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1.
Semin Musculoskelet Radiol ; 24(6): 676-691, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33307584

RESUMO

Knowledge of imaging findings related to therapy administered to patients with sarcoma is pivotal in selecting appropriate care for these patients. Imaging studies are performed as surveillance in asymptomatic patients or because symptoms, including anxiety, develop. In addition to detection of recurrent disease and assessment of response to therapy, diagnosis of conditions related to therapy that may or may not need treatment has a marked positive impact on quality of life. The purpose of this review is to assist radiologists, nuclear physicians, and others clinicians involved in the diagnosis and treatment of these patients in recognizing imaging findings related to therapy and not to activity of the previously treated sarcoma. Imaging findings are time dependent and often specific in relation to therapy given.

2.
Nat Neurosci ; 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257876

RESUMO

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.

3.
Oncologist ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289960

RESUMO

BACKGROUND: Pexidartinib is approved in the US for tenosynovial giant cell tumors (TGCT). Herein, we assessed the hepatic safety profile of pexidartinib across TGCT patients receiving pexidartinib. PATIENTS AND METHODS: Hepatic adverse reactions (ARs) were assessed by type and magnitude of liver test abnormalities, classified as: (1) isolated aminotransferase elevations (alanine [ALT] or aspartate [AST], without significant alkaline phosphatase [ALP] or bilirubin elevations), or (2) mixed or cholestatic hepatotoxicity (increase in ALP with or without ALT/AST and bilirubin elevations, based on adjudication). Median follow-up from initial pexidartinib treatment was 39 months (range, 32-82 months) in 140 TGCT patients across clinical studies NCT01004861, NCT02371369, NCT02734433, and NCT03291288. RESULTS: 95% of TGCT patients (133/140) treated with pexidartinib (median duration of exposure, 19 months [range, 1-76 months]), experienced a hepatic AR. 128 patients (91%) had reversible, low-grade dose-dependent isolated AST/ALT elevations without significant ALP elevations. Five patients (4%) experienced serious mixed or cholestatic injury. No case met Hy's law criteria. Onset of hepatic ARs was predominantly in the first 2 months. All five serious hepatic AR cases recovered 1-7 months following pexidartinib discontinuation. Five patients from the non-TGCT population (N = 658) experienced serious hepatic ARs, two irreversible cases. CONCLUSION: This pooled analysis provides information to help form the basis for the treating physician's risk assessment for patients with TCGT, a locally aggressive but typically non-metastatic tumor. In particular, long-term treatment with pexidartinib has a predictable effect on hepatic aminotransferases and unpredictable risk of serious cholestatic or mixed liver injury. IMPLICATIONS FOR PRACTICE: This is the first long-term pooled analysis to report on the long-term hepatic safety of pexidartinib in patients with TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. These findings extend beyond what has been previously published, describing the observed instances of hepatic toxicity following pexidartinib treatment across the clinical development program. This information is highly relevant for medical oncologists and orthopedic oncologists and provides guidance for its proper utilization for appropriate patients within the Pexidartinib Risk Evaluation and Mitigation Safety program.

4.
Cancers (Basel) ; 12(12)2020 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-33260481

RESUMO

Insulin-like growth factor-1 receptor (IGF1R) inhibitors are effective in preclinical studies, but so far, no convincing benefit in clinical studies has been observed, except in some rare cases of sustained response in Ewing sarcoma patients. The mechanism of resistance is unknown, but several hypotheses are proposed. In this review, multiple possible mechanisms of resistance to IGF-targeted therapies are discussed, including activated insulin signaling, pituitary-driven feedback loops through growth hormone (GH) secretion and autocrine loops. Additionally, the outcomes of clinical trials of IGF1-targeted therapies are discussed, as well as strategies to overcome the possible resistance mechanisms. In conclusion, lowering the plasma insulin levels or blocking its activity could provide an additional target in cancer therapy in combination with IGF1 inhibition. Furthermore, because Ewing sarcoma cells predominantly express the insulin receptor A (IRA) and healthy tissue insulin receptor B (IRB), it may be possible to synthesize a specific IRA inhibitor.

5.
Cancer ; 2020 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-33197285

RESUMO

BACKGROUND: The objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT). METHODS: This was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019. RESULTS: One hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months). CONCLUSIONS: This study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

6.
Artigo em Inglês | MEDLINE | ID: mdl-33179154

RESUMO

PURPOSE: In the phase II DIRECT study a fasting mimicking diet (FMD) improved the clinical response to neoadjuvant chemotherapy as compared to a regular diet. Quality of Life (QoL) and illness perceptions regarding the possible side effects of chemotherapy and the FMD were secondary outcomes of the trial. METHODS: 131 patients with HER2-negative stage II/III breast cancer were recruited, of whom 129 were randomly assigned (1:1) to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and the day of neoadjuvant chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires EORTC-QLQ-C30 and EORTC-QLQ-BR23; the Brief Illness Perception Questionnaire (BIPQ) and the Distress Thermometer were used to assess these outcomes at baseline, halfway chemotherapy, before the last cycle of chemotherapy and 6 months after surgery. RESULTS: Overall QoL and distress scores declined during treatment in both arms and returned to baseline values 6 months after surgery. However, patients' perceptions differed slightly over time. In particular, patients receiving the FMD were less concerned and had better understanding of the possible adverse effects of their treatment in comparison with patients on a regular diet. Per-protocol analyses yielded better emotional, physical, role, cognitive and social functioning scores as well as lower fatigue, nausea and insomnia symptom scores for patients adherent to the FMD in comparison with non-adherent patients and patients on their regular diet. CONCLUSIONS: FMD as an adjunct to neoadjuvant chemotherapy appears to improve certain QoL and illness perception domains in patients with HER2-negative breast cancer. Trialregister ClinicalTrials.gov Identifier: NCT02126449.

7.
Expert Opin Investig Drugs ; : 1-10, 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33252274

RESUMO

Introduction: Discovery of oncogenic mutations in the KIT and PDGFRA tyrosine kinase receptor was a crucial step for the development of tyrosine kinase inhibitors (TKIs). Since then, GIST became a model for the development of molecular-targeted therapy, which led to dramatically improved median overall survival of advanced GIST. Still, further progress is needed after third-line or for TKI resistant mutations. Areas covered: In this review, after a brief introduction on imatinib, sunitinib, and regorafenib, an overview of TKIs that was evaluated beyond these drugs is provided, with a main focus on the novel approved TKIs. Expert opinion: Combination therapies have thus far not fulfilled their promise in GIST, nor did immunotherapy. Increased understanding of GIST and advances in the development of molecular-targeted drugs led to the introduction of ripretinib and avapritinib. Furthermore, NTRK inhibitors became available for ultrarare NTRK fusions. Solutions for NF1 and BRAF mutated and SDH-deficient GIST are still to be awaited. This all underlines the need for adequate molecular profiling of high-risk GISTs before treatment is started. Possibly by using circulating tumor DNA in the future, targeting resistance mutations with specific drugs along the course of the disease would be easier, avoiding multiple tumor biopsies.

9.
Eur J Cancer ; 141: 9-20, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33125947

RESUMO

BACKGROUND: Pre-therapeutic UGT1A1 genotyping is not yet routinely performed in most hospitals in patients starting irinotecan chemotherapy. The aim of this position paper was to evaluate the available evidence and to assess the potential value of genotyping of UGT1A1∗28 and UGT1A1*6 in patients before starting treatment with irinotecan to reduce the risk of severe toxicity. METHODS: The literature was selected and assessed based on five pre-specified criteria: 1) the level of evidence for associations between UGT1A1 polymorphisms and irinotecan-induced severe toxicity, 2) clinical validity and utility of pre-therapeutic genotyping of UGT1A1, 3) safety and tolerability of irinotecan in carriers of UGT1A1 polymorphisms, 4) availability of specific dose recommendations for irinotecan in carriers of UGT1A1 polymorphisms, 5) evidence of cost benefits of pre-therapeutic genotyping of UGT1A1. RESULTS: On all five criteria, study results were favourable for pre-therapeutic genotyping of UGT1A1. A high level of evidence (level I) was found for a higher incidence of irinotecan-induced severe toxicity in homozygous carriers of UGT1A1*28 or UGT1A1*6. The clinical validity and utility of this genetic test proved to be acceptable. Dose-finding studies showed a lower maximum tolerated dose in homozygous variant allele carriers, and most of the drug labels and guidelines recommend a dose reduction of 25-30% in these patients. In addition, pre-therapeutic genotyping of UGT1A1 is likely to save costs. CONCLUSION: Pre-therapeutic genotyping of UGT1A1 in patients initiating treatment with irinotecan improves patient safety, is likely to be cost-saving, and should, therefore, become standard of care.

10.
Front Pharmacol ; 11: 577968, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117169

RESUMO

Background: The introduction of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with either oxaliplatin or mitomycin C for patients with colorectal peritoneal metastasis (CPM) has resulted in a major increase in overall survival. Nonetheless, despite critical patient selection, the majority of patients will develop recurrent disease within one year following CRS + HIPEC. Therefore, improvement of patient and treatment selection is needed and may be achieved by the incorporation of genetic biomarkers. This systematic review aims to provide an overview of genetic biomarkers in the DNA repair pathway that are potentially predictive for treatment outcome of patients with colorectal peritoneal metastases treated with CRS + HIPEC with oxaliplatin or mitomycin C. Methods: A systematic review was conducted according to the PRISMA guidelines. Given the limited number of genetic association studies of intraperitoneal mitomycin C and oxaliplatin in patients with CPM, we expanded the review and extrapolated the data from biomarker studies conducted in colorectal cancer patients treated with systemic mitomycin C- and oxaliplatin-based chemotherapy. Results: In total, 43 papers were included in this review. No study reported potential pharmacogenomic biomarkers in patients with colorectal cancer undergoing mitomycin C-based chemotherapy. For oxaliplatin-based chemotherapy, a total of 26 genetic biomarkers within 14 genes were identified that were significantly associated with treatment outcome. The most promising genetic biomarkers were ERCC1 rs11615, XPC rs1043953, XPD rs13181, XPG rs17655, MNAT rs3783819/rs973063/rs4151330, MMR status, ATM protein expression, HIC1 tandem repeat D17S5, and PIN1 rs2233678. Conclusion: Several genetic biomarkers have proven predictive value for the treatment outcome of systemically administered oxaliplatin. By extrapolation, these genetic biomarkers may also be predictive for the efficacy of intraperitoneal oxaliplatin. This should be the subject of further investigation.

11.
Eur J Radiol ; 133: 109345, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33120239

RESUMO

OBJECTIVE: This study evaluated the correlation between intratumoural stroma proportion, expressed as tumour-stroma ratio (TSR), and apparent diffusion coefficient (ADC) values in patients with rectal cancer. METHODS: This multicentre retrospective study included all consecutive patients with rectal cancer, diagnostically confirmed by biopsy and MRI. The training cohort (LUMC, Netherlands) included 33 patients and the validation cohort (VHIO, Spain) 69 patients. Two observers measured the mean and minimum ADCs based on single-slice and whole-volume segmentations. The TSR was determined on diagnostic haematoxylin & eosin stained slides of rectal tumour biopsies. The correlation between TSR and ADC was assessed by Spearman correlation (rs). RESULTS: The ADC values between stroma-low and stroma-high tumours were not significantly different. Intra-class correlation (ICC) demonstrated a good level of agreement for the ADC measurements, ranging from 0.84-0.86 for single slice and 0.86-0.90 for the whole-volume protocol. No correlation was observed between the TSR and ADC values, with ADCmeanrs= -0.162 (p= 0.38) and ADCminrs= 0.041 (p= 0.82) for the single-slice and rs= -0.108 (p= 0.55) and rs= 0.019 (p= 0.92) for the whole-volume measurements in the training cohort, respectively. Results from the validation cohort were consistent; ADCmeanrs= -0.022 (p= 0.86) and ADCminrs = 0.049 (p= 0.69) for the single-slice and rs= -0.064 (p= 0.59) and rs= -0.063 (p= 0.61) for the whole-volume measurements. CONCLUSIONS: Reproducibility of ADC values is good. Despite positive reports on the correlation between TSR and ADC values in other tumours, this could not be confirmed for rectal cancer.

12.
Oncologist ; 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33111480

RESUMO

BACKGROUND: Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. MATERIALS AND METHODS: MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. RESULTS: Interviews with 24 members of eight MTBs revealed that all participating MTBs focused on rare or complex mutational cancer profiles, operated independently of cancer type-specific multidisciplinary teams, and consisted of at least (thoracic and/or medical) oncologists, pathologists, and clinical scientists in molecular pathology. Differences were the types of cancer discussed and the methods used to achieve a recommendation. Nevertheless, agreement among MTB recommendations, based on identified actionable molecular alteration(s), was high for the 10 evaluated cases (86%). CONCLUSION: MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational cancer profiles. We propose a "Dutch MTB model" for an optimal, collaborative, and nationally aligned MTB workflow. IMPLICATIONS FOR PRACTICE: Interpretation of genomic analyses for optimal choice of target therapy for patients with cancer is becoming increasingly complex. A molecular tumor board (MTB) supports oncologists in rationalizing therapy options. However, there is no consensus on the most optimal setup for an MTB, which can affect the quality of recommendations. This study reveals that the eight MTBs associated with tertiary cancer referral centers in The Netherlands are similar in setup and reach a high agreement in recommendations for rare or complex mutational profiles. The Dutch MTB model is based on a collaborative and nationally aligned workflow with interinstitutional collaboration and data sharing.

13.
BMJ Open ; 10(10): e036376, 2020 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046463

RESUMO

OBJECTIVES: This study aimed at developing a dynamic prediction model for patients with Ewing sarcoma (ES) to provide predictions at different follow-up times. During follow-up, disease-related information becomes available, which has an impact on a patient's prognosis. Many prediction models include predictors available at baseline and do not consider the evolution of disease over time. SETTING: In the analysis, 979 patients with ES from the Gesellschaft für Pädiatrische Onkologie und Hämatologie registry, who underwent surgery and treatment between 1999 and 2009, were included. DESIGN: A dynamic prediction model was developed to predict updated 5-year survival probabilities from different prediction time points during follow-up. Time-dependent variables, such as local recurrence (LR) and distant metastasis (DM), as well as covariates measured at baseline, were included in the model. The time effects of covariates were investigated by using interaction terms between each variable and time. RESULTS: Developing LR, DM in the lungs (DMp) or extrapulmonary DM (DMo) has a strong effect on the probability of surviving an additional 5 years with HRs and 95% CIs equal to 20.881 (14.365 to 30.353), 6.759 (4.465 to 10.230) and 17.532 (13.210 to 23.268), respectively. The effects of primary tumour location, postoperative radiotherapy (PORT), histological response and disease extent at diagnosis on survival were found to change over time. The HR of PORT versus no PORT at the time of surgery is equal to 0.774 (0.594 to 1.008). One year after surgery, the HR is equal to 1.091 (0.851 to 1.397). CONCLUSIONS: The time-varying effects of several baseline variables, as well as the strong impact of time-dependent variables, show the importance of including updated information collected during follow-up in the prediction model to provide accurate predictions of survival.

14.
Clin Pharmacol Ther ; 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33020924

RESUMO

Fluoropyrimidines are widely used in the treatment of several types of solid tumors. Although most often well tolerated, severe toxicity is encountered in ~ 20-30% of the patients. Individualized dosing for these patients can reduce the incidence of severe fluoropyrimidine-related toxicity. However, no consensus has been achieved on which dosing strategy is preferred. The most established strategy for individualized dosing of fluoropyrimidines is upfront genotyping of the DPYD gene. Prospective research has shown that DPYD-guided dose-individualization significantly reduces the incidence of severe toxicity and can be easily applied in routine daily practice. Furthermore, the measurement of the dihydropyrimidine dehydrogenase (DPD) enzyme activity has shown to accurately detect patients with a DPD deficiency. Yet, because this assay is time-consuming and expensive, it is not widely implemented in routine clinical care. Other methods include the measurement of pretreatment endogenous serum uracil concentrations, the uracil/dihydrouracil-ratio, and the 5-fluorouracil (5-FU) degradation rate. These methods have shown mixed results. Next to these methods to detect DPD deficiency, pharmacokinetically guided follow-up of 5-FU could potentially be used as an addition to dosing strategies to further improve the safety of fluoropyrimidines. Furthermore, baseline characteristics, such as sex, age, body composition, and renal function have shown to have a relationship with the development of severe toxicity. Therefore, these baseline characteristics should be considered as a dose-individualization strategy. We present an overview of the current dose-individualization strategies and provide perspectives for a future multiparametric approach.

15.
J Clin Pharmacol ; 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33043474

RESUMO

Pexidartinib is a kinase inhibitor that induces tumor response and improvements in symptoms and functional outcomes in adult patients with symptomatic tenosynovial giant cell tumor (TGCT). A population pharmacokinetic (PK) model for pexidartinib and its metabolite, ZAAD, was developed, and effects of demographic and clinical factors on the PK of pexidartinib and ZAAD were estimated. The analysis included pooled data from 7 studies in healthy volunteers (N = 159) and 2 studies in patients with TGCT or other solid tumors (N = 216). A structural 2-compartment model with sequential zero- and first-order absorption and lag time, and linear elimination from the central compartment adequately described pexidartinib and ZAAD PKs. Clearance of pexidartinib was estimated at 5.83 L/h in a typical patient with reference covariates (male, non-Asian, weight = 80 kg, creatinine clearance ≥90 mL/min, aspartate aminotransferase ≤80 U/L, and total bilirubin ≤20.5 µmol/L). In the covariate analysis, Asians and healthy subjects had modestly lower pexidartinib exposure (21% decrease each) in terms of steady-state area under the curve values from 0 to 24 hours (AUC0-24,ss ). Effects of body weight, sex, and hepatic function parameters on pexidartinib AUC0-24,ss were generally <20%. Patients with TGCT with mild renal impairment were predicted to have approximately 23% higher AUC0-24,ss than those with normal renal function. The effects of covariates on ZAAD exposure were similar to those on pexidartinib. These results indicate small and generally clinically nonmeaningful effects of patient demographic and clinical characteristics on pexidartinib and ZAAD PK profiles.

16.
Clin Sarcoma Res ; 10: 18, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32944214

RESUMO

Background: Doxorubicin based chemotherapy is standard first line treatment for patients with soft tissue sarcoma. Currently several options to improve survival after doxorubicin based chemotherapy are being studied. This study reports on survival after completing 6 cycles of doxorubicin containing first line treatment, which is important when designing studies trying to improve outcomes of first line treatment. Methods: A retrospective database analysis was performed on 2045 patients from 12 EORTC sarcoma trials (inclusion period 1980-2012) receiving first line doxorubicin based chemotherapy for advanced soft tissue sarcoma in order to establish progression free survival and overall survival after completing 6 cycles of first line doxorubicin based chemotherapy. Endpoints were overall survival and progression free survival. Factors studied were histologic subtype and type of doxorubicin chemotherapy. Results: 748 of 2045 (36.6%) received at least 6 cycles and did not progress during or at the end of chemotherapy. 475 of 2045 (23.2%) of patients received exactly 6 cycles and did not progress during or at the end of chemotherapy. Median progression free survival after 6 cycles of doxorubicin based chemotherapy was 4.2 months (95% confidence interval 3.7-4.8) and median overall survival 15.7 months (14.0-17.8). Median progression free survival and overall survival from randomisation/registration were 8.7 months (95% confidence interval 8.2-9.1) and 20.1 months (95% confidence interval 18.3-22.3) respectively. Significant differences in progression free survival were found between chemotherapy regimens, but not for overall survival. These data are also reported for patients receiving 7 or more cycles of chemotherapy and for patients with 3 or more cycles of chemotherapy. Conclusion: This large retrospective study is the first to report progression free survival and overall survival after completion of 6 cycles of first line doxorubicin containing chemotherapy. These results are important when designing new studies exploring for example maintenance therapy after doxorubicin based chemotherapy.

17.
Lancet Oncol ; 21(10): 1366-1377, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32941794

RESUMO

BACKGROUND: Unlike for extremity sarcomas, the efficacy of radiotherapy for retroperitoneal sarcoma is not established. The aim of this study was to evaluate the impact of preoperative radiotherapy plus surgery versus surgery alone on abdominal recurrence-free survival. METHODS: EORTC-62092 is an open-label, randomised, phase 3 study done in 31 research institutions, hospitals, and cancer centres in 13 countries in Europe and North America. Adults (aged ≥18 years) with histologically documented, localised, primary retroperitoneal sarcoma that was operable and suitable for radiotherapy, who had not been previously treated and had a WHO performance status and American Society of Anesthesiologists score of 2 or lower, were centrally randomly assigned (1:1), using an interactive web response system and a minimisation algorithm, to receive either surgery alone or preoperative radiotherapy followed by surgery. Randomisation was stratified by hospital and performance status. Radiotherapy was delivered as 50·4 Gy (in 28 daily fractions of 1·8 Gy) in either 3D conformal radiotherapy or intensity modulated radiotherapy, and the objective of surgery was a macroscopically complete resection of the tumour mass with en-bloc organ resection as necessary. The primary endpoint was abdominal recurrence-free survival, as assessed by the investigator, and was analysed in the intention-to-treat population. Safety was analysed in all patients who started their allocated treatment. This trial is registered with ClinicalTrials.gov, NCT01344018. FINDINGS: Between Jan 18, 2012 and April 10, 2017, 266 patients were enrolled, of whom 133 were randomly assigned to each group. The median follow-up was 43·1 months (IQR 28·8-59·2). 128 (96%) patients from the surgery alone group had surgery, and 119 (89%) patients in the radiotherapy and surgery group had both radiotherapy and surgery. Median abdominal recurrence-free survival was 4·5 years (95% CI 3·9 to not estimable) in the radiotherapy plus surgery group and 5·0 years (3·4 to not estimable) in the surgery only group (hazard ratio 1·01, 95% CI 0·71-1·44; log rank p=0·95). The most common grade 3-4 adverse events were lymphopenia (98 [77%] of 127 patients in the radiotherapy plus surgery group vs one [1%] of 128 patients in the surgery alone group), anaemia (15 [12%] vs ten [8%]), and hypoalbuminaemia (15 [12%] vs five [4%]). Serious adverse events were reported in 30 (24%) of 127 patients in the radiotherapy plus surgery group, and in 13 (10%) of 128 patients in the surgery alone group. One (1%) of 127 patients in the radiotherapy plus surgery group died due to treatment-related serious adverse events (gastropleural fistula), and no patients in the surgery alone group died due to treatment-related serious adverse events. INTERPRETATION: Preoperative radiotherapy should not be considered as standard of care treatment for retroperitoneal sarcoma. FUNDING: European Organisation for Research and Treatment of Cancer, and European Clinical Trials in Rare Sarcomas.


Assuntos
Terapia Neoadjuvante , Neoplasias Retroperitoneais/radioterapia , Sarcoma/radioterapia , Idoso , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , América do Norte , Radioterapia Adjuvante/efeitos adversos , Radioterapia Conformacional/efeitos adversos , Neoplasias Retroperitoneais/patologia , Neoplasias Retroperitoneais/cirurgia , Sarcoma/patologia , Sarcoma/cirurgia , Resultado do Tratamento
18.
Front Pharmacol ; 11: 1241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32903464

RESUMO

High-dose methotrexate is a cornerstone agent in the chemotherapeutic treatment of patients with osteosarcoma. However, patients often develop methotrexate-induced toxicities. We aim to identify determinants of methotrexate-induced toxicities in osteosarcoma patients by investigating the relation between drug plasma levels, methotrexate-induced toxicities, and germline variants in genes related to drug absorption, distribution, metabolism, and elimination. A cohort of 114 osteosarcoma patients was genotyped for 1,931 variants in 231 genes using the Drug Metabolism Enzymes and Transporters Plus array. Methotrexate plasma levels and laboratory measurements during and after high-dose methotrexate treatment concerning renal function, liver damage, and myelopoiesis to reflect toxicity outcomes were obtained. One hundred and thirteen patients and a subset of 545 variants in 176 genes passed quality control checks. Methotrexate plasma levels showed associations with creatinine, alanine aminotransferase, and hemoglobin. Genetic variant rs3736599 in the 5'-untranslated region of SULT1E1 was associated with lower 48 hour methotrexate plasma levels [coef -0.313 (95% CI -0.459 - -0.167); p = 2.60 × 10-5]. Association with methotrexate-induced decreased thrombocyte counts was found for two intronic variants in CYP2B6 {rs4803418 [coef -0.187 (95% CI -0.275 - -0.099); p = 3.04 × 10-5] and rs4803419 [coef -0.186 (95% CI -0.278 - -0.093); p = 8.80 × 10-5]}. An association with increased thrombocyte counts was identified for the intronic variant rs4808326 in CYP4F8 [coef 0.193 (95% CI 0.099 - 0.287); p = 6.02 × 10-5]. Moreover, a secondary analysis with a binary approach using CTCAE toxicity criteria resulted in a nominal significant associations (p < 0.05) for two out of three variants (rs4803418 and rs4808326). This is the first study to identify genetic variants in SULT1E1, CYP2B6, and CYP4F8 to be associated with methotrexate pharmacokinetics and toxicities. Validation of these variants in an independent cohort and further functional investigation of variants in the identified genes is needed to determine if and how they affect methotrexate plasma levels and the development of methotrexate-induced toxicities.

19.
J Clin Oncol ; 38(28): 3294-3303, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32804590

RESUMO

PURPOSE: In advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations. PATIENTS AND METHODS: This first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated. RESULTS: At data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed. CONCLUSION: Ripretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST.

20.
ESMO Open ; 5(4)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32847839

RESUMO

INTRODUCTION: Angiosarcomas constitute approximately 2% to 3% of all soft tissue sarcomas, are characterised by an aggressive clinical behaviour and poor outcome. Optimal management of localised angiosarcomas consists of complete surgical resection with or without radiation. However, due to the infiltrating nature of this disease, complete resection is often not possible. Despite optimal management, the outcome of patients with localised disease remains poor. The role of (neo)adjuvant chemotherapy in angiosarcomas remains undefined. The aim of this study is to document the outcome of patients treated with (neo)adjuvant chemotherapy and assess the feasibility of performing a prospective trial by evaluating the number of patients treated at sarcoma referral centres. METHODS: A retrospective search within participating EORTC (European Organisation for Research and Treatment of Cancer) sites for patients treated with (neo)adjuvant chemotherapy was made. Patients treated between January 2007 and January 2016 were included. RESULTS: A total of 15 institutions participated and 86 patients were evaluable, 43 were treated with neoadjuvant, 27 with adjuvant chemotherapy and 16 with both. At the time of analysis, the median follow-up from diagnosis was 4.6 years. Median overall survival (OS) was 4.9 years (2.9 N) and the percentage alive at 4 years was 57.9 (45.5 to 68.4). The median disease-free survival was 1.4 years (0.9 to 1.7) and the percentage disease-free at 4 years was 26.8% (17.9 to 36.5). CONCLUSION: The outcome of angiosarcoma patients treated with (neo)adjuvant chemotherapy in this case series compares favourably with previously published data. Due to the aggressive nature of angiosarcoma, a prospective trial of neoadjuvant chemotherapy should be considered.

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