Visibility and Size of the Pancreatic Duct and Common Bile Duct on Routine 2D MRI Sequences in Children Without Pancreaticobiliary Disease.

Background: Pancreatic duct (PD) or common bile duct (CBD) dilatation can indicate ductal pathology, but limited data describe normal pediatric duct measurements on routine 2D MR sequences. Objective: To characterize the visibility and diameter of the PD and CBD on 2D MR images in children without pancreaticobiliary disease. Methods: This retrospective study included patients who underwent abdominal MRI using a rapid protocol (comprised of noncontrast axial and coronal 2D SSFSE sequences) to assess for suspected appendicitis or ovarian torsion in the emergency department setting between January 23, 2023, and September 13, 2023, excluding patients with a pancreatic or hepatobiliary abnormality on MRI or laboratory assessment. Four radiologists independently reviewed examinations. Reviewers recorded PD visibility in each of four segments (head, neck, body, and tail) and CBD visibility, and measured PD diameter in each segment and maximal CBD diameter. Duct measurements by age were characterized by linear regression analyses. Results: The study included 177 patients [112 female, 65 female; mean age, 12.3±3.4 years (range, 5.1-17.7 years)]. The observers reported PD visibility in the head in 32.5-93.5%, neck in 18.4-71.5%, body in 22.3-69.8%, and tail in 7.3-25.7%, and in all four segments in 6.2-22.4%, of patients. Maximum PD diameter in any segment, as a mean across observers, was 1.8 mm (range across observers, 0.7-3.5 mm). Expected maximal PD diameter in any segment, in terms of the 5th and 95th percentile values of observers' mean measurements, was 1.4-2.3 mm; the prediction interval's upper limit increased from age 5 to 17 from 2.1 to 2.5 mm. All observers reported CBD visibility in all patients. Mean CBD diameter across observers was 3.1 mm (range across observers, 2.9-3.4 mm). Expected CBD diameter, in terms of the 5th and 95th percentile values of observers' mean measurements, was 2.3-4.9 mm; the prediction interval's upper limit increased from age 5 to 17 from 3.9 to 5.0 mm. Conclusion: We report expected upper limits for PD and CBD measurements on 2D MR images in children without evidence of pancreaticobiliary disease. Clinical Impact: These findings may aid radiologists' identification of pancreaticobiliary duct abnormalities on routine abdominal MRI examinations.

Machine Learning Diagnosis of Small-Bowel Crohn Disease Using T2-Weighted MRI Radiomic and Clinical Data.

BACKGROUND. Radiologists have variable diagnostic performance and considerable interreader variability when interpreting MR enterography (MRE) examinations for suspected Crohn disease (CD). OBJECTIVE. The purposes of this study were to develop a machine learning method for predicting ileal CD by use of radiomic features of ileal wall and mesenteric fat from noncontrast T2-weighted MRI and to compare the performance of the method with that of expert radiologists. METHODS. This single-institution study included retrospectively identified patients who underwent MRE for suspected ileal CD from January 1, 2020, to January 31, 2021, and prospectively enrolled participants (patients with newly diagnosed ileal CD or healthy control participants) from December 2018 to October 2021. Using axial T2-weighted SSFSE images, a radiologist selected two slices showing greatest terminal ileal wall thickening. Four ROIs were segmented, and radiomic features were extracted from each ROI. After feature selection, support-vector machine models were trained to classify the presence of ileal CD. Three fellowship-trained pediatric abdominal radiologists independently classified the presence of ileal CD on SSFSE images. The reference standard was clinical diagnosis of ileal CD based on endoscopy and biopsy results. Radiomic-only, clinical-only, and radiomic-clinical ensemble models were trained and evaluated by nested cross-validation. RESULTS. The study included 135 participants (67 female, 68 male; mean age, 15.2 ± 3.2 years); 70 were diagnosed with ileal CD. The three radiologists had accuracies of 83.7% (113/135), 88.1% (119/135), and 86.7% (117/135) for diagnosing CD; consensus accuracy was 88.1%. Interradiologist agreement was substantial (κ = 0.78). The best-performing ROI was bowel core (AUC, 0.95; accuracy, 89.6%); other ROIs had worse performance (whole-bowel AUC, 0.86; fat-core AUC, 0.70; whole-fat AUC, 0.73). For the clinical-only model, AUC was 0.85 and accuracy was 80.0%. The ensemble model combining bowel-core radiomic and clinical models had AUC of 0.98 and accuracy of 93.5%. The bowel-core radiomic-only model had significantly greater accuracy than radiologist 1 (p = .009) and radiologist 2 (p = .02) but not radiologist 3 (p > .99) or the radiologists in consensus (p = .05). The ensemble model had greater accuracy than the radiologists in consensus (p = .02). CONCLUSION. A radiomic machine learning model predicted CD diagnosis with better performance than two of three expert radiologists. Model performance improved when radiomic data were ensembled with clinical data. CLINICAL IMPACT. Deployment of a radiomic-based model including T2-weighted MRI data could decrease interradiologist variability and increase diagnostic accuracy for pediatric CD.

Harnessing imaging tools to guide immunotherapy trials: summary from the National Cancer Institute Cancer Imaging Steering Committee workshop.

As the immuno-oncology field continues the rapid growth witnessed over the past decade, optimising patient outcomes requires an evolution in the current response-assessment guidelines for phase 2 and 3 immunotherapy clinical trials and clinical care. Additionally, investigational tools-including image analysis of standard-of-care scans (such as CT, magnetic resonance, and PET) with analytics, such as radiomics, functional magnetic resonance agents, and novel molecular-imaging PET agents-offer promising advancements for assessment of immunotherapy. To document current challenges and opportunities and identify next steps in immunotherapy diagnostic imaging, the National Cancer Institute Clinical Imaging Steering Committee convened a meeting with diverse representation among imaging experts and oncologists to generate a comprehensive review of the state of the field.

Introduction to the COG Diagnostic Imaging Committee/SPR Oncology Committee White Papers: Rationale and methods.

Pediatric cancer is a rare disease. Because of this, many sites do not have experience providing imaging for specific tumor types. The Children's Oncology Group Diagnostic Imaging Committee and the Society for Pediatric Radiology Oncology Committee are comprised of radiologists with expertise in pediatric cancer imaging. Recently, this group endeavored to create a series of 23 White Papers designed to provide evidence-based imaging recommendations and minimum achievable imaging protocols. The purpose of this manuscript is to describe the methods employed in authoring the White Paper series.

Imaging of pediatric extragonadal pelvic soft tissue tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

The most common pediatric extragonadal pelvic cancers include germ cell tumors, sacrococcygeal teratomas, and rhabdomyosarcomas (arising from the urinary bladder, prostate, paratesticular tissues, vagina, uterus, and perineum). This paper describes the radiological and nuclear medicine features of these entities and provides consensus-based recommendations for the assessment at diagnosis, during, and after treatment.

Imaging of pediatric adrenal tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Adrenal tumors other than neuroblastoma are uncommon in children. The most frequently encountered are adrenocortical carcinoma and pheochromocytoma. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary adrenal malignancy other than neuroblastoma at diagnosis and during follow-up.

Imaging of pediatric ovarian tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Ovarian tumors in children are uncommon. Like those arising in the adult population, they may be broadly divided into germ cell, sex cord, and surface epithelium subtypes; however, germ cell tumors comprise the majority of lesions in children, whereas tumors of surface epithelial origin predominate in adults. Diagnostic workup, including the use of imaging, requires an approach that often differs from that required in an adult. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary ovarian malignancy at diagnosis and during follow-up.

Imaging of pediatric testicular tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Primary intratesticular tumors are uncommon in children, but incidence and risk of malignancy both sharply increase during adolescence. Ultrasound is the mainstay for imaging the primary lesion, and cross-sectional modalities are often required for evaluation of regional or distant disease. However, variations to this approach are dictated by additional clinical and imaging nuances. This paper offers consensus recommendations for imaging of pediatric patients with a known or suspected primary testicular malignancy at diagnosis and during follow-up.

Assessing the role of positron emission tomography and bone scintigraphy in imaging of pleuropulmonary blastoma (PPB): A report from the International PPB/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Given the rarity of PPB, the role of positron emission tomography (PET) and bone scintigraphy (bone scans) in diagnostic evaluation and surveillance has not been documented to date. Available PET and bone scan data are presented in this study. PROCEDURES: Patients with PPB enrolled in the International PPB/DICER1 Registry and available PET imaging and/or bone scan reports were retrospectively abstracted. RESULTS: On retrospective analysis, 133 patients with type II and III (advanced) PPB were identified with available report(s) (PET scan only = 34, bone scan only = 83, and both bone scan and PET = 16). All advanced primary PPB (n = 11) and recurrent (n = 8) tumors prior to treatment presented with 18 F-fluorodeoxyglucose (FDG)-avid lesions, with median maximum standardized uptake values of 7.4 and 6.7, respectively. False positive FDG uptake in the thorax was noted during surveillance (specificity: 59%). Bone metastases were FDG-avid prior to treatment. Central nervous system metastases were not discernable on PET imaging. Sensitivity and specificity of bone scans for metastatic bone disease were 89% and 92%, respectively. Bone scans had a negative predictive value of 99%, although positive predictive value was 53%. Four patients with distant bone metastases had concordant true positive bone scan and PET. CONCLUSION: Primary, recurrent, and/or extracranial metastatic PPB presents with an FDG-avid lesion on PET imaging. Additional prospective studies are needed to fully assess the utility of nuclear medicine imaging in surveillance for patients with advanced PPB.

Imaging of pediatric liver tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee White Paper.

Primary hepatic malignancies are relatively rare in the pediatric population, accounting for approximately 1%-2% of all pediatric tumors. Hepatoblastoma and hepatocellular carcinoma are the most common primary liver malignancies in children under the age of 5 years and over the age of 10 years, respectively. This paper provides consensus-based imaging recommendations for evaluation of patients with primary hepatic malignancies at diagnosis and follow-up during and after therapy.

Vincristine/irinotecan/temsirolimus upfront window treatment of high-risk hepatoblastoma: A report from the Children's Oncology Group AHEP0731 Study Committee.

BACKGROUND: Survival for children with metastatic hepatoblastoma (HB) remains suboptimal. We report the response rate and outcome of two courses of vincristine/irinotecan/temsirolimus (VIT) in children with high-risk (HR)/metastatic HB. PROCEDURES: Patients with newly diagnosed HB received HR window chemotherapy if they had metastatic disease or a serum alpha-fetoprotein (AFP) level less than 100 ng/mL. Patients received vincristine (days 1 and 8), irinotecan (days 1-5), and temsirolimus (days 1 and 8). Cycles were repeated every 21 days. Responders had either a 30% decrease using RECIST (Response Evaluation Criteria in Solid Tumors) criteria OR a 90% (>1 log10 decline) AFP decline after two cycles. Responders received two additional cycles of VIT intermixed with six cycles of cisplatin/doxorubicin/5-fluorouracil/vincristine (C5VD). Nonresponders received six cycles of C5VD alone. RESULTS: Thirty-six eligible patients enrolled on study. The median age at enrollment was 27 months (range: 7-170). Seventeen of 36 patients were responders (RECIST and AFP = 3, RECIST only = 4, AFP only = 10). The median AFP at diagnosis was 222,648 ng/mL and the median AFP following two VIT cycles was 19,262 ng/mL. Three-year event-free survival was 47% (95% confidence interval [CI]: 30%-62%), while overall survival was 67% (95% CI: 49%-80%). CONCLUSION: VIT did not achieve the study efficacy endpoint. Temsirolimus does not improve the response rate seen in patients treated with vincristine and irinotecan (VI) alone as part of the initial treatment regimen explored in this study. Additionally, AFP response may be a more sensitive predictor of disease response than RECIST in HB.

Imaging of Right Lower Quadrant Pain in Children and Adolescents: AJR Expert Panel Narrative Review.

Right lower quadrant (RLQ) pain is a common clinical presentation in children, and accurate clinical diagnosis remains challenging given that this nonspecific presentation is associated with numerous surgical and nonsurgical conditions. The broad differential diagnosis varies by patient age and sex. Important considerations in the selection of a diagnostic imaging strategy include the sequencing, performance, and cost of tests. This article provides a comprehensive narrative review of the diagnostic imaging of RLQ pain in children and adolescents, including a discussion of the complementary roles of ultrasound, CT, and MRI; description of key imaging findings based on available evidence; and presentation of salient differential diagnoses. Subspecialized pediatric emergency medicine and surgical perspectives are also provided as further clinical insight into this common, but often challenging, scenario. Finally, the current status of imaging of RLQ pain in children and adolescents is summarized on the basis of expert consensus.

The Simplified MR Index of Activity Score in Pediatric Small-Bowel Crohn Disease: An Interreader Agreement and Responsiveness Study.

BACKGROUND. The simplified MR index of activity (MaRIA) score is used to assess the severity of small-bowel inflammation without use of IV contrast material. OBJECTIVE. The purposes of this study were to assess interreader agreement on the use of simplified MaRIA scores for evaluation of the inflammatory activity of terminal ileal Crohn disease in children and young adults and to assess whether simplified MaRIA scores change after biologic medical therapy. METHODS. This analysis was ancillary to a previously reported primary prospective research investigation. The study included 20 children and young adults with newly diagnosed ileal Crohn disease and 15 healthy control participants who underwent research small-bowel MRI examinations between December 2018 and October 2021. The participants with Crohn disease underwent baseline MRI and MRI 6 weeks and 6 months after beginning anti-tumor necrosis factor α-treatment as well as weighted pediatric Crohn disease activity index (wPCDAI) and C-reactive protein (CRP) assessment on the day of each examination. Control participants underwent one MRI examination. Four pediatric radiologists independently assigned simplified MaRIA scores using axial and coronal T2-weighted SSFSE images. Median simplified MaRIA score among readers was computed. Interreader agreement was assessed with Fleiss kappa coefficients and intra-class correlation coefficient (ICC). Analysis included the Mann-Whitney U test, Friedman test, and Spearman rank correlation. RESULTS. Simplified MaRIA scores (across time points and study groups) had substantial interreader agreement (κ = 0.65 [95% CI, 0.56-0.74]; ICC, 0.71 [95% CI, 0.63-0.78]). Median scores were higher in participants with Crohn disease at baseline than in healthy control participants (3.5 [IQR, 2.5-4.9] vs 0.5 [IQR, 0-2.0]; p < .001). Scores decreased after medical treatment in participants with Crohn disease (p = .005). The median score was 3.5 (IQR, 2.5-4.9) at baseline, 2.3 (IQR, 1.6-3.9) at 6 weeks, and 2.0 (IQR, 0.5-2.5) at 6 months. In participants with Crohn disease, median scores had significant correlations with wPCDAI (ρ = 0.46 [95% CI, 0.18-0.64]; p < .001) and CRP level (ρ = 0.48 [95% CI, 0.27-0.65]; p < .001). CONCLUSION. Radiologists had substantial agreement in use of simplified MaRIA scores to assess intestinal inflammation in ileal Crohn disease. Scores changed over time after medical therapy. CLINICAL IMPACT. The results support the simplified MaRIA score as an objective MRI-based clinical measure of intestinal inflammation in children and young adults with Crohn disease.

Respiratory-Triggered Flow-Independent Noncontrast Non-ECG-Gated MRV (REACT) Versus CE-MRV for Central Venous Evaluation in Children and Young Adults: A Six-Reader Study.

BACKGROUND. Contrast-enhanced MRI is commonly used to evaluate thoracic central venous patency in children and young adults. A flow-independent noncontrast non-ECG-gated 3D MRA-MR venography (MRV) technique described in 2019 as "relaxation-enhanced angiography without contrast and triggering (REACT)" may facilitate such evaluation. OBJECTIVE. The purpose of our study was to compare image quality, diagnostic confidence, and interreader agreement between respiratory-triggered REACT and 3D Dixon-based contrast-enhanced MRV (CE-MRV) for evaluating thoracic central venous patency in children and young adults. METHODS. This retrospective study included 42 consecutive children and young adults who underwent MRI of the neck and chest to evaluate central venous patency between August 2019 and January 2021 (median age, 5.2 years; IQR, 1.4-15.1 years; 22 female patients and 20 male patients). Examinations included respiratory-triggered REACT and navigator-gated CE-MRV sequences based on the institution's standard-of-care protocol. Six pediatric radiologists from four different institutions independently reviewed REACT and CE-MRV sequences; they assessed overall image quality (scale, 1-5; 5 = excellent), diagnostic confidence (scale, 1-5; 5 = extremely confident), and presence of clinically relevant artifact(s). Readers classified seven major central vessels as normal or abnormal (e.g., narrowing, thrombosis, or occlusion). Analysis used Wilcoxon signed rank and McNemar tests and Fleiss kappa coefficients. RESULTS. The distribution of overall image quality scores was higher (p = .02) for REACT than for CE-MRV for one reader (both sequences: median score, 5). Image quality scores were not significantly different between the sequences for the remaining five readers (all p > .05). Diagnostic confidence scores and frequency of clinically relevant artifact(s) were not significantly different between sequences for any reader (all p > .05). Interreader agreement for vessel classification as normal or abnormal was similar between sequences for all seven vessels (REACT: κ = 0.37-0.81; CE-MRV: κ = 0.34-0.81). Pooling readers and vessels, 65.4% of vessels were normal by both sequences; 18.7%, abnormal by both sequences; 9.8%, abnormal by REACT only; and 6.1%, abnormal by CE-MRV only. CONCLUSION. Respiratory-triggered REACT, in comparison with CE-MRV, showed no significant difference in image quality (aside from for one of six readers), diagnostic confidence, or frequency of artifact(s), with similar interreader agreement for vessel classification as normal or abnormal. CLINICAL IMPACT. High-resolution 3D MRV performed without IV contrast material can be used to assess central venous patency in children and young adults.

Optimizing Imaging of Pediatric Liver Lesions: Guidelines from the Pediatric LI-RADS Working Group.

A differential diagnosis based on a patient's age, clinical presentation, and serum α-fetoprotein level will help guide the initial imaging workup in children with a liver lesion. Children vary significantly in size, the ability to stay still, and the ability to breath hold for imaging examinations. Choosing and tailoring imaging techniques and protocols for each indication and age group is important for optimal care with minimal invasiveness. The need for sedation or anesthesia can be obviated by using techniques like feed and bundle, distraction, contrast-enhanced US, and motion-insensitive sequences for MRI. US is often the first imaging modality used in children with a suspected abdominal mass. Once a hepatic lesion is confirmed, multiphasic contrast-enhanced MRI is recommended for most lesions as the next imaging modality allowing full characterization of the lesion and assessment of the liver parenchyma. Contrast-enhanced CT can also be performed for assessment of pediatric focal liver lesions, especially in patients who have a contraindication to MRI. Contrast-enhanced US has shown promise to decrease the need for MRI or CT in some lesions such as hemangioma and focal nodular hyperplasia. Children with a history of malignancy can develop multiple types of hepatic lesions at various stages, including infections during an immunocompromised state, manifesting as focal liver lesions. Based on available limited data in the literature and the collective experiences of the Liver Imaging and Reporting Data System Pediatric Working Group, the authors provide guidelines for the imaging workup of pediatric focal liver lesions with an indication- and age-based approach and discuss the selection and performance of various imaging techniques and modalities. ©RSNA, 2022 See the invited commentary by Chojniak and Boaventura in this issue.

Cancer Therapy-related Hepatic Injury in Children: Imaging Review from the Pediatric LI-RADS Working Group.

The liver is the primary organ for the metabolism of many chemotherapeutic agents. Treatment-induced liver injury is common in children undergoing cancer therapy. Hepatic injury occurs due to various mechanisms, including biochemical cytotoxicity, hepatic vascular injury, radiation-induced cytotoxicity, and direct hepatic injury through minimally invasive and invasive surgical treatments. Treatment-induced liver injury can be seen contemporaneous with therapy and months to years after therapy is complete. Patients can develop a combination of hepatic injuries manifesting during and after treatment. Acute toxic effects of cancer therapy in children include hepatitis, steatosis, steatohepatitis, cholestasis, hemosiderosis, and vascular injury. Longer-term effects of cancer therapy include hepatic fibrosis, chronic liver failure, and development of focal liver lesions. Quantitative imaging techniques can provide useful metrics for disease diagnosis and monitoring, especially in treatment-related diffuse liver injury such as hepatic steatosis and steatohepatitis, hepatic iron deposition, and hepatic fibrosis. Focal liver lesions, including those developing as a result of treatment-related vascular injury such as focal nodular hyperplasia-like lesions and hepatic perfusion anomalies, as well as hepatic infections occurring as a consequence of immune suppression, can be anxiety provoking and confused with recurrent malignancy or hepatic metastases, although there often are imaging features that help elucidate the correct diagnosis. Radiologic evaluation, in conjunction with clinical and biochemical screening, is integral to diagnosing and monitoring hepatic complications of cancer therapy in pediatric patients during therapy and after therapy completion for long-term surveillance. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material See the invited commentary by Ferraciolli and Gee in this issue.

Prospective study of quantitative liver MRI in cystic fibrosis: feasibility and comparison to PUSH cohort ultrasound.

BACKGROUND: Pediatric radiologists can identify a liver ultrasound (US) pattern predictive of progression to advanced liver disease. However, reliably discriminating these US patterns remains difficult. Quantitative magnetic resonance imaging (MRI) may provide an objective measure of liver disease in cystic fibrosis (CF). OBJECTIVE: The purpose of this study was to determine if quantitative MRI, including MR elastography, is feasible in children with CF and to determine how quantitative MRI-derived metrics compared to a research US. MATERIALS AND METHODS: A prospective, multi-institutional trial was performed evaluating CF participants who underwent a standardized MRI. At central review, liver stiffness, fat fraction, liver volume, and spleen volume were obtained. Participants whose MRI was performed within 1 year of US were classified by US pattern as normal, homogeneous hyperechoic, heterogeneous, or nodular. Each MRI measure was compared among US grade groups using the Kruskal-Wallis test. RESULTS: Ninety-three participants (51 females [54.8%]; mean 15.6 years [range 8.1-21.7 years]) underwent MRI. MR elastography was feasible in 87 participants (93.5%). Fifty-eight participants had an US within 1 year of MRI. In these participants, a nodular liver had significantly higher stiffness (P<0.01) than normal or homogeneous hyperechoic livers. Participants with a homogeneous hyperechoic liver had a higher fat fraction (P<0.005) than others. CONCLUSION: MR elastography is feasible in children with CF. Participants with a nodular pattern had higher liver stiffness supporting the US determination of advanced liver disease. Participants with a homogeneous hyperechoic pattern had higher fat fractions supporting the diagnosis of steatosis.

Are the Pilots Onboard? Equipping Radiologists for Clinical Implementation of AI.

The incorporation of artificial intelligence into radiological clinical workflow is on the verge of being realized. To ensure that these tools are effective, measures must be taken to educate radiologists on tool performance and failure modes. Additionally, radiology systems should be designed to avoid automation bias and the potential decline in radiologist performance. Designed solutions should cater to every level of expertise so that patient care can be enhanced and risks reduced. Ultimately, the radiology community must provide education so that radiologists can learn about algorithms, their inputs and outputs, and potential ways they may fail. This manuscript will present suggestions on how to train radiologists to use these new digital systems, how to detect AI errors, and how to maintain underlying diagnostic competency when the algorithm fails.

Development and Implementation of a Semi-Automated Workflow for Point-of-Care Ultrasound Billing and Documentation Within an Electronic Health Record.

Point-of-care ultrasound (POCUS) is widely used for both diagnostic and therapeutic purposes. With its many advantages, including ease of use, real-time multisystem assessment, affordability, availability, and accuracy, it has been adopted by all medical specialties. Despite its advantages, the lack of standard workflow and automated billing solutions makes it difficult to launch a comprehensive POCUS program. In this work, we describe how we created and implemented an efficient standardized EHR-based workflow for POCUS that has been used across multiple division and settings within our organization.

Doxorubicin in combination with cisplatin, 5-flourouracil, and vincristine is feasible and effective in unresectable hepatoblastoma: A Children's Oncology Group study.

BACKGROUND: The Children's Oncology Group (COG) adopted cisplatin, 5-flourouracil, and vincristine (C5V) as standard therapy after the INT-0098 legacy study showed statistically equivalent survival but less toxicity in comparison with cisplatin and doxorubicin. Subsequent experience demonstrated doxorubicin to be effective in patients with recurrent disease after C5V, and this suggested that it could be incorporated to intensify therapy for patients with advanced disease. METHODS: In this nonrandomized, phase 3 COG trial, the primary aim was to explore the feasibility and toxicity of a novel therapeutic cisplatin, 5-flourouracil, vincristine, and doxorubicin (C5VD) regimen with the addition of doxorubicin to C5V for patients considered to be at intermediate risk. Patients were eligible if they had unresectable, nonmetastatic disease. Patients with a complete resection at diagnosis and local pathologic evidence of small cell undifferentiated histology were also eligible for an assessment of feasibility. RESULTS: One hundred two evaluable patients enrolled between September 14, 2009, and March 12, 2012. Delivery of C5VD was feasible and tolerable: the mean percentages of the target doses delivered were 96% (95% CI, 94%-97%) for cisplatin, 96% (95% CI, 94%-97%) for 5-fluorouracil, 95% (95% CI, 93%-97%) for doxorubicin, and 90% (95% CI, 87%-93%) for vincristine. Toxicity was within expectations, with death as a first event in 1 patient. The most common adverse events were febrile neutropenia (n = 55 [54%]), infection (n = 48 [47%]), mucositis (n = 31 [30%]), hypokalemia (n = 39 [38%]), and elevated aspartate aminotransferase (n = 28 [27%]). The 5-year event-free and overall survival rates for the 93 patients who did not have complete resection at diagnosis were 88% (95% CI, 79%-93%) and 95% (95% CI, 87%-98%), respectively. CONCLUSIONS: The addition of doxorubicin to the previous standard regimen of C5V is feasible, tolerable, and efficacious, and this suggests that C5VD is a good regimen for future clinical trials.