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Desmoplastic small round cell tumors (DSRCTs), Ewing sarcoma (ES), and alveolar and embryonal rhabdomyosarcoma (ARMS and ERMS) are malignant sarcomas typically occurring at young age, with a poor prognosis in the metastatic setting. New treatment options are necessary. Src family kinase inhibitor dasatinib single-agent treatment has been investigated in a phase 2 study in patients with advanced sarcomas including ES and RMS but failed as a single agent in these subtypes. Since previous studies demonstrated high FAK and Src activities in RMS and ES tissue and cell lines, and dasatinib treatment was shown to upregulate activated FAK, we hypothesized that FAK-Src combination treatment could potentially be an interesting treatment option for these tumor types. We examined the effects of targeting the FAK-Src complex by addressing (p)FAK and (p)Src expressions in tumor sections of DSRCT ( n  = 13), ES ( n  = 68), ARMS ( n  = 21), and ERMS ( n  = 39) and by determining the antitumor effects of single and combined treatment with FAK inhibitor defactinib and multikinase (Abl/SFK) inhibitor dasatinib in vitro on cell lines of each subtype. In vivo effects were assessed in DSRCT and ERMS models. Concurrent pFAK and pSrc expressions (H-score >50) were observed in DSRCT (67%), ES (6%), ARMS (35%), and ERMS (19%) samples. Defactinib treatment decreased pFAK expression and reduced cell viability in all subtypes. Dasatinib treatment decreased pSrc expression and cell viability in each subtype. Combination treatment led to a complete reduction in pFAK and pSrc in each cell line and showed enhanced cell viability reduction, drug synergy, DNA damage induction, and a trend toward higher apoptosis induction in DSRCT, ERMS, and ARMS but not in ES cells. These promising in vitro results unfortunately do not translate into promising in vivo results as we did not observe a significant effect on tumor volume in vivo , and the combination did not show superior effects compared to dasatinib single-agent treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Anke E. M. van Erp et al.)

Background: Uterine sarcomas are rare subtypes of primary urogenital tumours and need tailored treatment. This study aimed to examine the impact of diagnosis and treatment on health-related quality of life (HRQoL) in patients with uterine sarcoma and measures available to assess HRQoL in this group., Methods: Thirteen patients with uterine sarcoma and 23 health care professionals were purposively sampled from sarcoma reference centers and participated in a semi-structured interview exploring HRQoL. Patients were also asked to review the EORTC QLQ-C30 and EORTC QLQ-EN24 for relevance. Data were analysed using thematic analysis and descriptive statistics., Results: The most commonly reported physical health issues were related to sexual dysfunction and urological symptoms. Hormone-related issues and gastrointestinal symptoms were also identified. Cancer-generic issues such as functional problems, fatigue, pain, and treatment-related adverse effects were also reported. Regarding mental health, fears (about having sex, of recurrence, or of death), altered body-image, and dealing with lacking knowledge regarding sarcoma had an impact on HRQoL. Social health issues were related to the impact on relationships with others, limitations in undertaking activities, loss of independence, changes in work or study capacity, and financial difficulties. Most of the items of the EORTC QLQ-C30 and EORTC QLQ-EN24 questionnaires were rated as relevant. Questions about lack of knowledge about sarcoma, shock of diagnosis, and menopausal symptoms were lacking from existing measures., Conclusions: Uterine sarcoma patients experience a variety of concerns covering the physical, mental, and social domains of HRQoL that are in the main EORTC instruments, but not all of them. Combining cancer-generic, location- and sarcoma-specific items is recommended to assess HRQoL in this patient group. Trial registration NCT04071704., (© 2022. The Author(s).)

Purpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathologic variables with survival was evaluated in a large multi-institutional European cohort., Experimental Design: Data from 185 patients were retrospectively collected in 23 European GIST reference centers. Propensity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Univariate and multivariate unweighted and weighted Cox proportional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival., Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79-2.28]. The variables consistently associated with worse survival outcomes were high mitotic index and nongastric tumor location., Conclusions: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted., (©2021 The Authors; Published by the American Association for Cancer Research.)

Angiosarcoma (AS) is a rare malignancy with a poor prognosis. It can develop spontaneously or due to previous radiotherapy (RT), ultraviolet (UV) radiation, or lymphoedema (Stewart Treves AS). Novel therapeutic approaches are needed, but progress is hindered because of the heterogeneity and rarity of AS. In order to explore the potential of immune checkpoint inhibition (ICI), we investigated the protein expression of programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and CD8 + T cells in 165 AS cases in relation to AS subgroups based on clinical classification and in relation to whole-genome methylation profiling based clusters (A1, A2, B1, B2). High PD-L1 and PD-1 expression were predominantly shown in UV-associated, visceral, and soft tissue AS. RT-associated AS showed predominantly high PD-1 expression. CD8 + T cell infiltration was present in the majority of AS samples. Within the UV-associated AS, two different clusters can be distinguished by DNA methylation profiling. Cases in cluster A1 showed higher PD-1 (p = 0.015), PD-L1 (p = 0.015), and CD8 + T cells (p = 0.008) compared to those in cluster B2, suggesting that these UV-AS tumors are more immunogenic than B2 tumors showing a difference even within one subgroup. In soft tissue AS, combined PD-1 and PD-L1 expression showed a trend toward poor survival (p = 0.051), whereas in UV-associated AS, PD-1 expression correlated with better survival (p = 0.035). In conclusion, we show the presence of PD-1, PD-L1, and CD8 + T cells in the majority of AS but reveal differences between and within AS subgroups, providing prognostic information and indicating to be predictive for ICI., (© 2022. The Author(s).)

Aim: 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., Methods: Cabozantinib trough concentrations (C min ) were collected and average exposure was calculated per individual. Exposure-response analyses were performed using the earlier identified target of C min  > 750 ng/mL and median C min . In addition, the effect of dose reductions on response was explored. PFS was used as measure of response., Results: 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 min was 572 ng/mL (IQR: 496-701). Only 17% of patients had an average C min  ≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40-64). No improved PFS was observed for patients with C min  ≥ 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)., Conclusion: 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., (© 2022. The Author(s).)

Myxofibrosarcoma (MFS) is a rare mesenchymal soft tissue sarcoma type, with a high local recurrence (LR) rate. Robust epidemiological data on MFS are lacking. We, therefore, aimed to identify prognostic factors and describe real-life outcomes of a large cohort of 908 MFS patients obtained from the nationwide database of the Netherlands Cancer Registry and diagnosed between 2002 and 2019. Median Overall survival (OS) was 155 (range 0.1-215) months, with a five-year OS of 67.7%. No improvement of OS was found over time. Multivariable Cox regression survival analysis demonstrated known prognostic factors for OS, such as older age, tumour size, and histological grade with the addition of sex. Surgery at sarcoma expertise centres, instead of general hospitals, was associated with better OS outcomes. In a subcohort of 177 patients, 39% developed LR with a median time to recurrence of 20 months. From LR on, the median OS was 64.0 months (CI 95% 38.5-89.5). In 28%, distant metastases were diagnosed with a median OS of 34.3 months (CI 95% 28.8-39.8) after diagnosis of the primary tumour. In this largest nationwide cohort so far, survival outcomes and recurrence rates for MFS patients did not improve over time, emphasizing the need to improve treatment strategies and suggesting a role for sarcoma expertise centres.

Cabozantinib is registered in fixed 60 mg dose. However, 46% to 62% of patients in the registration studies needed a dose reduction due to toxicity. Improved clinical efficacy has been observed in renal cell carcinoma patients (RCC) with a cabozantinib exposure greater than 750 μg/L. In our study we explored the cabozantinib exposure in patients with different tumour types. We included RCC patients from routine care and salivary gland carcinoma (SGC) patients from a phase II study with ≥1 measured C min at steady-state. The geometric mean (GM) C min at the starting dose, at 40 mg and at best tolerated dose (BTD) were compared between both tumour types. Forty-seven patients were included. All SGC patients (n = 22) started with 60 mg, while 52% of RCC patients started with 40 mg. GM C min at the start dose was 1456 μg/L (95% CI: 1185-1789) vs 682 μg/L (95% CI: 572-812) (P < .001) for SGC and RCC patients, respectively. When dose-normalised to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (C min 971 μg/L [95% CI: 790-1193] vs 669 μg/L [95% CI: 568-788]) (P = .005). Dose reductions due to toxicity were needed in 91% and 60% of SGC and RCC patients, respectively. Median BTD was between 20 to 30 mg for SGC and 40 mg for RCC patients. GM C min at BTD were comparable between the SGC and the RCC group, 694 μg/L (95% CI: 584-824) vs 583 μg/L (95% CI: 496-671) (P = .1). The observed cabozantinib exposure at BTD of approximately 600 μg/L is below the previously proposed target. Surprisingly, a comparable exposure at BTD was reached at different dosages of cabozantinib for SGC patients compared to RCC patients Further research is warranted to identify the optimal exposure and starting dose to balance efficacy and toxicity., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Aim: The aim of this study was to investigate the impact of 18 F-FDG-PET/CT on treatment decision making in metastatic gastrointestinal stromal tumor (GIST) patients., Methods: This study retrospectively evaluated 18 F-FDG-PET/CT scans to monitor response of metastatic GIST patients treated with palliative intent. Data from the Dutch GIST Registry was used. Early scans (<10 weeks after start of treatment) and late scans (>10 weeks after start of treatment) were scored on the impact in change of treatment., Results: Sixty-one PET/CT scans were performed for treatment evaluation in 39 patients with metastatic GIST of which 36 were early scans and 25 were late scans. Early PET/CT scans led to a change in management in 5.6% of patients and late PET/CT scans led to a change in management in 56% of patients. Change in management was more often seen after scans with lack of metabolic response (48% vs. 11% in scans with metabolic response, p=0.002). Neither metabolic response nor change in treatment were more often seen in patients with KIT mutations compared to patients with non- KIT mutations (metabolic response 65% KIT vs. 46% non- KIT , p=0.33, and change in management 28% KIT vs. 21% non- KIT , p=0.74)., Conclusion: 18 F-FDG-PET/CT is not recommended for early response evaluation in an unselected patient population with metastatic GIST, since it does not influence treatment decisions. 18 F-FDG-PET/CT, however, can be useful for late response assessment, especially in case of indeterminate CT results., Competing Interests: Hans Gelderblom received research funding to the institute from Novartis, Ipsen, Deciphera and Daiichi Sankyo. Neeltje Steeghs had an advisory role for Boehringer Ingelheim, Ellipses Pharma and AIMM Therapeutics and she received research funding to the institute from Astrazenica/MedImmune, Bayer, Bristol-Myers Squibb, Novartis, GlaxoSmithKline, Pfizer, Roche, Genentech/Roche, Boehringer Ingelheim, Blueprint Medicines, AB Science, Deciphera, Genentech, Merck Sharp & Dohme, Amgen, Merus, Lilly, Incyte, Pierre Fabre, Abbvie, Actuate Therapeutics, Sanofi, Cytovation, InteRNA, Array BioPharma, Cantargia AB, Taiho Pharmaceutical and Takeda., (Thieme. All rights reserved.)

Thoracic and breast sarcomas constitute a rare subgroup within the sarcoma population. There is limited knowledge about their health-related quality of life (HRQoL) and a valid disease-specific HRQoL instrument is lacking. This qualitative study aimed to investigate the HRQoL issues experienced by a small group of thoracic and breast sarcoma patients. Semi-structured interviews with 19 thoracic and four breast sarcoma patients were conducted and thematically analysed. Physical issues mentioned by both groups were fatigue, sleep disturbances, pain, wound infections, and symptoms related to chemotherapy and radiotherapy. Tightness in the back and restrictions in performing tasks above arm height were specific physical issues for breast sarcoma patients, whereas respiratory problems were only mentioned by thoracic sarcoma patients. Body image issues, changes in mood, fear of recurrence, and living with uncertainty were important mental health issues for both subgroups. Social issues in both groups included challenges in work and relationships, financial difficulties, loss of independence, and limitations in social activities. The identified physical, mental, and social health challenges can significantly impact thoracic and breast sarcoma patients' HRQoL. Results of this qualitative study will guide personalised supportive care for breast and thoracic sarcoma patients and help in determining the best possible HRQoL measurement strategy for sarcoma patients with different primary sarcoma locations.

Introduction: Palliative chemotherapy is the principal treatment of patients with advanced soft tissue sarcomas (STS); however prognosis is limited (median overall survival 12-19 months). In this setting, patient values and priorities are central to personalised treatment decisions., Patients and Methods: The prospective HOLISTIC study was conducted in the UK and the Netherlands assessing health-related quality of life in STS patients receiving palliative chemotherapy. Participants completed a questionnaire before starting chemotherapy, including attitudes towards quality of life (QoL) versus length of life (LoL), decisional control preferences, and decisional conflict. Chi-square and Fisher's exact tests were used to evaluate associations between patient characteristics and preferences., Results: One hundred and thirty-seven patients with advanced STS participated (UK: n = 72, the Netherlands: n = 65). Median age was 62 (27-79) years. Preference for extended LoL (n = 66, 48%) was slightly more common than preference for QoL (n = 56, 41%); 12 patients (9%) valued LoL and QoL equally (missing: n = 3). Younger patients (age <40 years) prioritised LoL, whereas two-thirds of older patients (aged ≥65 years) felt that QoL was equally or more important than LoL (P = 0.020). Decisional conflict was most common in patients who prioritised QoL (P = 0.024). Most patients preferred an active (n = 45, 33%) or collaborative (n = 59, 44%) role in treatment decisions. Gender, performance status, and country were significantly associated with preferred role. Concordance between preferred and actual role in chemotherapy decision was high (n = 104, 76%)., Conclusions: Heterogeneous priorities and preferences among advanced STS patients support personalised decisions about palliative treatment. Considering individual differences during treatment discussions may enhance communication and optimise patient-centred care., Competing Interests: Disclosure RLJ is the recipient of grants/research support from Merck Sharp & Dohme, GlaxoSmithKline. RLJ is the recipient of consultation fees from Adaptimmune, Athenex, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immune Design, Lilly, Merck, Pharmamar, UptoDate. WvdG has received research grants from Novartis, has been on advisory board from Bayer and is consultant for SpringWorks. The other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Angiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition. We, therefore, investigated the presence of biomarkers PARP1 (poly(ADP-ribose)polymerase-1) and Schlafen-11 (SLFN11) in UV AS. Based on experiences in other sarcomas, we examined (combination) treatment of PARP inhibitor (PARPi) olaparib and temozolomide (TMZ) in UV AS cell lines., Methods: Previously collected UV AS (n = 47) and non-UV AS (n = 96) patient samples and two UV AS cell lines (MO-LAS and AS-M) were immunohistochemically assessed for PARP1 and SLFN11 expression. Both cell lines were treated with single agents PARPi olaparib and TMZ, and the combination treatment. Next, cell viability and treatment synergy were analyzed. In addition, effects on apoptosis and DNA damage were examined., Results: In 46/47 UV AS samples (98%), PARP1 expression was present. SLFN11 was expressed in 80% (37/46) of cases. Olaparib and TMZ combination treatment was synergistic in both cell lines, with significantly increased apoptosis compared to single agent treatment. Furthermore, a significant increase in DNA damage marker γH2AX was present in both cell lines after combination therapy., Conclusion: We showed combination treatment of olaparib with TMZ was synergistic in UV AS cell lines. Expression of PARP1 and SLFN11 was present in the majority of UV AS tumor samples. Together, these results suggest combination treatment of olaparib and TMZ is a potential novel AS subtype-specific treatment option for UV AS patients., (© 2021. The Author(s).)

Background: Oesophageal gastrointestinal stromal tumours (GISTs) account for ≤1% of all GISTs. Consequently, evidence to guide clinical decision-making is limited., Methods: Clinicopathological features and outcomes in patients with primary oesophageal GIST from seven European countries were collected retrospectively., Results: Eighty-three patients were identified, and median follow up was 55.0 months. At diagnosis, 59.0% had localized disease, 25.3% locally advanced and 13.3% synchronous metastasis. A biopsy (Fine Needle aspiration n = 29, histological biopsy n = 31) was performed in 60 (72.3%) patients. The mitotic count was low (<5 mitoses/50 High Power Fields (HPF)) in 24 patients and high (≥5 mitoses/50 HPF) in 27 patients. Fifty-one (61.4%) patients underwent surgical or endoscopic resection. The most common reasons to not perform an immediate resection (n = 31) were; unresectable or metastasized GIST, performance status/comorbidity, patient refusal or ongoing neo-adjuvant therapy. The type of resections were enucleation (n = 11), segmental resection (n = 6) and oesophagectomy with gastric conduit reconstruction (n = 33), with median tumour size of 3.3 cm, 4.5 cm and 7.7 cm, respectively. In patients treated with enucleation 18.2% developed recurrent disease. The recurrence rate in patients treated with segmental resection was 16.7% and in patients undergoing oesophagectomy with gastric conduit reconstruction 36.4%. Larger tumours (≥4.0 cm) and high (>5/5hpf) mitotic count were associated with worse disease free survival., Conclusion: Based on the current study, enucleation can be recommended for oesophageal GIST smaller than 4 cm, while oesophagectomy should be preserved for larger tumours. Patients with larger tumours (>4 cm) and/or high mitotic count should be treated with adjuvant therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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 (C min ) 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) C min 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 C min 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 C min 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., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Aim: Sunitinib is an oral tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumor (GIST). Because of the large interpatient pharmacokinetic variability and established exposure-response and exposure-toxicity relationships in clinical trial patients, therapeutic drug monitoring (TDM) seems promising for optimizing sunitinib exposure. We aimed to investigate the relationship between sunitinib exposure and treatment outcome in a real-world patient cohort., Methods: We performed a retrospective observational cohort study in 53 patients with metastatic RCC and 18 patients with metastatic GIST treated with sunitinib and receiving TDM-guided dosing. Time on treatment - as a surrogate for progression-free survival - in patients who achieved adequate sunitinib exposure was compared with patients who did not. Additionaly, the median sunitinib exposure was compared in patients with or without sunitinib-induced toxicity leading to dose reduction., Results: The median time on treatment in patients with RCC who achieved adequate sunitinib exposure (n = 39) was 32 weeks, compared to 15 weeks in patients who did not achieve adequate sunitinib exposure (n = 12) (P = 0.244). In 29 patients (41%) with toxicity leading to dose reduction, sunitinib sum plasma trough concentration (C trough ) until dose reduction was significantly higher compared to patients without toxicity leading to dose reduction (median 60 ng/mL vs 44 ng/mL; P < 0.001) and reduced to comparable levels after dose reduction (44 ng/mL; P = 0.488)., Conclusion: In our real-world patient cohort, patients with sunitinib-induced toxicity requiring dose reduction had significantly higher sunitinib exposure compared to patients without toxicity. The threshold for toxicity, however, was lower compared to that previously described in clinical trials., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Sarcomas comprise 1% of adult tumors and are very heterogeneous. Long-lasting and cumulative treatment side-effects detract from the (progression-free) survival benefit of treatment. Therefore, it is important to assess treatment effectiveness in terms of patient-reported outcomes (PROs), including health-related quality of life (HRQoL) as well. However, questionnaires capturing the unique issues of sarcoma patients are currently lacking. Given the heterogeneity of the disease, the development of such an instrument may be challenging. The study aims to (1) develop an exhaustive list of all HRQoL issues relevant to sarcoma patients and determine content validity; (2) determine a strategy for HRQoL measurement in sarcoma patients. We will conduct an international, multicenter, mixed-methods study (registered at clinicaltrials.gov: NCT04071704) among bone or soft tissue sarcoma patients ≥18 years, using EORTC Quality of Life Group questionnaire development guidelines. First, an exhaustive list of HRQoL issues will be generated, derived from literature and patient ( n = 154) and healthcare professional (HCP) interviews ( n = 30). Subsequently, another group of sarcoma patients ( n = 475) and HCPs ( n = 30) will be asked to rate and prioritize the issues. Responses will be analyzed by priority, prevalence and range of responses for each item. The outcome will be a framework for tailored HRQoL measurement in sarcoma patients, taking into account sociodemographic and clinical variables.

Background: Patients diagnosed with sarcoma are hypothesized to experience a prolonged route to a cancer diagnosis. This route, the total interval, can be divided into a patient interval (the time from the appearance of symptoms to physician consultation) and diagnostic interval (time from the first consultation to diagnosis). In the current study, the authors investigated these intervals among survivors of sarcoma and identified factors associated with prolonged intervals., Methods: A cross-sectional study was conducted among adult patients with sarcoma 2 to 10 years after diagnosis. Patients completed a questionnaire regarding their total interval, which was linked to clinical data from the Netherlands Cancer Registry. Descriptive statistics were used to describe intervals. Based on Dutch clinical guidelines, a diagnostic interval ≥1 month was considered to be prolonged and an interval ≥3 months was considered as very long. Multivariable regression analyses investigated associations between patient and tumor characteristics and interval length., Results: A total of 1099 participants were included (response rate, 58%); approximately 60% reported a patient interval ≥1 month and 36% reported a patient interval ≥3 months. Risk factors for a very long patient interval were sarcoma of the skin or pelvis, liposarcoma, or rhabdomyosarcoma. Stage III disease was associated with a shorter patient interval. The diagnostic interval length was ≥1 month in 55% of patients and ≥3 months in 28% of patients. Risk factors for a very long diagnostic interval were female sex, age <70 years, or having a synovial sarcoma or chordoma., Conclusions: The patient and diagnostic interval lengths were prolonged in a substantial percentage of this sarcoma survivorship population. Factors found to be associated with the length of the patient interval or the diagnostic interval differed. Creating awareness among (especially young) patients to consult a physician and awareness among physicians to consider a sarcoma diagnosis will contribute to optimization of the total interval., (© 2020 American Cancer Society.)

Introduction: 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., Methods: 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., Results: 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., Conclusion: The RtD of sarcoma patients is complex. Increasing awareness of patients and healthcare providers may contribute to shorten the RtD., Competing Interests: The authors have declared that no competing interests exist.

Sarcoma patients experience physical and psychological symptoms, depending on age of onset, subtype, treatment, stage, and location of the sarcoma, which can adversely affect patients' health-related quality of life (HRQoL). This study aimed to unravel the heterogeneity of sarcoma survivors' HRQoL regarding primary sarcoma location. A cross-sectional study was conducted among Dutch sarcoma survivors ( N = 1099) aged ≥18, diagnosed 2-10 years ago. Primary sarcoma locations were head and neck, chest, abdominal including retroperitoneal, pelvis including urogenital organs, axial skeleton, extremities (upper and lower), breast, skin and other locations. The European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC QLQ)-C30 was used to measure HRQoL accompanied by treatment-specific HRQoL questions. Sociodemographic and clinical characteristics were collected from the Netherlands Cancer Registry. Axial skeleton sarcomas had the lowest functioning levels and highest symptoms compared to other locations. Skin sarcomas had the highest functioning levels and lowest symptoms on most scales. Bone sarcomas scored worse on several HRQoL domains compared to soft tissue sarcomas. High prevalence of treatment-specific HRQoL issues were found per location. In conclusion, sarcomas can present everywhere, which is reflected by different HRQoL outcomes according to primary sarcoma location. The currently used HRQoL measure lacks treatment-specific questions and is too generic to capture all sarcoma-related issues, emphasizing the necessity for a comprehensive sarcoma-specific HRQoL measurement strategy.

Patients with sarcoma experience many physical and psychological symptoms, adversely affecting their health-related quality of life (HRQoL). HRQoL assessment is challenging due to the diversity of the disease. This review aims to unravel the heterogeneity of HRQoL of patients with sarcoma with regard to tumour location and to summarise the used measures in research. English-language literature from four databases published between January 2000 and April 2019 was reviewed. Studies that described adult sarcoma HRQoL outcomes were included and classified according to primary sarcoma location. Eighty-seven articles met the inclusion criteria covering sarcoma of the extremities (n=35), pelvis and axial skeleton (n=9), pelvis and extremities (n=5), head and neck (n=4), retroperitoneum (n=2) and multiple sarcoma locations (n=33), respectively. Urogenital and thoracic sarcoma were lacking. Fifty-four different questionnaires were used, most often cancer-generic or generic HRQoL questionnaires. Patients with sarcoma reported lower HRQoL than the general population. Distinctive patterns of HRQoL outcomes according to tumour location regarding symptoms, physical functioning, disability and psychosocial well-being were identified. In metastatic sarcoma, mostly constitutional symptoms were present. To comprehensively assess HRQoL, a sarcoma-specific measurement strategy should be developed and used covering the heterogeneity of sarcoma including location-specific issues to improve personalised HRQoL assessment in future research and clinical practice., Competing Interests: Competing interests: None declared., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Purpose: Epithelioid hemangioendothelioma (EHE) is an ultra-rare vascular sarcoma with unique clinical features. EHE is characterized by an unpredictable, often protracted, clinical course and highly variable clinical presentation. Due to difficulty recruiting ultra-rare cancer patients, health-related quality of life (HRQoL) of EHE patients has not yet been studied. The aim of this study was to assess EHE symptom burden and its impact on HRQoL and psychological distress. Methods: The study was initiated after EHE patients' foundations approached our research group to study HRQoL. Patients were recruited from the international EHE Facebook group from May through October 2018. Data were collected using the online PROFILES registry. Latent class cluster analysis was performed to identify groups based on frequently reported symptoms. Differences in HRQoL (EORTC-QLQ-C30) and psychological distress (Hospital Anxiety and Depression Scale) between symptom-based clusters were examined. Results: Among 115 EHE patients from 20 countries, three clusters were identified, with low-, intermediate- and high-symptom burden, respectively. Highly symptomatic patients (33%) had clinically relevantly lower scores on HRQoL compared to the other two groups ( p  < 0.001). These patients suffered mostly from pain, insomnia and fatigue. Symptom burden significantly correlated with reduced daily functioning and high levels of psychological distress. Only for highly symptomatic patients, HRQoL and symptom levels were worse compared to healthy individuals. Conclusion: For the first time, we studied HRQoL in a large international cohort of ultra-rare cancer patients with distinct clinical characteristics, enabled by collaboration with patients and use of social media. We showed a considerable number of EHE patients were highly symptomatic, with a significant impact on HRQoL and psychological distress.

Background: Sarcoma patients often experience a long time to diagnosis, known as the total interval. This interval can be divided into the patient (time from symptoms to doctor consultation) and diagnostic intervals (time from first consultation to diagnosis). In other cancers, a long total interval has been associated with worse outcomes, but its effect on health-related quality of life (HRQoL) has never been investigated among sarcoma patients. This study investigates the association between (1) the actual time to diagnosis and HRQoL; (2) the perceived impact of the diagnostic interval length and HRQoL; (3) the actual length and perceived impact of the length and the HRQoL of sarcoma survivors., Methods: A cross-sectional study was performed among sarcoma patients aged ≥18, diagnosed 2-10 years ago in the Netherlands. The participants completed a questionnaire on HRQoL, the time to diagnosis, the perceived impact of the diagnostic interval on HRQoL, and coping., Results: 1099 participants were included (response rate, 58%). The mean time since diagnosis was 67.4 months. More than half reported a patient (60%) or diagnostic interval (55%) ≥1 month. A third (31%) perceived a negative impact of the diagnostic interval length on HRQoL. Patient or diagnostic interval length was not associated with HRQoL. By contrast, participants perceiving a negative impact (32%) had lower HRQoL scores than those perceiving a positive (11%) or no impact (58%) ( p = 0.000). This association remained significant in a multivariable model, in which maladaptive coping strategies and tumour characteristics were also found to be associated with HRQoL. Participants perceiving a negative impact of the length of the diagnostic interval related this to high psychological distress levels, more physical disabilities, and worse prognosis., Conclusion: The perceived impact of the diagnostic interval length was associated with the HRQoL of sarcoma survivors, whereas the actual length was not associated with HRQoL. Maladaptive coping strategies were independently associated with HRQoL. This offers opportunities for early intervention to improve HRQoL.

Purpose: Desmoplastic small round cell tumors (DSRCTs) are highly malignant and very rare soft tissue sarcomas with a high unmet need for new therapeutic options. Therefore, we examined poly(ADP-ribose) polymerase 1 (PARP1) and Schlafen-11 (SLFN11) expression in DSRCT tumor tissue and the combination of PARP inhibitor olaparib with the alkylating agent temozolomide (TMZ) in a preclinical DSRCT model., Methods: PARP1 and SLFN11 have been described as predictive biomarkers for response to PARP inhibition. Expression of PARP1 and SLFN11 was assessed in 16 and 12 DSRCT tumor tissue samples, respectively. Effects of single-agent olaparib, and olaparib and TMZ combination treatment were examined using the preclinical JN-DSRCT-1 model. In vitro, single-agent and combination treatment effects on cell viability, the cell cycle, DNA damage and apoptosis were examined. Olaparib and TMZ combination treatment was also assessed in vivo., Results: PARP1 and SLFN11 expression was observed in 100% and 92% of DSRCT tumor tissues, respectively. Olaparib treatment reduced cell viability and cell migration in a dose-dependent manner in vitro. Drug synergy between olaparib and TMZ was observed in vitro and in vivo. Combination treatment led to a cell-cycle arrest and induction of DNA damage and apoptosis, even when combined at low dosages., Conclusion: We show high PARP1 and SLFN11 expression in DSRCT tumor material and antitumor effects following olaparib and TMZ combination treatment in a preclinical DSRCT model. This suggests that olaparib and TMZ combination treatment could be a potential treatment option for DSRCTs.

Introduction: Chemotherapy is the mainstay of treatment for patients with advanced soft tissue sarcomas (STS). Treatment intent is usually palliative, aiming to improve symptoms, stabilise or reduce tumour burden and extend life. Clinical trials have traditionally used radiological response, time to progression and survival as measures of treatment efficacy. Health-related quality of life (HRQoL) is at least equally important or more important than survival for many patients with advanced cancer. Systematically collecting HRQoL data during chemotherapy can provide greater insight into treatment efficacy from the patient perspective.The primary aims of this study are to evaluate HRQoL in patients with advanced STS treated with chemotherapy over time, explore the decision-making process and patient reflection post-treatment., Methods and Analysis: This is an observational, international cohort study for 132 patients aged ≥18 years with advanced STS treated at eight centres (three in the UK, five in the Netherlands). Patients will be recruited prior to starting first-line or third-line chemotherapy and invited to complete questionnaires using the Patient-Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship registry (PROFILES); an established international registry for collection of cancer patient-reported outcomes. Online (or paper) questionnaires will be completed at baseline, each cycle of chemotherapy and 2-3 monthly during follow-up. The questionnaire package includes the Decisional Conflict Scale, Control Preferences Scale, Quality-Quantity Questionnaire, treatment expectations, European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30), EORTC financial toxicity items, Work Ability Index, Functional Assessment of Cancer Therapy-General (FACT-G) items and Decisional Regret Scale. Clinical data will be extracted from patient records and linked with questionnaire responses. The primary outcome measure is the change in global HRQoL from baseline to after cycle 4 of first-line chemotherapy (based on published data showing that patients with advanced STS complete a median number of four cycles of first-line chemotherapy)., Ethics and Dissemination: Heath Research Authority and Research Ethics Committee (REC 17/NI/0197). Results from the Health-related quality Of Life In patients with advanced Soft TIssue sarcomas treated with Chemotherapy (HOLISTIC) study will be published in peer-reviewed journals and disseminated at local, national and international conferences. We will also present our findings at any appropriate patient meetings and involve patients in study-related publications., Trial Registration Number: NCT03621332., Competing Interests: Competing interests: RLJ is a consultant for: Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar. WTAvDG has received research grants from Novartis and has been on advisory board from Bayer. The other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Gastrointestinal stromal tumour (GIST) is a disease of older adults and is dominated by KIT / PDGFR mutations. In children, GIST is rare, predominantly occurs in girls, has a stomach location and generally lacks KIT / PDGFR mutations. For young adults (YA), aged 18 to 40 years, the typical phenotypic and genotypic patterns are unknown. We therefore aimed to describe the clinical, pathological and molecular characteristics of GIST in in YA. YA GIST patients registered in the Dutch GIST Registry (DGR) were included, and data were compared to those of older adults (OA). From 1010 patients in the DGR, 52 patients were YA (54% male). Main tumour locations were stomach (46%) and small intestine (46%). GIST genetic profiles were mutations in KIT (69%), PDGFRA (6%), SDH deficient (8%), NF1 associated (4%), ETV6-NTRK3 gene fusion (2%) or wildtype (10%). Statistically significant differences were found between the OA and YA patients (localisation, syndromic and mutational status). YA presented more often than OA in an emergency setting (18% vs. 9%). The overall five-year survival rate was 85%. In conclusion, YA GISTs are not similar to typical adult GISTs and also differ from paediatric GISTs, as described in the literature. In this series, we found a relatively high percentage of small intestine GIST, emergency presentation, 25% non- KIT/PDGFRA mutations and a relatively good survival.

Myxofibrosarcoma(MFS) is the most common soft tissue sarcoma(STS) in elderly patients. Surgical resection remains the main treatment modality but tumor borders can be difficult to delineate with conventional clinical methods. Incomplete resections are a common problem and local recurrence remains a clinical issue. A technique that has shown great potential in improving surgical treatment of solid tumors is tumor targeted imaging and image-guided surgery with near-infrared fluorescence. To facilitate this technique, it is essential to identify a biomarker that is highly and homogenously expressed on tumor cells, while being absent on healthy non-malignant tissue. The purpose of this study was to identify suitable molecular targets for tumor-targeted imaging of myxofibrosarcoma. Ten potential molecular targets for tumor targeted imaging were investigated with immunohistochemical analysis in myxofibrosarcoma tissue (n = 34). Results were quantified according to the immunoreactive score(IRS). Moderate expression rates were found for uPAR, PDGFRa and EMA/MUC1. High expression rates of VEGF and TEM1 were seen. Strong expression was most common for TEM1 (88.2%). These results confirms that TEM1 is a suitable target for tumor-targeted imaging of myxofibrosarcoma. Keywords Image-guided surgery; Immunohistochemistry; Molecular imaging; Myxofibrosarcoma; Soft tissue sarcoma; Tumor endothelial marker 1(TEM1), Vascular endothelial growth factor (VEGF).

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., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: DNA methylation profiling has previously uncovered biologically and clinically meaningful subgroups within many tumor types, but was not yet performed in angiosarcoma. Angiosarcoma is a rare sarcoma with very heterogeneous clinical presentations, which may be based on differences in biological background. In this exploratory study, DNA methylation profiling of 36 primary angiosarcoma samples from visceral, deep soft tissue, radiation-induced, and UV-induced localizations was performed., Experimental Design: Primary angiosarcoma formalin-fixed paraffin-embedded samples from visceral, soft tissue, radiation-induced, and UV-induced origin were collected from a nationwide search for angiosarcoma in the Netherlands. DNA was extracted for methylation profiling with the Illumina Infinium MethylationEPIC array. Quality control assessment and unsupervised hierarchical clustering were performed. Copy-number profiles were generated and analyzed for chromosomal stability. Clinical data were obtained from the Netherlands Cancer Registry., Results: DNA methylation profiling by unsupervised hierarchical clustering of 36 angiosarcoma samples (6 visceral, 5 soft tissue, 14 radiation-induced, 11 UV-induced) revealed two main clusters (A and B), which were divided into four subclusters. The clusters largely corresponded with clinical subtypes, showing enrichment of UV-induced cases in cluster A1 and radiation-induced cases in cluster A2. Visceral and soft tissue cases almost exclusively fell into cluster B. Cluster A showed significantly increased chromosomal instability and better overall survival (22 vs. 6 months, P = 0.046) compared with cluster B., Conclusions: In this novel methylation profiling study, we demonstrated for the first time four different angiosarcoma clusters. These clusters correlated with clinical subtype, overall survival, and chromosomal stability., (©2019 American Association for Cancer Research.)

Angiosarcoma (AS) is a rare sarcoma of endothelial origin, arising spontaneously (primary AS) or after external damage such as radiation therapy or UV exposure (secondary AS). To date, reliable assessment of prognostic factors has proven difficult, due to disease rarity and heterogeneity of study cohorts. Although large registries provide relatively large AS patient series, these cases often lack histological confirmation. This study aimed to analyze AS prognostic factors in a large nationwide cohort of histologically confirmed cases, established through linkage of clinical data from the Netherlands Cancer Registry and pathology data from the Dutch pathology registry (PALGA). All cases were reviewed by an expert pathologist, showing a 16% discordance rate. Multivariable Cox regression survival analysis among 479 confirmed AS patients revealed remarkably poorer overall survival (OS) for primary AS compared to secondary AS (7 vs 21 months, Hazard ratio (HR) = 1.5; 95% confidence interval (CI) = 1.2-1.9). Age above 65 years, male gender, and no surgical treatment also significantly correlated to worse OS. Overall, OS was relatively poor, with a median of 13 months (95% CI = 10-16 months) and 22% five-year survival rate. With this study, we illustrate AS heterogeneity in clinical behavior and show for the first time better survival for secondary AS compared to primary AS.

Introduction: Sunitinib is a standard second-line treatment in advanced gastrointestinal stromal tumours (GIST). We aimed to search for predictive factors for grade 3 and 4 toxicity, progression-free survival (PFS) and overall survival (OS) in a GIST reference center patient population, outside clinical trials. Methods: A retrospective analysis was performed of patients treated in two European Comprehensive Cancer Centers between January 2005 and December 2015. Demographic and clinical features, tumour characteristics and biological parameters were investigated. Logistic regression models were used to find factors associated with grade 3 and 4 toxicity. To identify predictive factors for PFS and OS, variables that were statistically significant in univariate analysis were used in the multivariate Cox proportional hazards model. Results: Ninety-one patients were included in this analysis. Age >60 years (HR 5.0, p  = .006) and body weight ≤70 kg (HR 4.7, p  = .009) were predictive factors for grade 3 and 4 toxicity. When divided into two categories, non-haematological grade 3 and 4 toxicity was predicted by age >60 years (HR 3.8, p  = .012) and body weight ≤70 kg (HR 3.3, p  = .025) whereas haematological toxicity had no significantly associated predictive factors. The median PFS and OS with sunitinib were 8.8 months and 27.5 months, respectively. The use of imatinib less than six months compared to 6-12 months (HR 0.2, p  = .013) and to >12 months (HR 0.3, p  = .016) and liver and/or peritoneal metastases (HR 0.1, p  < .001, HR 0.2, p  = .003 and HR 0.2, p  = .004) compared to locally advanced disease only were predictive for longer PFS. High neutrophil (HR 3.1, p  = 0.04) and platelet count (HR 2.4, p  = .046) predicted a shorter OS. Flexible sunitinib dosing was associated with superior OS ( p  = .021). Conclusion: In advanced GIST patients treated with sunitinib, older and low-weight patients are at risk for grade 3 and 4 toxicity. Clinical (prior imatinib use and metastases), biological (neutrophil and platelet count) and treatment characteristics independently predict PFS and OS.

Introduction: For optimal oncological care, it is recommended to discuss every patient with cancer in a multidisciplinary team meeting (MDTM). This is a time consuming and expensive practice, leading to a growing demand to change the current workflow. We aimed to investigate the number of patients discussed in MDTMs and to identify characteristics associated with not being discussed., Methods: Data of patients with a newly diagnosed solid malignant tumour in 2015 and 2016 were analysed through the nationwide population-based Netherlands Cancer Registry (NCR). We clustered tumour types in groups that were frequently discussed within a tumour-specific MDTM. Tumour types without information about MDTMs in the NCR were excluded. Multivariable logistic regression analyses were used to analyse factors associated with not being discussed., Results: Out of 105.305 patients with cancer, 91% were discussed in a MDTM, varying from 74% to 99% between the different tumour groups. Significantly less frequently discussed were patients aged ≥75 years (odds ratio [OR] = 0.7, 95% confidence interval [CI] = 0.6-0.7), patients diagnosed with disease stage I (OR = 0.5, 95% CI = 0.5-0.6), IV (OR = 0.4, 95% CI = 0.4-0.4) or unknown (OR = 0.2, 95% CI = 0.2-0.2) and patients who received no treatment (OR = 0.3, 95% CI = 0.3-0.3). Patients who received a multidisciplinary treatment were more likely to be discussed in contrary to a monodisciplinary treatment (OR = 4.6, 95% CI = 4.2-5.1)., Conclusion: In general, most patients with cancer were actually discussed in a MDTM, although differences were observed between tumour groups. Factors associated with not being discussed may, at least partially, reflect the absence of a multidisciplinary question. These results form a starting point for debate on a more durable and efficient new MDTM strategy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes., Methods: In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (Cmin) will be calculated. In cases where Cmin falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase., Discussion: Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs.

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., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The prevalence of cancer is rising, on the one hand because of increasing cancer incidence as a consequence of lifestyle changes, aging and screening and on the other hand because of increasing survival rates thanks to increasingly successful therapeutic possibilities. Since virtually all caregivers are confronted with cancer patients or survivors, a basic knowledge of oncology is required. In this article we present a brief update on the current situation in the field of oncology. We pay attention to diagnostics, treatment and palliative care for patients with cancer.

Angiosarcomas are rare malignant tumors with a heterogeneous clinical presentation and generally poor prognosis. It has been difficult to establish consistent molecular characteristics and driver events in angiosarcoma development. Oncogenic and angiogenesis-related pathways have been investigated pre-clinically and clinically with varying results. A few promising responses to checkpoint inhibitors have been described, but immunological features require further elucidation. With this review we present an overview of the critical biological pathways and processes affected in angiosarcoma, and their potential role in novel, non-cytotoxic, systemic treatments., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: A cohort of 201 patients with small bowel gastrointestinal stromal tumors (GIST) treated between January 1st, 2009 and December 31st, 2016 in five GIST expertise centers in the Netherlands was analyzed. Goal of this study was to describe the clinical, surgical and pathological characteristics of this rare subpopulation of GIST patients, registered in the Dutch GIST registry., Methods: Clinical outcomes and risk factors of patients with small bowel GIST who underwent surgery or treated with systemic therapy were analyzed. A classification was made based on disease status at diagnosis (localized vs. metastasized)., Results: 201 patients with small bowel GIST were registered of which 138 patients (69%) were diagnosed with localized disease and 63 patients (31%) with metastatic disease. Approximately 19% of the patients had emergency surgery, and in 22% GIST was an accidental finding. In patients with high risk localized disease, recurrence occurred less often in patients who received adjuvant treatment (4/32) compared to patients who did not (20/31, p < 0.01). Disease progression during palliative imatinib treatment occurred in 23 patients (28%) after a median of 20.7 (range 1.8-47.1) months. Ongoing response was established in 52/82 patients on first line palliative treatment with imatinib after a median treatment time of 30.6 (range 2.5-155.3) months., Conclusion: Patients with small-bowel GIST more frequently present with metastatic disease when compared to patients with gastric GIST in literature. We advocate for Prospective registration of these patients and investigate the use of surgery in patients with limited metastatic disease., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background/aim: Pazopanib is approved for advanced soft tissue sarcoma (STS) patients. The aim of the study was to examine the usefulness of ( 18 F)-Fluorodeoxyglucose-positron emission tomography/ computed tomography (FDG-PET/CT) imaging for early evaluation of the response of STS patients to pazopanib, as well as the association between pazopanib pharmacokinetics and early metabolic response., Patients and Methods: Twenty STS patients underwent FDG-PET scans at baseline, two- and eight-weeks following treatment with pazopanib. The FDG-PET scans were evaluated by quantitative PERCIST analysis and visually by an independent nuclear medicine physician and related to RECIST1.1 outcome at eight weeks., Results: After eight weeks of therapy, 14 out of 20 patients had discontinued pazopanib due to tumor progression identified radiologically ('non-responders' n=12) or toxicity (n=2). Quantitative FDG-PET scoring at two weeks, according to PERCIST guidelines, identified 25% (3 of 12) of the patients radiologically as non-responders versus 42% (5 of 12) identified by visual response analysis., Conclusion: In this heterogeneous STS patients' cohort, early FDG-PET/CT identified a substantial part of pazopanib non-responders., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease progression or unacceptable toxicity. Dose was escalated from 20 mg once daily to 500 mg twice daily (BID). Dose-limiting toxicities, recommended phase 2 dose (RP2D), food effect, objective response rate, and biomarkers predicting response were determined. Results Ninety-three patients were treated with ABT-767; 80 had a primary diagnosis of ovarian cancer. ABT-767 demonstrated dose-proportional PK up to 500 mg BID and half-life of ~2 h. Food had no effect on ABT-767 bioavailability. Most common grade 3/4 treatment-related adverse events were nausea, fatigue, decreased appetite, and anemia. Anemia showed dose-dependent increase. RP2D was 400 mg BID. Objective response rate by RECIST 1.1 was 21% (17/80) in all evaluable patients and 20% (14/71) in evaluable patients with ovarian cancer. Response rate by RECIST 1.1 and/or CA-125 was 30% (24/80) in patients with ovarian cancer. Mutations in BRCA1 or BRCA2, homologous recombination deficiency (HRD), and platinum sensitivity were associated with tumor response. Median progression-free survival was longer for HRD positive (6.7 months) versus HRD negative patients (1.8 months) with ovarian cancer. Conclusions ABT-767 had an acceptable safety profile up to the established RP2D of 400 mg BID and dose-proportional PK. Patients with BRCA1 or BRCA2 mutation, HRD positivity, and platinum sensitivity were more sensitive to ABT-767.

Importance: Epithelioid sarcoma (ES) is an exceedingly rare malignant neoplasm with distinctive pathologic, molecular, and clinical features as well as the potential to respond to new targeted drugs. Little is known on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in this disease., Objective: To report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with advanced ES., Design, Setting, and Participants: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis of patients with locally advanced/metastatic ES diagnosed between 1990 and 2016. Local pathological review was performed in all cases to confirm diagnosis according to most recent criteria., Exposures: All patients included in the study received anthracycline-based regimens, gemcitabine-based regimens, or pazopanib., Main Outcome and Measures: Response was assessed by RECIST. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method. Classic and proximal subtypes were defined based on morphology (according to 2013 World Health Organization guidelines)., Results: Overall, 115 patients were included, 80 (70%) were men and 35 (30%) were women, with a median age of 32 years (range, 15-77 years). Of the 115 patients with ES, 85 were treated with anthracycline-based regimens, 41 with gemcitabine-based regimens, and 18 with pazopanib. Twenty-four received more than 1 treatment. Median follow-up was 34 months. Response rate for anthracycline-based regimens was 22%, with a median PFS of 6 months. One complete response (CR) was reported. A trend toward a higher response rate was noticed in morphological proximal type (26%) vs classic type (19%) and in proximal vs distal primary site (26% vs 18%). The response rate for gemcitabine-based regimens was 27%, with 2 CR and a median PFS of 4 months. In this group, a trend toward a higher response rate was reported in classic vs proximal morphological type (30% vs 22%) and in distal vs proximal primary site (40% vs 14%). In the pazopanib group, no objective responses were seen, and median PFS was 3 months., Conclusions and Relevance: This is the largest retrospective series of systemic therapy in ES. We confirm a moderate activity of anthracycline-based and gemcitabine-based regimens in ES, with a similar response rate and PFS in both groups. The value of pazopanib was low. These data may serve as a benchmark for trials of novel agents in ES.

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., (© 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

In the current guidelines to prevent hemotherapyinduced nausea and vomiting, multiple antiemetic drugs are administered simultaneously. In patients who receive highly emetogenic chemotherapy, aprepitant, an NK1-receptor antagonist, is combined with ondansetron and dexamethasone. Aprepitant can influence the pharmacokinetics of other drugs, as it is an inhibitor and inducer of CYP3A4. Some anticancer drugs and other co-medication frequently used in cancer patients are CYP3A4 or CYP29C substrates. We give an overview of the metabolism and current data on clinically relevant drug-drug interactions with aprepitant during chemotherapy. Physicians should be aware of the potential risk of drug-drug interactions with aprepitant, especially in regimens with curative intent. More research should be performed on drug-drug interactions with aprepitant and their clinical consequences to make evidence-based recommendations.

Opinion Statement: Synovial sarcoma (SS) is a rare, yet highly malignant, type of soft tissue sarcoma (STS), for which survival has not improved significantly during the past years. In this review, we focus on systemic treatment in adults. Compared to other STS, SS are relatively chemosensitive. Ifosfamide and ifosfamide combinations are active in different lines of treatment. In high-risk extremity and chest wall STS, neoadjuvant doxorubicin and ifosfamide has shown as much activity as high-dose ifosfamide. There are indications that combination chemotherapy with doxorubicin and ifosfamide in this setting improves outcome. In the first-line metastatic setting, combination treatment with doxorubicin and ifosfamide is a preferred option in fit patients, while in other patients, sequential doxorubicin and ifosfamide can be considered. In second and later lines, pazopanib and trabectedin have shown activity. Many new approaches to treat metastatic SS are currently under investigation, both preclinical as well as clinical, including other receptor tyrosine kinase inhibitors, epigenetic modulators, compounds interfering with DNA damage response (DDR), and immunotherapy.

Background: Gastrointestinal stromal tumors (GISTs) are characterized by oncogenic KIT mutations that cluster in two exon 11 hotspots. The aim of this study was to develop a single, sensitive, quantitative digital droplet PCR (ddPCR) assay for the detection of common exon 11 mutations in both GIST tumor tissue and in circulating tumor DNA (ctDNA) isolated from GIST patients' plasma., Methods: A ddPCR assay was designed using two probes that cover both hotspots. Available archival FFPE tumor tissue from 27 consecutive patients with known KIT exon 11 mutations and 9 randomly selected patients without exon 11 mutations were tested. Plasma samples were prospectively collected in a multicenter bio-databank from December 2014. ctDNA was analyzed of 22 patients with an exon 11 mutation and a baseline plasma sample., Results: The ddPCR assay detected the exon 11 mutation in 21 of 22 tumors with exon 11 mutations covered by the assay. Mutations in ctDNA were detected at baseline in 13 of 14 metastasized patients, but in only 1 of 8 patients with localized disease. In serial plasma samples from 11 patients with metastasized GIST, a decrease in mutant droplets was detected during treatment. According to RECIST 1.1, 10 patients had radiological treatment response and one patient stable disease., Conclusion: A single ddPCR assay for the detection of multiple exon 11 mutations in ctDNA is a feasible, promising tool for monitoring treatment response in patients with metastasized GIST and should be further evaluated in a larger cohort., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Uterine sarcomas (US) are rare mesenchymal tumours of the uterus and are divided mainly into uterine leiomyosarcoma (uLMS), low grade endometrial stromal sarcoma (LG-ESS), high grade endometrial stromal sarcoma (HG-ESS), adenosarcomas and high grade undifferentiated sarcoma (HGUS). US are often high-grade tumours with a high local recurrence rate and metastatic risk. We here discuss the current standard of care and knowledge of systemic therapy for adult uterine sarcomas, in particular uLMS, LG-ESS, HG-ESS and HGUS, in both the adjuvant as well as the metastatic setting., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Aim: Fixed dose oral tyrosine kinase inhibitors imatinib, sunitinib and pazopanib show a high interpatient variability in plasma exposure. A relationship between plasma exposure and treatment outcome has been established, which supports the rationale for dose optimization of these drugs. The aim of this study was to monitor how many patients reached adequate trough levels after therapeutic drug monitoring-based dose optimization in daily practice., Methods: A cohort study was performed in patients treated with imatinib, sunitinib or pazopanib of whom follow-up drug levels were measured between August 2012 and April 2016. Patients' characteristics were collected by reviewing electronic patient records. Drug levels were measured using high-performance liquid chromatography coupled with tandem mass spectrometry and trough levels were estimated using a predefined algorithm. Dose interventions were proposed based on trough levels., Results: In total, 396 trough levels were determined in 109 patients. Median sample frequency per patient was 3. During the first measurement only 38% of patients showed trough levels within the predefined target ranges despite standard dosing; 52% of the patients showed drug levels below and 10% above the target range. In 35 out of 41 patients (85%) dose interventions led to adequate trough levels. Eventually, 64% of the total cohort reached adequate trough levels., Conclusions: 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., (© 2017 The British Pharmacological Society.)