Tyrosine kinase inhibitors (TKIs) are anti‐cancer drugs that target tyrosine kinases, enzymes that are involved in multiple cellular processes. Currently, multiple oral TKIs have been introduced in ...the treatment of solid tumours, all administered in a fixed dose, although large interpatient pharmacokinetic (PK) variability is described. For imatinib, sunitinib and pazopanib exposure‐treatment outcome (efficacy and toxicity) relationships have been established and therapeutic windows have been defined, therefore dose optimization based on the measured blood concentration, called therapeutic drug monitoring (TDM), can be valuable in increasing efficacy and reducing the toxicity of these drugs.
In this review, an overview of the current knowledge on TDM guided individualized dosing of imatinib, sunitinib and pazopanib for the treatment of solid tumours is presented. We summarize preclinical and clinical data that have defined thresholds for efficacy and toxicity. Furthermore, PK models and factors that influence the PK of these drugs which partly explain the interpatient PK variability are summarized. Finally, pharmacological interventions that have been performed to optimize plasma concentrations are described. Based on current literature, we advise which methods should be used to optimize exposure to imatinib, sunitinib and pazopanib.
Abstract
Background
Discussing patients with cancer in a multidisciplinary team meeting (MDTM) is customary in cancer care worldwide and requires a significant investment in terms of funding and ...time. Efficient collaboration and communication between healthcare providers in all the specialisms involved is therefore crucial. However, evidence-based criteria that can guarantee high-quality functioning on the part of MDTMs are lacking. In this systematic review, we examine the factors influencing the MDTMs’ efficiency, functioning and quality, and offer recommendations for improvement.
Methods
Relevant studies were identified by searching Medline, EMBASE, and PsycINFO databases (01–01-1990 to 09–11-2021), using different descriptions of ‘MDTM’ and ‘neoplasm’ as search terms. Inclusion criteria were: quality of MDTM, functioning of MDTM, framework and execution of MDTM, decision-making process, education, patient advocacy, patient involvement and evaluation tools. Full text assessment was performed by two individual authors and checked by a third author.
Results
Seventy-four articles met the inclusion criteria and five themes were identified: 1) MDTM characteristics and logistics, 2) team culture, 3) decision making, 4) education, and 5) evaluation and data collection. The quality of MDTMs improves when the meeting is scheduled, structured, prepared and attended by all core members, guided by a qualified chairperson and supported by an administrator. An appropriate amount of time per case needs to be established and streamlining of cases (i.e. discussing a predefined selection of cases rather than discussing every case) might be a way to achieve this. Patient centeredness contributes to correct diagnosis and decision making. While physicians are cautious about patients participating in their own MDTM, the majority of patients report feeling better informed without experiencing increased anxiety. Attendance at MDTMs results in closer working relationships between physicians and provides some medico-legal protection. To ensure well-functioning MDTMs in the future, junior physicians should play a prominent role in the decision-making process. Several evaluation tools have been developed to assess the functioning of MDTMs.
Conclusions
MDTMs would benefit from a more structured meeting, attendance of core members and especially the attending physician, streamlining of cases and structured evaluation. Patient centeredness, personal competences of MDTM participants and education are not given sufficient attention.
Sarcomas are rare tumours. Early diagnosis is challenging, but important for local control and potentially survival and quality of life(QoL). We investigated (1)the route to diagnosis (RtD) ...experienced by sarcoma patients, including factors contributing to the length of the RtD from patients' perspective; (2)the impact of the RtD on QoL and care satisfaction; and (3)differences in aims 1-2 between English and Dutch patients.
Fifteen sarcoma patients from The Royal Marsden Hospital, United Kingdom, and Radboud University Medical Centre, The Netherlands, were interviewed, exploring RtD experiences. Interviews were analysed according to qualitative content analysis.
The main themes were: patient interval, diagnostic interval, reflection on the RtD and recommendations for improvement. Patient interval was long if symptoms were attributed as benign, did not interfere with daily life or were expected to cease. An incorrect working diagnosis, ineffective process of additional investigations, long referral times and lack of a lead clinician lengthened the diagnostic interval. Long waiting times, false reassurance and inadequate information provision led to dissatisfaction and a high emotional burden. Factors for improvement included increasing awareness of patients and healthcare providers, empowering patients, and having a lead clinician.
The RtD of sarcoma patients is complex. Increasing awareness of patients and healthcare providers may contribute to shorten the RtD.
In the registration trial, cabozantinib exposure ≥ 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell ...cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure-response relationship in patients with mRCC treated in routine care.
Cabozantinib trough concentrations (C
) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of C
> 750 ng/mL and median C
. In addition, the effect of dose reductions on response was explored. PFS was used as measure of response.
In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0-5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median C
was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average C
≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with C
≥ 750 ng/mL or ≥ 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. ≥ 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14-0.70, p = .004).
In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy.
Angiosarcomas are a heterogeneous group of rare endothelial malignancies with a complex, not completely unravelled biology. They encompass primary (sporadically occurring) angiosarcomas of several ...origins and secondary angiosarcomas, which often arise due to DNA damaging factors including radiotherapy or ultraviolet light exposure. The optimal treatment of metastatic angiosarcomas is unclear and the prognosis is poor. In order to discover novel treatment strategies for angiosarcomas it is important to take the heterogeneity of these tumors into account. For this reason it is also important to have preclinical models available for the different clinical subtypes. Owing to the rarity of angiosarcomas, models are scarce. So far, only five human cell lines of angiosarcomas (all of the scalp after UV exposure) are available worldwide. In this paper we describe a novel established patient-derived xenograft model of a radiotherapy-induced angiosarcoma of the breast. The tumor was characterized by a MYC amplification, CD31 and ERG immunohistochemical positivity and was further characterized by using next generation sequencing (TruSight Oncology 500) in combination with the R-package XenofilteR to separate mouse from human sequence reads.
Background
Chondrosarcoma is a heterogeneous group of primary bone sarcoma with an excellent overall survival after local therapy. However, the small percentage of patients who have no surgical ...treatment options have a very poor prognosis. We retrospectively collected data from these patients in four sarcoma centers and compared the progression‐free survival (PFS) for the different treatment regimens used for the four chondrosarcoma subtypes.
Materials and Methods
Patients diagnosed with unresectable chondrosarcoma in all four major sarcoma centers were included, and data on first‐line systemic therapy were retrospectively collected for analysis.
Results
A total of 112 patients were enrolled in this retrospective analysis: 50 conventional, 25 mesenchymal, 34 dedifferentiated, and 3 clear cell chondrosarcoma patients. In conventional chondrosarcoma patients, the longest mean PFS (6.7 months) was found in the group treated with antihormonal therapy. Patients diagnosed with mesenchymal chondrosarcoma were all treated with multidrug chemotherapy, and the mean PFS was 6.7 months. Doxorubicin monotherapy seems to have an unexplained better PFS than doxorubicin‐based combination therapy in patients with dedifferentiated chondrosarcoma (5.5 vs. 2.8 months, respectively; p = .275).
Conclusion
Prospective studies need to be conducted based on preclinical work to develop a uniform regimen to treat advanced chondrosarcoma patients according to the diagnosed subtype and improve survival.
Implications for Practice
Currently, there are no uniform treatment lines for advanced chondrosarcoma patients, which results in a very diverse group of treatment regimens being used. In this study, the data of 112 patients was collected. It was concluded that some treatment regimens seem to have a better progression‐free survival compared with others, and that these results also differ between the chondrosarcoma subtypes. Prospective studies need to be conducted based on preclinical work to develop a uniform regimen to treat advanced chondrosarcoma patients according to the diagnosed histological subtype to improve their survival.
Chondrosarcoma is a heterogeneous group of primary bone sarcoma with an excellent overall survival after local therapy; however, a small percentage of patients have metastatic disease, which has no surgical treatment options. This article describes data from patients diagnosed with unresectable chondrosarcoma in four major sarcoma centers, comparing progression free survival for the different treatment regimens used for four chondrosarcoma subtypes.
Renal or hepatic impairment is a common comorbidity for patients with cancer either because of the disease itself, toxicity of previous anticancer treatments, or because of other factors affecting ...organ function, such as increased age. Because renal and hepatic function are among the main determinants of drug exposure, the pharmacokinetic profile might be altered for patients with cancer who have renal or hepatic impairment, necessitating dose adjustments. Most anticancer drugs are dosed near their maximum tolerated dose and are characterised by a narrow therapeutic index. Consequently, selecting an adequate dose for patients who have either hepatic or renal impairment, or both, is challenging and definitive recommendations on dose adjustments are scarce. In this Review, we discuss the effect of renal and hepatic impairment on the pharmacokinetics of anticancer drugs. To guide clinicians in selecting appropriate dose adjustments, information from available drug labels and from the published literature were combined to provide a practical set of recommendations for dose adjustments of 160 anticancer drugs for patients with hepatic and renal impairment.
The prognosis of adult soft tissue sarcoma (STS) patients with metastases is generally poor. As little is known about the impact of the involvement of different metastatic sites and the extent of ...pulmonary lesions on the outcome for patients receiving first‐line chemotherapy, we aimed to establish prognostic factors for STS patients with lung metastases only. A retrospective, exploratory analysis was performed on 2,913 metastatic STS patients who received first‐line chemotherapy. Detailed information from 580 patients who had lung metastases only, was used for prognostic factor analysis. Patients with lung metastases only were more often asymptomatic and had undergone complete primary tumor resection more frequently compared to patients with additional metastases outside the lung or without lung metastases. For extremity STS, the incidence of lung metastases only was much higher compared to non‐extremity STS. Lung involvement only was an independent favorable prognostic factor for overall survival (OS) with regard to metastatic site. Within this subgroup, in a multivariate model, other factors associated with improved OS included: good performance status (PS), no progression at primary site, low histological grade, younger age, long interval between initial diagnosis and trial registration, and smaller diameter of the largest lung lesion. This unique analysis on prognostic factors in STS patients with lung metastases confirms well‐known patient factors (such as age and PS), and tumor characteristics (including tumor grade, interval between primary diagnosis, and metastases), but also identifies diameter of the largest lung lesion as a new prognostic factor. Knowledge about these factors may support decision‐making within multidisciplinary tumor boards.
What's new?
About 25% of soft tissue sarcoma patients develop lung metastases but prognostic factors for those who cannot get operated remain scarce. Here the authors performed a retrospective study of datasets obtained from 580 patients where metastases have not spread beyond the lung and who received first‐line chemotherapy but no resection. Interestingly, the largest diameter of a lung lesion emerged as a new prognostic factor, a finding, which may influence clinical decisions in the future.
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 (
= 46), Ewing sarcoma (
= 32), alveolar rhabdomyosarcoma (
= 20), embryonal rhabdomyosarcoma (
= 77), synovial sarcoma (
= 22) and desmoplastic small round cell tumors (DSRCT) (
= 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.
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