Multi-institutional Protocol Guidance for Pediatric Photon-counting CT.

Performing CT in children comes with unique challenges such as greater degrees of patient motion, smaller and densely packed anatomy, and potential risks of radiation exposure. The technical advancements of photon-counting detector (PCD) CT enable decreased radiation dose and noise, as well as increased spatial and contrast resolution across all ages, compared with conventional energy-integrating detector CT. It is therefore valuable to review the relevant technical aspects and principles specific to protocol development on the new PCD CT platform to realize the potential benefits for this population. The purpose of this article, based on multi-institutional clinical and research experience from pediatric radiologists and medical physicists, is to provide protocol guidance for use of PCD CT in the imaging of pediatric patients.

Discrepant Assessments of Progressive Disease in Clinical Trials between Routine Clinical Reads and Formal RECIST 1.1 Interpretations.

Purpose To analyze the frequency of discrepant interpretations of progressive disease (PD) between routine clinical and formal Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 interpretations in patients enrolled in solid tumor clinical trials and investigate the causes of discordance. Materials and Methods This retrospective study included patients in solid tumor clinical trials undergoing imaging response assessments based on RECIST 1.1 from January to July 2021. Routine clinical interpretations (RCIs) performed as part of standard workflow and not requiring formal use of any established response criteria were compared with separate local core laboratory interpretations (CLIs) by specially trained radiologists who used software that tracks target lesion measurements, changes in nontarget lesions, and appearance of new lesions longitudinally. The comparison focused on discordant interpretations of PD. Results Among 1053 patients who had both RCIs and CLIs performed, PD was diagnosed on one or both reads in 327 patients (median age, 63.6 [range, 22.4-83.2] years; 57.8% female patients). The RCIs and CLIs agreed with PD status in 65% (213 of 327) of assessments. In 32% (105 of 327) of assessments, RCIs overdiagnosed PD when CLIs diagnosed stable disease, and in 3% (nine of 327), CLIs diagnosed PD when RCIs diagnosed stable disease. Reasons for discrepant RCIs of PD included erroneous target lesion measurements (58%, 61 of 105), erroneous diagnosis of nontarget progression (30%, 32 of 105), and misclassification of new lesions as cancer (11%, 12 of 105). Most patients (93%, 98 of 105) with RCI overdiagnosis of PD remained in the clinical trial for one or more treatment cycles. Conclusion PD was frequently overdiagnosed on RCIs versus formal RECIST 1.1 CLIs which could result in patients removed from the clinical trial inappropriately. Keywords: Oncology, Cancer, Tumor Response, MR Imaging, CT © RSNA, 2023 See also commentary by Margolis and Ruchalski in this issue.

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear. METHODS: We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed. RESULTS: Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements. CONCLUSIONS: Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.

Dual-Energy CT for Pediatric Thoracic Imaging: A Review.

Dual-energy CT has expanded the potential of thoracic imaging in both children and adults. Data processing allows material- and energy-specific reconstructions, which improve material differentiation and tissue characterization compared with single-energy CT. Material-specific reconstructions include iodine, virtual unenhanced, perfusion blood volume, and lung vessel images, which can improve assessment of vascular, mediastinal, and parenchymal abnormalities. The energy-specific reconstruction algorithm allows virtual monoenergetic reconstructions, including low-energy images to increase iodine conspicuity and high-energy images to reduce beam-hardening and metal artifacts. This review highlights dual-energy CT principles, hardware, and postprocessing algorithms; the clinical applications of dual-energy CT; and the potential benefits of photon counting (the most recently introduced iteration of spectral imaging) in pediatric thoracic imaging.

Heterogeneous liver on research ultrasound identifies children with cystic fibrosis at high risk of advanced liver disease.

BACKGROUND: This study examines whether heterogeneous (HTG) pattern on liver ultrasound (US) identifies children at risk for advanced cystic fibrosis liver disease (aCFLD). METHODS: Prospective 6-year multicenter case-controlled cohort study. Children with pancreatic insufficient cystic fibrosis (CF) aged 3-12 years without known cirrhosis underwent screening US. Participants with HTG were matched (by age, Pseudomonas infection status and center) 1:2 with participants with normal (NL) US pattern. Clinical status and laboratory data were obtained annually and US bi-annually for 6 years. Primary endpoint was development of nodular (NOD) US pattern consistent with aCFLD. RESULTS: 722 participants underwent screening US, with 65 HTG and 592 NL. Final cohort included 55 HTG and 116 NL with ≥ 1 follow-up US. ALT, AST, GGTP, FIB-4, GPR and APRI were higher, and platelets were lower in HTG compared to NL. HTG had a 9.5-fold increased incidence (95% confidence interval [CI]:3.4, 26.7, p<0.0001, 32.7% vs 3.4%) of NOD versus NL. HTG had a sensitivity of 82% and specificity of 75% for subsequent NOD. Negative predictive value of a NL US for subsequent NOD was 96%. Multivariate logistic prediction model that included baseline US, age, and log(GPR) improved the C-index to 0.90 compared to only baseline US (C-index 0.78). Based on survival analysis, 50% of HTG develop NOD after 8 years. CONCLUSIONS: Research US finding of HTG identifies children with CF with a 30-50% risk for aCFLD. A score based on US pattern, age and GPR may refine the identification of individuals at high risk for aCFLD. CLINICAL TRIAL REGISTRATION: Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF: NCT 01,144,507 (observational study, no consort checklist).

Comparison of Radiation Dose and Image Quality of Pediatric High-Resolution Chest CT Between Photon-Counting Detector CT and Energy-Integrated Detector CT: A Matched Study.

BACKGROUND. Photon-counting detector (PCD) CT has been shown to reduce radiation dose and improve image quality in adult chest CT examinations; its potential impact in pediatric CT is not well documented. OBJECTIVE. The purpose of our study was to compare radiation dose, objective image quality, and subjective image quality of PCD CT and energy-integrating detector (EID) CT in children undergoing high-resolution CT (HRCT) of the chest. METHODS. This retrospective study included 27 children (median age, 3.9 years; 10 girls, 17 boys) who underwent PCD CT between March 1, 2022, and August 31, 2022, and 27 children (median age, 4.0 years; 13 girls, 14 boys) who underwent EID CT between August 1, 2021, and January 31, 2022; all examinations comprised clinically indicated chest HRCT. The patients in the two groups were matched by age and water-equivalent diameter. Radiation dose parameters were recorded. One observer placed ROIs to measure objective parameters (lung attenuation, image noise, and SNR). Two radiologists independently assessed subjective measures (overall image quality and motion artifacts) using 5-point Likert scales (1 = highest quality). Groups were compared. RESULTS. PCD CT, in comparison with EID CT, showed lower median CTDIvol (0.41 vs 0.71 mGy, p < .001), DLP (10.2 vs 13.7 mGy × cm, p = .008), size-specific dose estimate (0.82 vs 1.34 mGy, p < .001), and tube current-exposure time product (48.0 vs 202.0 mAs, p < .001). PCD CT and EID CT showed no significant difference in right upper lobe (RUL) lung attenuation (mean, -793 vs -750 HU; p = .09), right lower lobe (RLL) lung attenuation (mean, -745 vs -716 HU; p = .23), RUL image noise (mean, 55 vs 51 HU; p = .27), RLL image noise (mean, 59 vs 57 HU; p = .48), RUL SNR (mean, -14.9 vs -15.8; p = .89), or RLL SNR (mean, -13.1 vs -13.6; p = .79). PCD CT and EID CT showed no significant difference in median overall image quality for reader 1 (1.0 vs 1.0, p = .28) or reader 2 (1.0 vs 1.0, p = .17) or median motion artifacts for reader 1 (1.0 vs 1.0, p = .07) or reader 2 (1.0 vs 1.0, p = .22). CONCLUSION. PCD CT showed significantly reduced dose levels without a significant difference in objective or subjective image quality compared with EID CT. CLINICAL IMPACT. These data expand understanding of the capabilities of PCD CT and support its routine use in children.

Long-term follow-up and liver outcomes in children with cystic fibrosis and nodular liver on ultrasound in a multi-center study.

BACKGROUND: Nodular liver (NOD) in cystic fibrosis (CF) suggests advanced CF liver disease (aCFLD); little is known about progression of liver disease (LD) after detection of sonographic NOD. METHODS: Clinical, laboratory, and ultrasound (US) data from Prediction by Ultrasound of the Risk of Hepatic Cirrhosis in CFLD Study participants with NOD at screening or follow-up were compared with normal (NL). Linear mixed effects models were used for risk factors for LD progression and Kaplan-Meier estimator for time-to-event. RESULTS: 54 children with NOD (22 screening, 32 follow-up) and 112 NL were evaluated. Baseline (BL) and trajectory of forced expiratory volume, forced vital capacity, height/BMI z-scores were similar in NOD vs NL. Platelets were lower in NOD at BL (250 vs 331×103/microL; p < 0.001) and decreased by 8600/year vs 2500 in NL. Mean AST to Platelet Ratio Index (1.1 vs 0.4; p < 0.001), Fibrosis-4 Index (0.4 vs 0.2, p < 0.001), and spleen size z-score (SSZ) [1.5 vs 0.02; p < 0.001] were higher in NOD at BL; SSZ increased by 0.5 unit/year in NOD vs 0.1 unit/year in NL. Median liver stiffness (LSM) by transient elastography was higher in NOD (8.2 kPa, IQR 6-11.8) vs NL (5.3, 4.2-7, p < 0.0001). Over 6.3 years follow-up (1.3-10.3), 6 NOD had esophageal varices (cumulative incidence in 10 years: 20%; 95% CI: 0.0%, 40.0%), 2 had variceal bleeding, and 2 underwent liver transplantation; none had ascites or hepatic encephalopathy. No NL experienced liver-related events. CONCLUSIONS: NOD developed clinically evident portal hypertension faster than NL without worse growth or lung disease.

Imaging of pediatric hematopoietic stem cell transplant recipients: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Imaging in hematopoietic stem cell transplantation patients is not targeted at evaluating the transplant per se. Rather, imaging is largely confined to evaluating peri-procedural and post-procedural complications. Alternatively, imaging may be performed to establish a baseline study for comparison should the patient develop certain post-procedural complications. This article looks to describe the various imaging modalities available with recommendations for which imaging study should be performed in specific complications. We also provide select imaging protocols for different indications and modalities for the purpose of establishing a set minimal standard for imaging in these complex patients.

Health-related Quality of Life in a Prospective Study of Ultrasound to Detect Cystic Fibrosis-related Liver Disease in Children.

OBJECTIVES: Cystic fibrosis liver disease (CFLD) begins early in life. Symptoms may be vague, mild, or nonexistent. Progressive liver injury may be associated with decrements in patient health before liver disease is clinically apparent. We examined Health-Related Quality of Life (HRQOL) in children enrolled in a multi-center study of CFLD to determine the impact of early CFLD on general and disease-specific QOL. METHODS: Ultrasound (US) patterns of normal (NL), heterogeneous (HTG), homogeneous (HMG), or nodular (NOD) were assigned in a prospective manner to predict those at risk for advanced CFLD. Parents were informed of results. We assessed parent/child-reported (age ≥5 years) HRQOL by PedsQL 4.0 Generic Core and CF Questionnaire-revised (CFQ-R) prior to US and annually. HRQOL scores were compared by US pattern at baseline (prior to US), between baseline and 1 year and at 5 years. Multivariate analysis of variance (MANOVA) with Hotelling-Lawley trace tested for differences among US groups. RESULTS: Prior to US, among 515 participants and their parents there was no evidence that HTG or NOD US was associated with reduced PedsQL/CFQ-R at baseline. Parents of NOD reported no change in PedsQL/CFQ-R over the next year. Child-report PedsQL/CFQ-R (95 NL, 20 NOD) showed improvement between baseline and year 5 for many scales, including Physical Function. Parents of HMG children reported improved CFQ-R scores related to weight. CONCLUSIONS: Early undiagnosed or pre-symptomatic liver disease had no impact on generic or disease-specific HRQoL, and HRQoL was remarkably stable in children with CF regardless of liver involvement.

Comparison of 100-Kilovoltage Tin Filtration With Advanced Modeled Iterative Reconstruction Protocol to an Automated Kilovoltage Selection With Filtered Back Projection Protocol on Radiation Dose and Image Quality in Pediatric Noncontrast-Enhanced Chest Computed Tomography.

OBJECTIVE: The aim of the study was to compare effects of a 100-kilovoltage (kVp) tin filtration (Sn100kVp) with Advanced Modeled Iterative Reconstruction (ADMIRE) protocol to an automated kVp selection and filtered back projection (FBP) protocol on radiation dose and image quality of in noncontrast-enhanced pediatric chest computed tomography (CT). METHODS: This retrospective study included 55 children (12 ± 6 years) undergoing baseline imaging using automated kVp selection with FBP on a second-generation dual-source CT scanner and follow-up CT using Sn100kVp with ADMIRE on a third-generation dual-source CT scanner. The volume CT dose index, dose length product, size-specific dose estimate, and milliamperage were compared. Image quality was calculated using signal-to-noise ratio and subjectively evaluated by 2 radiologists. RESULTS: Mean volume CT dose index, dose length product, and size-specific dose estimate were lower for the Sn100kVp protocol with ADMIRE (0.83 ± 0.18 mGy, 21.9 ± 7.5 mGy × cm, 1.28 ± 0.24 mGy) compared with the automated kVp protocol with FBP (2.17 ± 1.10 mGy, 65.1 ± 41.1 mGy × cm, 3.25 ± 1.44 mGy, P < 0.001), whereas milliamperage was and subjective image quality were higher for Sn100kVp (P < 0.001). CONCLUSIONS: A Sn100kVp protocol with ADMIRE lowers dose while maintaining image quality in noncontrast-enhanced pediatric chest CT.

Phase II study of dacarbazine given with modern prophylactic anti-emetics and growth factor support to patients with metastatic, resistant soft tissue, and bone sarcoma.

Historically, administration of dacarbazine to sarcoma patients was limited by frequent treat-ment-related nausea/vomiting and neutropenia. These toxicities are now largely preventable with contemporary antiemetics and growth factor support. In this single-arm, phase II study, dacarbazine 850 mg/m2 was given on day 1 of each 3-week cycle until disease progression or intolerance with prophylactic serotonin-3 receptor, neurokinin-1 antagonists, corticosteroids, and pegfilgrastim. Coprimary endpoints included clinical benefit rate (CBR), and any grade of nausea/vomiting and/or grade 3-4 neutropenia. With a sample size of 80 patients, >24 patients with clinical benefit would indicate that the CBR exceeds the historical (<20%) [Power 0.80; alpha 0.05]. In addition, we hypothesized that the rates of nausea/vomiting would be 27% and grade 3-4 neutropenia would be 1% (historical: 90% and 36%, respectively) [power 0.95; alpha 0.05]. The CBR was 30% (24 patients: PR-2 and stable-22). The rate of nausea/vomiting was 37.5% (31 patients) and grades 3-4 neutropenia was 10% (8 patients). Median time-to-progression was 8.1 weeks (95% CI 8-9.7) and median overall survival was 35.8 weeks (95% CI 26.2-55.4). PET scans demonstrated no association with response. Modern prophylactic anti-emetics and pegfilgrastim given with dacarbazine reduced the rates of treatment related nausea/vomiting and serious neutropenia.

Comparison of radiation dose and image quality between contrast-enhanced single- and dual-energy abdominopelvic computed tomography in children as a function of patient size.

BACKGROUND: Widespread adoption of dual-energy computed tomography (DECT) requires evidence it does not cause higher radiation dose than conventional single-energy CT (SECT). While a few publications involving pediatric patients exist, most have focused on small cohorts. Hence, there is still a need for studies that ascertain what radiation doses are expected in larger populations that include representative ranges of patient sizes and ages. OBJECTIVE: To compare radiation dose and image quality of DECT and SECT abdominopelvic examinations in children as a function of patient size. MATERIALS AND METHODS: This retrospective study included 860 children (age range: 12.3±5.3 years) who underwent contrast-enhanced abdominopelvic exams on second-generation dual-source CT in a five-year period. Two groups, SECT and DECT, consisting of 430 children each, were matched by 5 effective diameters. Volume CT dose index (CTDIvol) and size-specific dose estimate (SSDE) were analyzed as a function of effective diameter. Objective image quality was compared between the groups. RESULTS: DECT SSDEs were lower across all effective patient diameters compared with SECT (mean: 8.5±1.8 mGv vs. 9.3±2.0 mGv, respectively, P≤0.001). DECT CTDIvol was lower compared to SECT (mean: 5.6±2.4 mGv vs. 6.1±2.7 mGv, respectively, P≤0.001) except in the smallest diameter group (<15 cm) where it was comparable to SECT (P=0.065). Objective image quality versus effective diameter between the two CT groups was comparable (P>0.05). CONCLUSION: In children, regardless of effective diameter, contrast-enhanced abdominopelvic DECT can be performed with a similar or lower dose and similar image quality compared with SECT examinations.

Dual-Energy CT Material Decomposition in Pediatric Thoracic Oncology.

Technical advances in CT have enabled implementation of dual-energy CT into routine clinical practice. By acquiring images at two different energy spectra, dual-energy CT enables material decomposition, allowing generation of material- and energy-specific images. Material-specific images include virtual nonenhanced images and iodine-specific images (iodine maps). Energy-specific images include virtual monoenergetic images. The reconstructed images can provide unique qualitative and quantitative information about tissue composition and contrast media distribution. In thoracic oncologic imaging, dual-energy CT provides advantages in characterization of thoracic malignancies and lung nodules, determination of extent of disease, and assessment of response to therapy. An especially important feature in children is that dual-energy CT does not come at a higher radiation exposure. Keywords: CT, CT-Quantitative, Lung, Mediastinum, Neoplasms-Primary, Pediatrics, Thorax, Treatment Effects © RSNA, 2021.

Heterogeneous Liver on Research Ultrasound Identifies Children with Cystic Fibrosis at High Risk of Advanced Liver Disease: Interim Results of a Prospective Observational Case-Controlled Study.

OBJECTIVE: To assess if a heterogeneous pattern on research liver ultrasound examination can identify children at risk for advanced cystic fibrosis (CF) liver disease. STUDY DESIGN: Planned 4-year interim analysis of a 9-year multicenter, case-controlled cohort study (Prospective Study of Ultrasound to Predict Hepatic Cirrhosis in CF). Children with pancreatic insufficient CF aged 3-12 years without known cirrhosis, Burkholderia species infection, or short bowel syndrome underwent a screening research ultrasound examination. Participants with a heterogeneous liver ultrasound pattern were matched (by age, Pseudomonas infection status, and center) 1:2 with participants with a normal pattern. Clinical status and laboratory data were obtained annually and research ultrasound examinations biannually. The primary end point was the development of a nodular research ultrasound pattern, a surrogate for advanced CF liver disease. RESULTS: There were 722 participants who underwent screening research ultrasound examination, of which 65 were heterogeneous liver ultrasound pattern and 592 normal liver ultrasound pattern. The final cohort included 55 participants with a heterogeneous liver ultrasound pattern and 116 participants with a normal liver ultrasound pattern. All participants with at least 1 follow-up research ultrasound were included. There were no differences in age or sex between groups at entry. Alanine aminotransferase (42 ± 22 U/L vs 32 ± 19 U/L; P = .0033), gamma glutamyl transpeptidase (36 ± 34 U/L vs 15 ± 8 U/L; P < .001), and aspartate aminotransferase to platelet ratio index (0.7 ± 0.5 vs 0.4 ± 0.2; P < .0001) were higher in participants with a heterogeneous liver ultrasound pattern compared with participants with a normal liver ultrasound pattern. Participants with a heterogeneous liver ultrasound pattern had a 9.1-fold increased incidence (95% CI, 2.7-30.8; P = .0004) of nodular pattern vs a normal liver ultrasound pattern (23% in heterogeneous liver ultrasound pattern vs 2.6% in normal liver ultrasound pattern). CONCLUSIONS: Research liver ultrasound examinations can identify children with CF at increased risk for developing advanced CF liver disease.

Dual-Energy CT in Children: Imaging Algorithms and Clinical Applications.

Dual-energy CT enables the simultaneous acquisition of CT images at two different x-ray energy spectra. By acquiring high- and low-energy spectral data, dual-energy CT can provide unique qualitative and quantitative information about tissue composition, allowing differentiation of multiple materials including iodinated contrast agents. The two dual-energy CT postprocessing techniques that best exploit the advantages of dual-energy CT in children are the material-decomposition images (which include virtual nonenhanced, iodine, perfused lung blood volume, lung vessel, automated bone removal, and renal stone characterization images) and virtual monoenergetic images. Clinical applications include assessment of the arterial system, lung perfusion, neoplasm, bowel diseases, renal calculi, tumor response to treatment, and metal implants. Of importance, the radiation exposure level of dual-energy CT is equivalent to or less than that of conventional single-energy CT. In this review, the authors discuss the basic principles of the dual-energy CT technologies and postprocessing techniques and review current clinical applications in the pediatric chest and abdomen.

The Importance of Imaging in Radiation Oncology for National Clinical Trials Network Protocols.

Imaging is essential in successfully executing radiation therapy (RT) in oncology clinical trials. As technically sophisticated diagnostic imaging and RT were incorporated into trials, quality assurance in the National Clinical Trials Network groups entered a new era promoting image acquisition and review. Most trials involving RT require pre- and post-therapy imaging for target validation and outcome assessment. The increasing real-time (before and during therapy) imaging and RT object reviews are to ensure compliance with trial objectives. Objects easily transmit digitally for review from anywhere in the world. Physician interpretation of imaging and image application to RT treatment plans is essential for optimal trial execution. Imaging and RT data sets are used to credential RT sites to confirm investigator and institutional ability to meet trial target volume delineation and delivery requirements. Real-time imaging and RT object reviews can be performed multiple times during a trial to assess response to therapy and application of RT objects. This process has matured into an effective data management mechanism. When necessary, site and study investigators review objects together through web media technologies to ensure the patient is enrolled on the appropriate trial and the intended RT is planned and executed in a trial-compliant manner. Real-time imaging review makes sure: (1) the patient is entered and eligible for the trial, (2) the patient meets trial-specific adaptive therapy requirements, if applicable, and (3) the intended RT is according to trial guidelines. This review ensures the study population is uniform and the results are believable and can be applied to clinical practice.

Pazopanib plus cetuximab in recurrent or metastatic head and neck squamous cell carcinoma: an open-label, phase 1b and expansion study.

BACKGROUND: Angiogenesis is a hallmark of head and neck squamous cell carcinoma (HNSCC), and a mechanism of resistance to EGFR inhibition. We investigated the safety and potential activity of pazopanib, an angiogenesis inhibitor, plus cetuximab, an EGFR inhibitor, in patients with recurrent or metastatic HNSCC. METHODS: We did an open-label, single-centre, dose-escalation phase 1b trial using a standard 3 + 3 design, followed by an expansion cohort phase. Eligible participants were patients with histologically or cytologically confirmed recurrent or metastatic HNSCC, aged at least 18 years, had measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and an Eastern Cooperative Oncology Group performance status of 0-1. During dose escalation, pazopanib oral suspension was administered daily in 8-week cycles at doses of 200 mg/day, 400 mg/day, 600 mg/day, or 800 mg/day, with cetuximab given intravenously once per week (400 mg/m2 first dose and 250 mg/m2 in consecutive cycles). The primary endpoint was to determine the maximum tolerated dose or recommended phase 2 dose of pazopanib in combination with cetuximab. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT01716416, and it is ongoing but closed to accrual. FINDINGS: Between June 5, 2013, and April 4, 2017, we enrolled 22 patients into the phase 1b, dose-escalation phase of the trial. A maximum tolerated dose of pazopanib in combination with cetuximab was not reached. Single dose-limiting toxic events (all grade 3) during dose escalation occurred with pazopanib 400 mg/day (neutropenia with infection), 600 mg/day (proteinuria), and 800 mg/day (fatigue). The established recommended phase 2 dose for the combination was 800 mg/day of pazopanib during cycles of 8 weeks each, plus cetuximab 400 mg/m2 on day 1 of cycle 1, then cetuximab 250 mg/m2 weekly. A further nine patients were enrolled into the expansion cohort and treated with the established recommended phase 2 dose. The most common (grade 3-4) adverse events for all patients were hypertension (ten [32%] of 31), lymphocyte count decrease (seven [23%]), and dysphagia (seven [23%]). There were no treatment-related deaths. 11 (35%; 95% CI 19·2-54·6) of 31 patients achieved an overall response, as assessed by the investigator; two (6%) had a complete response and nine (29%) a partial response. Tumour responses were also observed in six (55%) of 11 patients with platinum-naive and cetuximab-naive disease, three (25%) of 12 patients with cetuximab-resistant disease, and five (28%) of 18 patients with platinum-resistant disease. INTERPRETATION: Pazopanib oral suspension at a dose of 800 mg/day was feasible to administer in combination with standard weekly cetuximab for patients with recurrent or metastatic HNSCC. Encouraging preliminary antitumour activity was observed with this combination therapy and warrants further validation in randomised trials. FUNDING: GlaxoSmithKline and Novartis.

Dasatinib Plus Intensive Chemotherapy in Children, Adolescents, and Young Adults With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0622.

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.