Publications by authors named "Cindy L Schwartz"

73 Publications

Gene expression-based model predicts outcome in children with intermediate-risk classical Hodgkin lymphoma.

Blood 2021 Oct 18. Epub 2021 Oct 18.

University of British Columbia, Canada.

Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, determine molecular correlates of treatment failure, and develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared to adult cHL data. Eosinophils, B-cells, and mast cell signatures were enriched in children, while macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs. 90.3%; log-rank P = .0138) independent of interim response, stage, fever and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. ClinicalTrials.gov Identifier: NCT00025259.
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http://dx.doi.org/10.1182/blood.2021011941DOI Listing
October 2021

Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.

Cancer 2021 Oct 13. Epub 2021 Oct 13.

Oishei Children's Hospital, Roswell Park Comprehensive Center, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York.

Background: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials.

Methods: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods.

Results: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m ) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35).

Conclusions: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.
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http://dx.doi.org/10.1002/cncr.33974DOI Listing
October 2021

Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031.

Pediatr Blood Cancer 2021 Sep 10;68(9):e29212. Epub 2021 Jul 10.

Department of Radiology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.

Background: Positron emission tomography (PET)-based measures of baseline total-body tumor burden may improve risk stratification in intermediate-risk Hodgkin lymphoma (HL).

Materials And Methods: Evaluable patients were identified from a cohort treated homogeneously with the same combined modality regimen on the Children's Oncology Group AHOD0031 study. Eligible patients had high-quality baseline PET scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were each measured based on 15 thresholds for every patient. Univariate and multivariable Cox regression and Kaplan-Meier survival analyses assessed for an association of MTV and TLG with event-free survival (EFS).

Results: From the AHOD0031 cohort (n = 1712), 86 patients were identified who (i) were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy followed by involved field radiotherapy, and (ii) had a baseline PET scan that was amenable to quantitative analysis. Based on univariate Cox regression analysis, six PET-derived parameters were significantly associated with EFS. For each of these, Kaplan-Meier analyses and the log-rank test were used to compare patients with highest tumor burden (i.e., highest 15%) to the remainder of the cohort. EFS was significantly associated with all six PET parameters (all p < .029). In a multivariable model controlling for important covariates including disease bulk and response to chemotherapy, MTV was significantly associated with EFS (p = .012).

Conclusion: Multiple baseline PET-derived volumetric parameters were associated with EFS. MTV was highly associated with EFS when controlling for disease bulk and response to chemotherapy. Incorporation of baseline MTV into risk-based treatment algorithms may improve outcomes in intermediate-risk HL.
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http://dx.doi.org/10.1002/pbc.29212DOI Listing
September 2021

Pediatric classical Hodgkin lymphoma.

Pediatr Blood Cancer 2021 05;68 Suppl 2:e28562

Radiation Oncology, Princess Margaret Cancer Center and University of Toronto, Toronto, Canada.

Over the past century, classical Hodgkin lymphoma (HL) has been transformed from a uniformly fatal disease to one of the most curable cancers. Given the high cure rate, a major focus of classical HL management is reducing the use of radiation therapy (RT) and chemotherapy agents such as procarbazine and doxorubicin to minimize long-term toxicities. In both North America and Europe, an important philosophy in the management of classical HL is to guide the intensity of treatment according to the risk category of the disease. The main factors used for risk classification are tumor stage, bulk of disease, and the presence of B symptoms. Response to chemotherapy is an important factor guiding the utilization of RT in ongoing Children's Oncology Group (COG) and European Network Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials. Both trial groups have transitioned to reduced RT volumes that target the highest risk sites using highly conformal techniques, along with standard or intensified chemotherapy regimens to improve outcomes in higher risk patients. However, given the potential acute toxicities of intensified chemotherapy, immunoregulatory drugs are being investigated in upcoming trials. The purpose of this review is to summarize current approaches to treating pediatric classical HL according to the COG and EuroNet-PHL.
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http://dx.doi.org/10.1002/pbc.28562DOI Listing
May 2021

Subsequent malignant neoplasms among children with Hodgkin lymphoma: a report from the Children's Oncology Group.

Blood 2021 03;137(11):1449-1456

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN; and.

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children's Oncology Group study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1711 patients enrolled in AHOD0031. Patients were treated with 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved-field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to 2 additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow-up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% confidence interval [CI], 0.6-2.0). SMNs included 3 patients with acute myeloid leukemia (AML), 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI, 4.5-15.2) with an excess absolute risk of 1.2 per 1000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (P = .037). In multivariate analysis, RT, B symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia and myelodysplastic syndrome (MDS). Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. This trial was registered at www.clinicaltrials.gov as #NCT00025259.
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http://dx.doi.org/10.1182/blood.2020007225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7976513PMC
March 2021

Automated quantification of baseline imaging PET metrics on FDG PET/CT images of pediatric Hodgkin lymphoma patients.

EJNMMI Phys 2020 Dec 14;7(1):76. Epub 2020 Dec 14.

Department of Radiology, University of Wisconsin-Madison, Madison, WI, USA.

Purpose: For pediatric lymphoma, quantitative FDG PET/CT imaging features such as metabolic tumor volume (MTV) are important for prognosis and risk stratification strategies. However, feature extraction is difficult and time-consuming in cases of high disease burden. The purpose of this study was to fully automate the measurement of PET imaging features in PET/CT images of pediatric lymphoma.

Methods: F-FDG PET/CT baseline images of 100 pediatric Hodgkin lymphoma patients were retrospectively analyzed. Two nuclear medicine physicians identified and segmented FDG avid disease using PET thresholding methods. Both PET and CT images were used as inputs to a three-dimensional patch-based, multi-resolution pathway convolutional neural network architecture, DeepMedic. The model was trained to replicate physician segmentations using an ensemble of three networks trained with 5-fold cross-validation. The maximum SUV (SUV), MTV, total lesion glycolysis (TLG), surface-area-to-volume ratio (SA/MTV), and a measure of disease spread (Dmax) were extracted from the model output. Pearson's correlation coefficient and relative percent differences were calculated between automated and physician-extracted features.

Results: Median Dice similarity coefficient of patient contours between automated and physician contours was 0.86 (IQR 0.78-0.91). Automated SUV values matched exactly the physician determined values in 81/100 cases, with Pearson's correlation coefficient (R) of 0.95. Automated MTV was strongly correlated with physician MTV (R = 0.88), though it was slightly underestimated with a median (IQR) relative difference of - 4.3% (- 10.0-5.7%). Agreement of TLG was excellent (R = 0.94), with median (IQR) relative difference of - 0.4% (- 5.2-7.0%). Median relative percent differences were 6.8% (R = 0.91; IQR 1.6-4.3%) for SA/MTV, and 4.5% (R = 0.51; IQR - 7.5-40.9%) for Dmax, which was the most difficult feature to quantify automatically.

Conclusions: An automated method using an ensemble of multi-resolution pathway 3D CNNs was able to quantify PET imaging features of lymphoma on baseline FDG PET/CT images with excellent agreement to reference physician PET segmentation. Automated methods with faster throughput for PET quantitation, such as MTV and TLG, show promise in more accessible clinical and research applications.
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http://dx.doi.org/10.1186/s40658-020-00346-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736382PMC
December 2020

Effects of dexrazoxane on doxorubicin-related cardiotoxicity and second malignant neoplasms in children with osteosarcoma: a report from the Children's Oncology Group.

Cardiooncology 2019 28;5:15. Epub 2019 Oct 28.

6Department of Pediatrics, University at Buffalo, Oishei Children's Hospital, Roswell Park Comprehensive Cancer Center, Buffalo, NY USA.

Background: Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown.

Methods: We evaluated children with osteosarcoma (OS) on two Children's Oncology Group trials with higher dose doxorubicin (375-600 mg/m) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected.

Results: All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness scores ( < 0.01) and LV mass scores ( < 0.01) were significantly smaller than normal for body-surface area in both sexes. The average LV mass scores were significantly smaller for girls ( < 0.01) and marginally smaller for boys ( = 0.06). Girls had significantly smaller LV end-diastolic dimension scores normalized to BSA ( < 0.01) compared to healthy controls and had significant increases in NT-proBNP. Four children developed SMNs as first events, a rate similar to historical controls.

Conclusions: Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity.

Trial Registrations: ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.
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http://dx.doi.org/10.1186/s40959-019-0050-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048050PMC
October 2019

Creating a bridge for transition: From pediatric cancer survival to life-long, risk-based health care of the adult cancer survivor.

Authors:
Cindy L Schwartz

Cancer 2020 02 18;126(3):473-476. Epub 2019 Oct 18.

Division of Pediatric Hematology, Oncology, and Bone Marrow Transplant, Department of Pediatrics, Medical College of Wisconsin/Children's Hospital of Wisconsin, Milwaukee, Wisconsin.

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http://dx.doi.org/10.1002/cncr.32569DOI Listing
February 2020

Survival by Race and Ethnicity in Pediatric and Adolescent Patients With Hodgkin Lymphoma: A Children's Oncology Group Study.

J Clin Oncol 2019 11 20;37(32):3009-3017. Epub 2019 Sep 20.

Emory University School of Medicine, Atlanta, GA.

Purpose: Population-based studies of children and adolescents with Hodgkin lymphoma (HL) report a survival disadvantage in nonwhite-non-Hispanic black (NHB) and Hispanic-patients. Whether disparities persist after adjustment for clinical and treatment-related variables is unknown. We examined survival by race/ethnicity in children receiving risk-based, response-adapted, combined-modality therapy for HL in contemporary Children's Oncology Group trials.

Patients And Methods: This pooled analysis used individual-level data from 1,605 patients (younger than age 1 to 21 years) enrolled in phase III trials for low-risk (AHOD0431), intermediate-risk (AHOD0031), and high-risk (AHOD0831) HL from 2002 to 2012. Event-free survival (EFS) and overall survival (OS) were compared between non-Hispanic white (NHW) and nonwhite patients. Cox proportional hazards for survival were estimated for both de novo and relapsed HL, adjusting for demographics, disease characteristics, and therapy.

Results: At median follow up of 6.9 years, cumulative incidence of relapse was 17%. Unadjusted 5-year EFS and OS were 83% (SE, 1.2%) and 97% (SE, < 1%), respectively. Neither differed by race/ethnicity. In multivariable analyses for OS, nonwhite patients had a 1.88× higher hazard of death (95% CI, 1.1 to 3.3). Five-year postrelapse survival probabilities by race were as follows: NHW, 90%; NHB, 66%; and Hispanic, 80% ( < .01). Compared with NHW, Hispanic and NHB children had 2.7-fold (95% CI, 1.2 to 6.2) and 3.5-fold (95% CI, 1.5 to 8.2) higher hazard of postrelapse mortality, respectively.

Conclusion: In patients who were treated for de novo HL in contemporary Children's Oncology Group trials, EFS did not differ by race/ethnicity; however, adjusted OS was significantly worse in nonwhite patients, a finding driven by increased postrelapse mortality in this population. Additional studies examining treatment and survival disparities after relapse are warranted.
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http://dx.doi.org/10.1200/JCO.19.00812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839907PMC
November 2019

Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.

Eur J Cancer 2019 03 25;109:36-50. Epub 2019 Jan 25.

CDC MRC Clinical Trials Unit at UCL, London, UK.

Background: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials.

Methods: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients.

Results: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome.

Conclusions: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider.
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http://dx.doi.org/10.1016/j.ejca.2018.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506906PMC
March 2019

Outcomes in intermediate-risk pediatric lymphocyte-predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2018 12 14;65(12):e27375. Epub 2018 Sep 14.

Department of Pediatrics, Vanderbilt University, Nashville, Tennessee.

Purpose: Optimal management of patients with intermediate-risk lymphocyte-predominant Hodgkin lymphoma (LPHL) is unclear due to their small numbers in most clinical trials. Children's Oncology Group AHOD0031, a randomized phase III trial of pediatric patients with intermediate-risk Hodgkin lymphoma (HL), included patients with LPHL. We report the outcomes of these patients and present directions for future therapeutic strategies.

Procedure: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to two additional ABVE-PC cycles ± two dexamethasone, etoposide, cisplatin, and cytarabine cycles and all received involved field radiotherapy (IFRT). Rapid early responders (RERs) received two additional ABVE-PC cycles. RERs with complete response (CR) were randomized to IFRT or no further therapy. RERs without CR received IFRT.

Results: Ninety-six (5.6%) of 1711 patients on AHOD0031 had LPHL. Patients with LPHL were more likely to achieve RER (93.6% vs. 81.0%; P = 0.002) and CR (74.2% vs. 49.3%; P = 0.000005) following chemotherapy compared with patients with classical HL. Five-year event-free survival (EFS) was superior in patients with LPHL (92.2%) versus classical HL (83.5%) (P = 0.04), without difference in overall survival (OS). Among RERs with CR following chemotherapy (n = 33), there was no difference in EFS or OS between those randomized to receive or not receive IFRT.

Conclusion: Children and adolescents with intermediate-risk LPHL represent ideal candidates for response-adapted therapy based on their favorable outcomes. The majority of patients treated with the ABVE-PC backbone achieve RER with CR status and can be treated successfully without IFRT.
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http://dx.doi.org/10.1002/pbc.27375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6192844PMC
December 2018

Factors influencing survival after recurrence in osteosarcoma: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2019 01 25;66(1):e27444. Epub 2018 Sep 25.

Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, Connecticut.

Background: Despite drastic improvement in overall survival for pediatric patients with cancer, those with osteosarcoma have stable rates of survival since the 1980s. This project evaluates the effect of several variables on survival after first recurrence in patients with osteosarcoma.

Methods: Data from three prospective North American cooperative group trials for newly diagnosed osteosarcoma are included: INT-0133, POG-9754, and AOST0121. The analytic population for this study is all enrolled patients with first event-free survival (EFS) event of relapse. The primary outcome measure for this retrospective analysis was survival after recurrence (SAR).

Results: The analytic population consisted of N = 431 patients. SAR was statistically significantly associated with age at enrollment (<10 years, P = 0.027), presence of metastatic disease at diagnosis (localized, P < 0.0001), site of relapse (combination lung + bone, unfavorable, P = 0.005), and time to first relapse (2+ years, favorable, P < 0.0001) in multivariate analysis. Ethnicity, primary site of tumor, race, and sex were not significantly related to SAR.

Conclusions: Prolonged SAR in patients with relapsed osteosarcoma is associated with age, extent of disease at diagnosis, site of and time to relapse. Adolescent and young adult patients with osteosarcoma have shorter SAR than younger patients, consistent with studies showing decreased overall survival in this group. Although patients with primary metastatic disease have shorter SAR, there is a subset of patients who relapse greater than 2 years from initial diagnosis that will become survivors. Histological response was significantly associated with time to relapse, but was not predictive of SAR.
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http://dx.doi.org/10.1002/pbc.27444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249072PMC
January 2019

Significance of pleural effusion at diagnosis in pediatric Hodgkin lymphoma: a report from Children's Oncology Group protocol AHOD0031.

Pediatr Radiol 2018 11 16;48(12):1736-1744. Epub 2018 Jul 16.

Department of Pediatrics, Roswell Park Cancer Institute, Buffalo, NY, USA.

Background: Pleural effusion at presentation in Hodgkin lymphoma has been associated with inferior outcome but has not been systematically evaluated.

Objective: To determine whether pleural effusion at presentation in children with Hodgkin lymphoma is a primary indicator of poor prognosis or secondary to associated factors.

Materials And Methods: Children's Oncology Group (COG) AHOD0031, a randomized, response-based, centrally reviewed protocol, enrolled 1,712 eligible patients <22 years of age with initial presentation of intermediate risk, biopsy-proven Hodgkin lymphoma; 1,423 had available imaging for retrospective review. We coded effusions as fluid-only or with associated pleural nodule or adjacent lung or bone involvement and correlated this with disease stage, tumor response, large mediastinal adenopathy, and mass effect on the superior vena cava (SVC) and left innominate vein. We recorded change in size and character of effusions post-chemotherapy.

Results: Pleural effusions were present in 217, with 204 having fluid-only and 13 having associated solid components. Patients with effusions were more likely to have large mediastinal adenopathy (P<0.0001), be slow early responders (P<0.0001) and have higher relapse rate (P<0.0001). Vascular compression was not significantly correlated with pleural effusion. Of 121 patients with adequate [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT imaging, no FDG PET avidity was seen in any pleural effusion but was present in solid components. The side of the pleural effusion in those with moderate or large effusions was highly associated with the side of large mediastinal adenopathy (P<0.0001). Statistical analysis indicates that pleural effusion is an independent risk factor for poorer response and relapse.

Conclusion: Pleural effusion in Hodgkin lymphoma is an important independent poor prognostic indicator for response and relapse.
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http://dx.doi.org/10.1007/s00247-018-4197-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208959PMC
November 2018

Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group.

Cancer 2018 08 8;124(15):3210-3219. Epub 2018 May 8.

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin.

Background: The Children's Oncology Group AHOD0431 study evaluated a response-directed treatment paradigm in which minimal initial chemotherapy and low-dose radiation was received only by patients who did not achieve a complete remission, and a chemotherapy/low-dose radiation salvage regimen was received by those who had a protocol-defined, low-risk recurrence.

Methods: Patients younger than 21 years who had stage IA or IIA nonbulky disease were eligible. The treatment strategy was evaluated by determining the proportion that received minimal chemotherapy alone, the proportion that had a first or second remission without the receipt of high-dose chemotherapy/stem cell rescue or higher dose involved-field radiation therapy (>21 grays), and overall survival.

Results: In total, 278 patients were eligible. At 4 years, 49.0% had received minimal chemotherapy and no radiation, 88.8% were in remission without receiving high-dose chemotherapy with stem cell rescue or >21 grays of involved-field radiation therapy, and the overall survival rate was 99.6%. Patients who had mixed cellularity histology had a 4-year event-free survival (EFS) rate of 95.2%, which was significantly better than the 75.8% EFS for those who had nodular sclerosis histology (P = .008). A red blood cell sedimentation rate ≤20 mm/hour and a negative fluorodeoxyglucose-positron emission tomography scan after 1 cycle of chemotherapy (PET1) were associated with a favorable EFS outcome. The study was closed early when the receipt of radiation therapy exceeded the predefined monitoring boundary.

Conclusions: This limited chemotherapy response-based approach was successful in patients who had a negative PET1 result, had MC histology, or had a low red blood cell sedimentation rate. In this treatment paradigm, evaluation of increased chemotherapy intensity or the integration of active new agents is indicated for patients who have nodular sclerosis histology with a high ESR or who have a positive PET1 result. Cancer 2018. © 2018 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.31519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097921PMC
August 2018

Patterns of Involved-Field Radiation Therapy Protocol Deviations in Pediatric Versus Adolescent and Young Adults With Hodgkin Lymphoma: A Report From the Children's Oncology Group AHOD0031.

Int J Radiat Oncol Biol Phys 2018 04 6;100(5):1119-1125. Epub 2018 Jan 6.

Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Purpose: The presented protocol for pediatric intermediate-risk Hodgkin lymphoma evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, prednisone]) with response-based therapy augmentation (addition of DECA [dexamethasone, etoposide, cisplatin, cytarabine]) or therapy reduction (elimination of radiation).

Methods And Materials: A central review of the radiation therapy data for quality assurance was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in the pediatric group (age <15 years) and adolescent and young adult (AYA) group (age ≥15-21 years). Involved-field radiation therapy (IFRT) planning was reviewed before the start of treatment and at treatment completion. The records were reviewed through the Quality Assurance Review Center's central review to identify RPD, classified according to dose deviation (DD), volume deviation (VD), undertreatment (UT), and overtreatment (OT). DDs and VDs were further classified as major or minor.

Results: Of the 1712 patients enrolled, 1155 received IFRT, of whom, 216 (18.7%) had RPDs. The DD and VD patterns were similar between the pediatric and AYA groups. Minor VDs were most common. UT RPDs accounted for 69% in the pediatric group and 75% in the AYA group. Of the 35 patients with relapse and a RPD, 29 had an undertreatment RPD. Among the patients who received IFRT, a significant difference was found in the cumulative incidence rates of relapse between the pediatric and AYA groups (P = .03); however, no significant difference was found between patients with and without RPD (P = .2).

Conclusions: Most RPDs were minor and consisted of UT in the AYA and pediatric populations both. No difference was observed in RPDs between the pediatric and AYA patients. Thus, in a well-defined and standardized protocol, the RPD distributions for AYA patients will be similar to those for pediatric population. However, the increased cumulative incidence of relapse in the AYA patients who had received IFRT compared with the pediatric population requires further exploration, given the potential differences in clinical outcomes in the AYA population.
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http://dx.doi.org/10.1016/j.ijrobp.2018.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555555PMC
April 2018

Epstein-Barr virus DNA in serum as an early prognostic marker in children and adolescents with Hodgkin lymphoma.

Blood Adv 2017 Apr 24;1(11):681-684. Epub 2017 Apr 24.

Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD.

Assay of cell-free DNA in blood offers an approach to assessment of tumor DNA. We sought to determine whether Epstein-Barr virus (EBV) DNA in cell-free blood is also a good surrogate for the presence of tumor DNA in children with Hodgkin lymphoma, as it is in adults, and whether it correlates with pediatric outcomes. Pediatric patients enrolled in a Children's Oncology Group trial (AHOD0031) were studied at baseline and at 8 days after the initiation of treatment. At baseline, EBV DNA in cell-free blood correlated with the presence of EBV in tumor, and EBV DNA 8 days after the initiation of therapy predicted inferior event-free survival. EBV DNA in cell-free blood warrants further investigation as a marker of inadequate tumor response in Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00025259.
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http://dx.doi.org/10.1182/bloodadvances.2016002618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727814PMC
April 2017

Outcomes in adolescents and young adults with Hodgkin lymphoma treated on US cooperative group protocols: An adult intergroup (E2496) and Children's Oncology Group (COG AHOD0031) comparative analysis.

Cancer 2018 01 13;124(1):136-144. Epub 2017 Sep 13.

Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts.

Background: There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL).

Methods: Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study.

Results: Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P < .001) and B symptoms (63% vs 27%; P < .001), and fewer had bulk disease (33% vs 77%; P < .001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study.

Conclusions: Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2018;124:136-44. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30979DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735034PMC
January 2018

Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2018 Jan 12;65(1). Epub 2017 Aug 12.

Division of Clinical Pathology, Department of Pathology, State University of New York Upstate Medical University, Syracuse, New York.

Background: Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL.

Procedure: One hundred sixty-eight cases of localized NLPHL were examined for histologic variants, CD30 and immunoglobulin D (IgD) expression, and outcome. Histologic types were scored categorically as 0 = 0, 1 ≤ 25%, and 2 > 25% of the sample.

Results: Fifty-eight (35.1%) cases showed only typical nodular with or without serpiginous histology (types A and B). The remainder showed mixtures of histologies. The numbers of patients with score 2 are 85 (50.6%) type A, 21 (12.5%) type B, 46 (27.4%) with extranodular large B cells (type C), 3 with T-cell-rich nodular pattern (type D), 55 (32.7%) with diffuse T-cell-rich (type E) pattern, and 2 (1.2%) with diffuse B-cell pattern (type F). Higher level of types C (P = 0.048) and D (P = 0.033) resulted in lower event-free survival (EFS). Cytoplasmic IgD was found in 65 of 130 tested (50%), did not significantly associate with EFS but positively correlated with types C and E histology (P < 0.0001) and negatively correlated with types A (P = 0.0003) and B (P = 0.006). Seventeen (10%) expressed CD30, with no adverse effect.

Conclusions: Variant histology is common in pediatric NLPHL, especially types C and E, which are associated with IgD expression. Type C variant histology and possibly type D are associated with decreased EFS, but neither IgD nor CD30 are adverse features. Variant histology may warrant increased surveillance, but did not affect overall survival.
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http://dx.doi.org/10.1002/pbc.26753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699946PMC
January 2018

Outcome of adolescents and young adults compared to children with Hodgkin lymphoma treated with response-based chemotherapy on pediatric protocols: A Children's Oncology Group report.

Pediatr Blood Cancer 2017 Dec 14;64(12). Epub 2017 Jun 14.

University of Illinois College of Medicine at Peoria, Peoria, Illinois.

Purpose: We evaluated the outcome of children (<15 years) versus that of adolescents and young adults (AYA; 15-≤ 21 years) treated for Hodgkin lymphoma (HL) in two Pediatric Oncology Group/Children's Oncology Group clinical trials, P9425 and P9426, that used dose-dense, response-based chemotherapy and reduced dose radiotherapy.

Patients And Methods: Subjects 21 years or younger with HL were eligible for these studies. Subjects with low-risk (stages IA, IIA, and IIIA1) without large mediastinal adenopathy biopsy-proven HL, eligible for P9426, were treated with two to four 28-day cycles of doxorubicin, bleomycin, vincristine, and etoposide (ABVE) chemotherapy and 25.5 Gy of involved field radiotherapy. Subjects with intermediate-risk (stages IB, IIA, IIIA1 with large mediastinal adenopathy, and IIIA2) and high-risk (stages IIB, IIIB, and IV) biopsy-proven HL, eligible for P9425, were treated with three to five 21-day cycles of ABVE plus prednisone and cyclophosphamide (ABVE-PC) chemotherapy and 21 Gy of involved region radiotherapy. We compared the 5-year event-free survival (EFS), based on Kaplan-Meier product-limit method, of children versus that of AYA.

Results: Four hundred seventy-one subjects were enrolled on P9425 and P9426 combined. Of these subjects, 203 were AYA, 104 with intermediate and high-risk HL, and 99 with low-risk HL. The 5-year EFS of children did not significantly differ from that of AYA (85.9 vs. 87.1%) with a median follow up of 7.7 years (P = 0.51).

Conclusion: Given the equivalent and excellent results of therapy, HL represents an opportunity for adult and pediatric cancer treatment collaborative groups to jointly design clinical trials targeted to AYA. These trials should focus on both treatment efficacy and the quality of life of AYA while receiving chemotherapy and in reduction of long-term side effects in the survivorship years.
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http://dx.doi.org/10.1002/pbc.26681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799083PMC
December 2017

Multisite external validation of a risk prediction model for the diagnosis of blood stream infections in febrile pediatric oncology patients without severe neutropenia.

Cancer 2017 Oct 23;123(19):3781-3790. Epub 2017 May 23.

Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee.

Background: Pediatric oncology patients are at an increased risk of invasive bacterial infection due to immunosuppression. The risk of such infection in the absence of severe neutropenia (absolute neutrophil count ≥ 500/μL) is not well established and a validated prediction model for blood stream infection (BSI) risk offers clinical usefulness.

Methods: A 6-site retrospective external validation was conducted using a previously published risk prediction model for BSI in febrile pediatric oncology patients without severe neutropenia: the Esbenshade/Vanderbilt (EsVan) model. A reduced model (EsVan2) excluding 2 less clinically reliable variables also was created using the initial EsVan model derivative cohort, and was validated using all 5 external validation cohorts. One data set was used only in sensitivity analyses due to missing some variables.

Results: From the 5 primary data sets, there were a total of 1197 febrile episodes and 76 episodes of bacteremia. The overall C statistic for predicting bacteremia was 0.695, with a calibration slope of 0.50 for the original model and a calibration slope of 1.0 when recalibration was applied to the model. The model performed better in predicting high-risk bacteremia (gram-negative or Staphylococcus aureus infection) versus BSI alone, with a C statistic of 0.801 and a calibration slope of 0.65. The EsVan2 model outperformed the EsVan model across data sets with a C statistic of 0.733 for predicting BSI and a C statistic of 0.841 for high-risk BSI.

Conclusions: The results of this external validation demonstrated that the EsVan and EsVan2 models are able to predict BSI across multiple performance sites and, once validated and implemented prospectively, could assist in decision making in clinical practice. Cancer 2017;123:3781-3790. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610619PMC
October 2017

Understanding predictors of continued long-term pediatric cancer care across the region: A report from the Consortium for New England Childhood Cancer Survivors.

Pediatr Blood Cancer 2017 Oct 28;64(10). Epub 2017 Apr 28.

Hasbro Children's Hospital, Alpert Medical School of Brown University, Providence, RI.

Background: Many survivors of childhood cancer do not receive recommended longitudinal oncology care. Factors present at the time of childhood cancer diagnosis may identify patients who are vulnerable to poor adherence to follow-up.

Methods: This cohort of survivors of acute lymphoblastic leukemia (ALL) diagnosed from 1996 to 1999 at seven Consortium for New England Childhood Cancer Survivors institutions was evaluated for attendance at oncology clinics at 5 and 10 years from diagnosis. Demographic, socioeconomic, disease, and treatment characteristics were analyzed as risk factors for nonadherence to follow-up.

Results: Of 317 patients, 90% were alive 5 years from diagnosis and 88% of those remained in active follow-up. At 10 years from diagnosis, 88% were alive, 73% of whom continued in active follow-up. Insurance status at diagnosis was significantly associated with adherence at both 5 and 10 years. At 10 years, initial enrollment on therapeutic study was associated with increased attendance and central nervous system (CNS) leukemia with decreased attendance. In multivariable modeling of follow-up at 5 years, patients who were adults were less likely to participate and those with private insurance at diagnosis more likely to participate. At 10 years, insurance status at diagnosis remained a predictor of adherence to follow-up.

Conclusions: In this regional cohort, many patients who are survivors of ALL continue to participate in oncology care at 5 and 10 years from diagnosis. Factors known at diagnosis including insurance status, CNS leukemia, older age, and enrollment on therapeutic study were associated with differential attendance to follow-up visits.
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http://dx.doi.org/10.1002/pbc.26564DOI Listing
October 2017

Osteogenic Sarcoma: Systemic Chemotherapy Options for Localized Disease.

Curr Treat Options Oncol 2017 04;18(4):24

MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.

Opinion Statement: Treatment for osteosarcoma, the most common malignant tumor of bone in children and adolescents, has not changed in decades. Treatment is multimodal, employing neoadjuvant chemotherapy followed by aggressive and complete surgical resection to achieve negative margins and a prolonged course of adjuvant chemotherapy. The primary tumor is usually successfully managed via surgery, but micrometastases are likely present in most patients at diagnosis. Death is the result of tumor recurrence in the lungs or more rarely in other bones despite aggressive treatment regimens and is likely attributable to innate resistance to chemotherapy. Better therapies are desperately needed. The three most active agents-high-dose methotrexate, doxorubicin, and cisplatin-commonly referred to as "MAP," form the backbone of therapy. After 2 cycles of MAP, surgical resection is performed of all sites of disease if possible. Histologic response following neoadjuvant chemotherapy is prognostic in non-metastatic osteosarcoma, but augmentation of adjuvant therapy for poor responders with additional agents (ifosfamide, etoposide) has not improved outcome. Inclusion of immunotherapy into treatment regimens is promising. Specifically, liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE), a macrophage and monocyte activator, improved 10-year overall survival for patients with localized disease, with a similar pattern of response in patients with metastatic disease. L-MTP-PE (mifamurtide) is approved and in widespread use in Europe and elsewhere but has not been approved for use by the Federal Drug Administration in the USA. Identifying novel targeted therapies to improve outcomes for patients with osteosarcoma remains an area of active research.
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http://dx.doi.org/10.1007/s11864-017-0464-2DOI Listing
April 2017

Mental distress and health care use among survivors of adolescent and young adult cancer: A cross-sectional analysis of the National Health Interview Survey.

Cancer 2017 03 17;123(5):869-878. Epub 2016 Nov 17.

Division of Pediatrics, Department of Pediatrics Patient Care, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: The current study was conducted to examine the prevalence and correlates of mental distress among survivors of adolescent and young adult (AYA) cancer and a comparison group.

Methods: A total of 875 AYA cancer survivors who were diagnosed between the ages of 15 and 39 years and who were at least 5 years from their initial diagnosis were identified from the 2013 and 2014 National Health Interview Surveys. A comparison group was created. The Kessler nonspecific mental/psychological distress scale was used to examine none/low, moderate, and severe distress. The issues of whether individuals talked to mental health professionals within the previous year and if they could afford mental health care also were examined. Variables (ie, demographics, behavioral [eg, smoking status], comorbidity, and mental health visits) associated with distress among the 2 groups were identified using multinomial logistic regressions.

Results: Survivors reported mental distress more often than the comparison group (moderate: 23.2% vs 16.9%; and severe: 8.4% vs 3.0% [P<.001]). Survivors cited not being able to afford mental health care more often (6.4% vs 2.3%; P = .002). Moreover, 74.7% and 52.2% of survivors, respectively, with moderate and severe distress had not talked to a mental health professional. Contrary to the comparison group, survivors who were current smokers reported severe distress more often compared with nonsmokers (relative risk, 3.59; 95% confidence interval, 1.46-8.84 [P = .01]). Having public and no insurance versus private insurance and report of sleep-related trouble within the previous week were found to be associated with greater distress among survivors.

Conclusions: AYA cancer survivors are more likely to demonstrate mental distress than individuals without cancer. Nevertheless, few survivors may be receiving professional mental health services. Survivors need greater access to mental health screening and counseling to address the current gaps in care delivery. Cancer 2017;123:869-78. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30417DOI Listing
March 2017

Childhood Hodgkin International Prognostic Score (CHIPS) Predicts event-free survival in Hodgkin Lymphoma: A Report from the Children's Oncology Group.

Pediatr Blood Cancer 2017 04 27;64(4). Epub 2016 Oct 27.

Vanderbilt University School of Medicine, Ingram Cancer Center, Nashville, Tennessee.

Background: Early response to initial chemotherapy in Hodgkin lymphoma (HL) measured by computed tomography (CT) and/or positron emission tomography (PET) after two to three cycles of chemotherapy may inform therapeutic decisions. Risk stratification at diagnosis could, however, allow earlier and potentially more efficacious treatment modifications.

Patients And Methods: We developed a predictive model for event-free survival (EFS) in pediatric/adolescent HL using clinical data known at diagnosis from 1103 intermediate-risk HL patients treated on Children's Oncology Group protocol AHOD0031 with doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy and radiation. Independent predictors of EFS were identified and used to develop and validate a prognostic score (Childhood Hodgkin International Prognostic Score [CHIPS]). A training cohort was randomly selected to include approximately half of the overall cohort, with the remainder forming the validation cohort.

Results: Stage 4 disease, large mediastinal mass, albumin (<3.5), and fever were independent predictors of EFS that were each assigned one point in the CHIPS.  Four-year EFS was 93.1% for patients with CHIPS = 0, 88.5% for patients with CHIPS = 1, 77.6% for patients with CHIPS = 2, and 69.2% for patients with CHIPS = 3.

Conclusions: CHIPS was highly predictive of EFS, identifying a subset (with CHIPS 2 or 3) that comprises 27% of intermediate-risk patients who have a 4-year EFS of <80% and who may benefit from early therapeutic augmentation.  Furthermore, CHIPS identified higher risk patients who were not identified by early PET or CT response. CHIPS is a robust and inexpensive approach to predicting risk in patients with intermediate-risk HL that may improve ability to tailor therapy to risk factors known at diagnosis.
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http://dx.doi.org/10.1002/pbc.26278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702912PMC
April 2017

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.

Lancet Oncol 2016 Oct 25;17(10):1396-1408. Epub 2016 Aug 25.

Center for Cancer and Blood Disorders, Connecticut Children's Medical Center, Hartford, CT, USA.

Background: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma.

Methods: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m, doxorubicin 37·5 mg/m per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m) at 2·8 g/m per day with equidose mesna uroprotection, followed by etoposide 100 mg/m per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030.

Findings: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate.

Interpretation: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting.

Funding: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.
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http://dx.doi.org/10.1016/S1470-2045(16)30214-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052459PMC
October 2016

Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children's Oncology Group.

J Clin Oncol 2016 07 16;34(20):2372-9. Epub 2016 May 16.

Burton E. Appel, Hackensack University Medical Center, Hackensack, NJ; Lu Chen and Allen B. Buxton, Children's Oncology Group, Monrovia, CA; Robert E. Hutchison, State University of New York Upstate Medical University, Syracuse; Louis S. Constine, University of Rochester, Rochester, NY; David C. Hodgson, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Peter F. Ehrlich, University of Michigan, Ann Arbor, MI; and Cindy L. Schwartz, University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Children's Oncology Group study AHOD03P1 was designed to determine whether excellent outcomes can be maintained for patients with low-risk, pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) with a strategy of resection alone or minimal chemotherapy.

Patients And Methods: Patients with stage IA LPHL in a single node that was completely resected were observed without further therapy; recurrences were treated with three cycles of doxorubicin/vincristine/prednisone/cyclophosphamide (AV-PC). Patients with unresected stage IA or stage IIA LPHL were treated with three cycles of AV-PC. Patients with less than a complete response (CR) to AV-PC received 21-Gy involved-field radiation therapy (IFRT).

Results: A total of 183 eligible patients were enrolled; 178 were evaluable. Of these, 52 patients underwent complete resection of a single node. There were 13 relapses at a median of 11.5 months; 5-year event-free survival (EFS) was 77% (range, 62% to 87%). A total of 135 patients received AV-PC; 126 were treated at diagnosis and nine at relapse after surgery alone. Eleven patients receiving AV-PC had less than CR and received IFRT. Fourteen first events occurred among 135 patients (12 relapses and two second malignancies). Two relapses occurred in patients who had received IFRT. Five-year EFS was 88.8% (95% CI, 81.8% to 93.2%). Five-year EFS for the entire cohort was 85.5% (95% CI, 79.2% to 90.1%); overall survival was 100%.

Conclusion: Some 75% of highly selected pediatric patients with LPHL may be spared chemotherapy after surgical resection alone. Pediatric LPHL has excellent EFS with chemotherapy that is less intensive than standard regimens; > 90% of patients can avoid radiation therapy. The salvage rate for the few relapses is high, with 100% survival overall.
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http://dx.doi.org/10.1200/JCO.2015.65.3469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981978PMC
July 2016

Assessing the Prognostic Significance of Histologic Response in Osteosarcoma: A Comparison of Outcomes on CCG-782 and INT0133-A Report From the Children's Oncology Group Bone Tumor Committee.

Pediatr Blood Cancer 2016 10 29;63(10):1737-43. Epub 2016 Apr 29.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York.

Background: The prognostic value of histologic response for osteosarcoma may have changed with induction chemotherapy schedules over time. We hypothesized that the increased intensity of induction therapy provided on INT0133 compared to the Children's Cancer Group study CCG-782 would diminish the impact of histologic response on the risk of events after definitive surgery.

Methods: Retrospective analysis was performed for patients aged <22 with newly diagnosed nonmetastatic osteosarcoma enrolled on CCG-782 and INT0133. Clinical factors were evaluated for association with response and outcome. Good response was defined as <5% viable tumor at resection. Associations of response, study, and postdefinitive surgery event-free survival (EFS-DS) were determined using Cox proportional hazard models. EFS-DS was estimated by Kaplan-Meier methodology.

Results: Data were available for 814 patients (206 CCG-782, 608 INT0133). For good responders, 10-year EFS-DS (±SE) was 75.4% ± 7.7% for CCG-782 and 70.8% ± 3.1% for INT0133. For poor responders, 10-year EFS-DS was 39.9% ± 4.9% for CCG-782 and 58.4% ± 3.1% for INT0133. Histologic response predicted outcome across studies (P < 0.0001). Significant interaction between study and histologic response was observed for EFS-DS (P = 0.011). Using proportional hazards regression, INT0133 poor responders had less risk of events compared to CCG-782 poor responders (relative hazard ratio (RHR) = 0.6:1), but good responders on INT0133 had a greater risk of events compared to CCG-782 good responders (RHR = 1.53:1).

Conclusion: We observed an inverse relationship between the predictive value of tumor necrosis and intensity of induction therapy, raising questions about the true prognostic value of histologic response. This highlights the need for novel markers to develop strategies for treatment in future trials.
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http://dx.doi.org/10.1002/pbc.26034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5136499PMC
October 2016

Exercise and Fatigue in Adolescent and Young Adult Survivors of Hodgkin Lymphoma: A Report from the Children's Oncology Group.

J Adolesc Young Adult Oncol 2015 Sep;4(3):137-40

Department of Biostatistics, University of Nebraska Medical Center Department of Biostatistics , Omaha, Nebraska.

Fatigue is a significant problem for adolescent and young adult (AYA) Hodgkin lymphoma (HL) survivors. The relationship between exercise and fatigue is complex. This study explored the trajectory of and the relationship between exercise and fatigue over 36 months post-therapy in a cohort of 103 AYA-aged HL survivors treated on Children's Oncology Group (COG) study AHOD0031. Descriptive statistics and generalized estimating equations were used in this secondary data analysis. Exercise and fatigue improved over time but were unrelated; amount of exercise at end of therapy predicted amount of exercise at 12 (p = 0.02) and 36 (p = 0.0008) months post-therapy.
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http://dx.doi.org/10.1089/jayao.2015.0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575513PMC
September 2015
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