcoma (n = 46), Ewing sarcoma (n = 32), alveolar rhabdomyosarcoma (n = 20), embryonal rhabdomyosarcoma (n = 77), synovial sarcoma (n = 22) and desmoplastic small round cell tumors (DSRCT) (n = 11) were examined immunohistochemically. PD-L1 expression was predominantly detected in alveolar and embryonal rhabdomyosarcomas (15% and 16%, respectively). In the alveolar subtype PD-L1 expression was associated with better overall, event-free and metastases-free survival. PD-1 expression on lymphocytes was predominantly seen in synovial sarcomas (18%). High levels of CD8+ lymphocytes were predominantly detected in osteosarcomas (35%) and associated with worse event-free survival in synovial sarcomas. Ewing sarcoma and DSRCTs showed PD-1 on tumor cells instead of on tumor infiltrating lymphocytes. Overall, expression and clinical associations were found to be subtype dependent. For the first time PD-1 expression on Ewing sarcoma (19%) and DSRCT (82%) tumor cells was described.
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.
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