Hu14.18K.322A Causes Direct Cell Cytotoxicity and Synergizes with Induction Chemotherapy in High-Risk Neuroblastoma.

The disialoganglioside, GD2, is a promising therapeutic target due to its overexpression in certain tumors, particularly neuroblastoma (NB), with limited expression in normal tissues. Despite progress, the intricate mechanisms of action and the full spectrum of the direct cellular responses to anti-GD2 antibodies remain incompletely understood. In this study, we examined the direct cytotoxic effects of the humanized anti-GD2 antibody hu14.18K322A (hu14) on NB cell lines, by exploring the associated cell-death pathways. Additionally, we assessed the synergy between hu14 and conventional induction chemotherapy drugs. Our results revealed that hu14 treatment induced direct cytotoxic effects in CHLA15 and SK-N-BE1 cell lines, with a pronounced impact on proliferation and colony formation. Apoptosis emerged as the predominant cell-death pathway triggered by hu14. Furthermore, we saw a reduction in GD2 surface expression in response to hu14 treatment. Hu14 demonstrated synergy with induction chemotherapy drugs with alterations in GD2 expression. Our comprehensive investigation provides valuable insights into the multifaceted effects of hu14 on NB cells, shedding light on its direct cytotoxicity, cell-death pathways, and interactions with induction chemotherapy drugs. This study contributes to the evolving understanding of anti-GD2 antibody therapy and its potential synergies with conventional treatments in the context of NB.

Impact of a Regional Pediatric Hematology/Oncology Fellowship Program in Guatemala.

PURPOSE: This study aimed to describe and assess the regional experience of a pediatric hematology/oncology fellowship program based in Guatemala. METHODS: The Unidad Nacional de Oncología Pediátrica (UNOP) in Guatemala City, Guatemala, is the only hospital in Central America dedicated exclusively to childhood and adolescent cancer. To address the regional need for specialists, a fellowship program in pediatric hematology/oncology was launched in 2003. The UNOP fellowship program comprises 3 years of training. Although the program is based at UNOP, it also includes rotations locally and internationally to enhance clinical exposure. The curriculum is based on international standards to cover clinical expertise, research, professionalism, communication, and health advocacy. Trainees are selected according to country or facility-level need for pediatric hematologists/oncologists, with a plan for them to be hired immediately after completing their training. RESULTS: Forty physicians from 10 countries in Latin America have completed training. In addition, there are currently 13 fellows from five countries in training. Of the graduates, 39 (98%) are now practicing in pediatric hematology/oncology in Latin America. Moreover, many of them have leadership positions within their institutions and participate in research, advocacy, and policy making. Graduates from the UNOP program contribute to institutions by providing care for an increasing number of patients with pediatric cancer. The UNOP program is the first pediatric hematology/oncology fellowship program in the world to be accredited by Accreditation Council for Graduate Medical Education-International, an international body accrediting clinical training programs. CONCLUSION: The UNOP program has trained specialists to increase the available care for children with cancer in Latin America. This regional approach to specialist training can maximize resources and serve as a model for other programs and regions.

Late cognitive and adaptive outcomes of patients with neuroblastoma-associated opsoclonus-myoclonus-ataxia-syndrome: A report from the Children's Oncology Group.

BACKGROUND: Opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare autoimmune disorder of the nervous system presenting with abnormal eye and limb movements, altered gait, and increased irritability. Two to four percent of children diagnosed with neuroblastoma have neuroblastoma-associated OMAS (NA-OMAS). These children typically present with non-high-risk neuroblastoma that is cured with surgery, with or without chemotherapy. Despite excellent overall survival, patients with NA-OMAS can have significant persistent neurological and developmental issues. OBJECTIVE: This study aimed to describe long-term neurocognitive and adaptive functioning of patients with NA-OMAS treated with multimodal therapy, including intravenous immunoglobulin (IVIG) on Children's Oncology Group (COG) protocol ANBL00P3. METHODS: Of 53 children enrolled on ANBL00P3, 25 submitted evaluable neurocognitive data at diagnosis and at least one additional time point within 2 years and were included in the analyses. Adaptive development was assessed via the Vineland Adaptive Behavior Scale, and validated, age-appropriate measures of intellectual function were also administered. RESULTS: Twenty-one of the 25 patients in this cohort ultimately received IVIG. Descriptive spaghetti plots suggest that this cohort demonstrated stable long-term cognitive functioning and adaptive development over time. This cohort also demonstrated decreased OMAS scores over time consistent with improved OMAS symptoms. CONCLUSIONS: While statistical significance is limited by small sample size and loss to follow-up over 10 years, findings suggest stable long-term cognitive and adaptive functioning over time in this treated cohort.

Treatment of high-risk Hodgkin lymphoma with a modified Stanford V regimen in the AHOPCA: Substituting chemotherapy agents and hampered outcomes.

BACKGROUND/OBJECTIVES: High-risk Hodgkin lymphoma (HRHL) in children is curable with combined modality therapy. The Association of Pediatric Hematology-Oncology of Central America (AHOPCA) is a consortium of cancer centers from Central America. In 2004, AHOPCA implemented a guideline with a short course of chemotherapy (mStanfordV), strict diagnostics, and radiation guidelines, aimed at reducing abandonment and improving outcomes. METHODS: Newly diagnosed children less than 18 years of age with high-risk HL (Ann Arbor stages: IIB, IIIB, IV) from AHOPCA centers were staged with chest radiography and ultrasound or computed tomography. Therapy was a modified Stanford V (mStanfordV), substituting cyclophosphamide for mechlorethamine and involved field radiation. RESULTS: Of 219 patients with HRHL, 181 patients were eligible and evaluable; 146 (81%) were boys, 22% being less than 6 years; 43 were stage IIB, 84 IIIB, and 54 IV. Thirty-one (17%) abandoned therapy, 28 (15%) progressed, 30 (17%) relapsed, and eight (4%) died of toxicity. Radiation guidelines were not followed. Five-year abandonment-sensitive event-free survival and overall survival (AS-EFS, AS-OS ± SE) for the cohort were 46% ± 4% and 56% ± 4%; 5-year AS-OS for stages IIB, IIIB, and IV was 76% ± 7%, 59% ± 7%, and 35% ± 7% (p = .0006). CONCLUSION: Despite instituting a short treatment guideline, it did not improve the abandonment rate (17%) and did not achieve the reported outcomes of Stanford V. The cyclophosphamide dose used to replace merchlorethamine was inadequate. Despite strict guidelines, the radiation therapy application was inaccurate. Weekly chemotherapy may have adversely affected abandonment of therapy by increasing the burden of travel time. Based on these results, AHOPCA established a new abandonment strategy and a new guideline.

SARS-CoV-2 vaccination response in pediatric oncology patients.

BACKGROUND: There remains limited knowledge about the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in pediatric oncology patients, which is essential to provide counseling and risk adaptation in this vulnerable population. The goal of this study was to understand immunogenicity after vaccination in pediatric oncology patients, and determine if certain clinical factors impacted response. METHODS: Patients 0-25 years of age with a diagnosis of cancer and actively receiving therapy were enrolled on study. We excluded patients who were completely vaccinated prior to their cancer diagnosis. Blood samples were collected pre-vaccination, as well as 2, 4-6, and 8-12 weeks after vaccination. Healthy children who were fully vaccinated enrolled as controls. Clinical data and complete blood counts around time of vaccination were collected. To study B- and T-cell immunity, we measured neutralizing antibodies by enzyme-linked immunoassay and interferon gamma secretion by enzyme-linked immunospot, respectively. RESULTS: Twenty-six patients enrolled on study, for which 11 were evaluable oncology patients and seven were healthy controls. Adequate B-cell response was seen in 36.4% of patients, and adequate T-cell response in 77.8% of patients. Numbers were too small to detect differences based on malignancy type. There was no differences in immunity based on absolute lymphocyte count (ALC) or intensity of therapy. CONCLUSION: Pediatric oncology patients have a suboptimal immune response to SARS-CoV-2 vaccination. Booster doses will be imperative to provide optimal protection against COVID-19; however, blood counts may not be a useful guide to optimize the time of administration.

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma.

Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas. We found greater B and T cell infiltration in OMAS-associated tumors compared to controls and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (MHC) class II allele HLA-DOB∗01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.

Evaluation of angiogenic signaling molecules associated with reactive thrombocytosis in an iron-deficient rat model.

BACKGROUND: Iron deficiency anemia (IDA)-induced reactive thrombocytosis can occur in children and adults. The underlying mechanism for this phenomenon is indeterminate. Traditional cytokines such as thrombopoietin (TPO), interleukin-6 (IL-6), and IL-11 involved in megakaryopoiesis have not been shown to be the cause. Recent studies suggest that growth factors and signaling molecules involved with angiogenesis influence the proliferation and differentiation of megakaryocytes. METHODS: We investigated the possible association between angiogenic cytokines with reactive thrombocytosis due to IDA in an iron-deficient (ID) rat model. Complete blood count, iron panels, and TPO levels were measured at baseline and 5 weeks later in both control (C) and ID rats. Angiogenic cytokines were evaluated in the bone marrow in all rats. RESULTS: We successfully induced IDA in our rats by phlebotomy and reduced iron diet. We did not find an increase of TPO in ID rats. A review of the bone marrow showed an increase in the number of megakaryocytes, vascular structures, as well as increased intensity of stain for vascular endothelial growth factor (VEGF), and CXC chemokine receptor 4 (CXCR4) in rats with IDA compared to controls. CONCLUSIONS: Our results of histological bone marrow data suggest an important role for angiogenesis in the development of IDA-induced thrombocytosis. IMPACT: Thrombocytosis is common with IDA in both children and adults, but the mechanism is unclear. We confirmed that TPO is not the major driver of iron deficiency-associated thrombocytosis. We confirmed the increase in the number of megakaryocytes in the bone marrow despite stable TPO levels. We provided evidence supporting an important role of angiogenesis in megakaryocytopoiesis/thrombopoiesis with increased vascular structures and angiogenic cytokines in the bone marrow of iron-deficient rats. The demonstration that angiogenesis may play an important role in secondary thrombocytosis could lead to a new approach in treating symptomatic reactive thrombocytosis by targeting angiogenesis.

Expert consensus statements for Waldeyer's ring involvement in pediatric Hodgkin lymphoma: The staging, evaluation, and response criteria harmonization (SEARCH) for childhood, adolescent, and young adult Hodgkin lymphoma (CAYAHL) group.

Waldeyer's ring (WR) involvement in pediatric Hodgkin lymphoma (HL) is extremely rare and criteria for determining involvement and response to treatment are unclear. The international Staging, Evaluation, and Response Criteria Harmonization for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (SEARCH for CAYAHL) Group performed a systematic review of the literature in search of involvement or response criteria, or evidence to support specific criteria. Only 166 cases of HL with WR involvement were reported in the literature, 7 of which were pediatric. To date no standardized diagnostic or response assessment criteria are available. Given the paucity of evidence, using a modified Delphi survey technique, expert consensus statements were developed by the SEARCH group to allow for a more consistent definition of disease and response evaluation related to this rare site of involvement among pediatric oncologists. The available evidence and expert consensus statements are summarized.

Intravenous immunoglobulin with prednisone and risk-adapted chemotherapy for children with opsoclonus myoclonus ataxia syndrome associated with neuroblastoma (ANBL00P3): a randomised, open-label, phase 3 trial.

Purpose: No previous clinical trial has been conducted for patients with neuroblastoma associated opsoclonus myoclonus ataxia syndrome (OMA), and current treatment is based on case reports. To evaluate the OMA response to prednisone and risk-adapted chemotherapy and determine if the addition of intravenous gammaglobulin (IVIG) further improves response, the Children's Oncology Group designed a randomized therapeutic trial. Patient and Methods: Eligible subjects were randomized to receive twelve cycles of IVIG (IVIG+) or no IVIG (NO-IVIG) in addition to prednisone and neuroblastoma risk-adapted chemotherapy. All low-risk patients were treated with cyclophosphamide. The severity of OMA symptoms was evaluated at 2, 6, and 12 months using a scale developed by Mitchell and Pike and baseline versus best response scores were compared. A single patient who did not undergo neurologic assessment was excluded from OMA response analysis. This study is registered with Clinical Trials.gov (identifier NCT00033293). Results: Of the 53 patients enrolled in the study, 62% (33/53) were female. There were 44 low-risk, 7 intermediate-risk, and 2 high-risk neuroblastoma patients. Twenty-six subjects were randomized to receive IVIG+ and 27 were randomized to NO-IVIG. The neuroblastoma 3-year event-free survival (95% confidence interval (CI)) was 94.1% (87.3%, 100%) and overall survival was 98.0% (94.1%, 100%). Significantly higher rates of OMA response were observed in patients randomized to IVIG+ compared to NO-IVIG [21/26=80.8% for IVIG+; 11/27=40.7% for NO-IVIG (odds ratio=6.1; 95% CI: (1.5, 25.9), p=0.0029)]. For the majority of patients, the IVIG+ OMA regimen combined with cytoxan or other risk-based chemotherapy was well tolerated, although there was one toxic death in a high-risk subject. Conclusion: This is the only randomized prospective therapeutic clinical trial in children with neuroblastoma-associated OMA. The addition of IVIG to prednisone and risk-adapted chemotherapy significantly improves OMA response rate. IVIG+ constitutes a back-bone upon which to build additional therapy.

Family-based exome-wide association study of childhood acute lymphoblastic leukemia among Hispanics confirms role of ARID5B in susceptibility.

We conducted an exome-wide association study of childhood acute lymphoblastic leukemia (ALL) among Hispanics to confirm and identify novel variants associated with disease risk in this population. We used a case-parent trio study design; unlike more commonly used case-control studies, this study design is ideal for avoiding issues with population stratification bias among this at-risk ethnic group. Using 710 individuals from 323 Guatemalan and US Hispanic families, two inherited SNPs in ARID5B reached genome-wide level significance: rs10821936, RR = 2.31, 95% CI = 1.70-3.14, p = 1.7×10-8 and rs7089424, RR = 2.22, 95% CI = 1.64-3.01, p = 5.2×10-8. Similar results were observed when restricting our analyses to those with the B-ALL subtype: ARID5B rs10821936 RR = 2.22, 95% CI = 1.63-3.02, p = 9.63×10-8 and ARID5B rs7089424 RR = 2.13, 95% CI = 1.57-2.88, p = 2.81×10-7. Notably, effect sizes observed for rs7089424 and rs10821936 in our study were >20% higher than those reported among non-Hispanic white populations in previous genetic association studies. Our results confirmed the role of ARID5B in childhood ALL susceptibility among Hispanics; however, our assessment did not reveal any strong novel inherited genetic risks for acute lymphoblastic leukemia among this ethnic group.

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.

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.

Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL): Methodology statement.

International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence-based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies.

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

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.

Family-based exome-wide assessment of maternal genetic effects on susceptibility to childhood B-cell acute lymphoblastic leukemia in hispanics.

BACKGROUND: Children of Hispanic ancestry have a higher incidence of acute lymphoblastic leukemia (ALL) compared with other ethnic groups, but to the authors' knowledge, the genetic basis for these racial disparities remain incompletely understood. Genome-wide association studies of childhood ALL to date have focused on inherited genetic effects; however, maternal genetic effects (the role of the maternal genotype on phenotype development in the offspring) also may play a role in ALL susceptibility. METHODS: The authors conducted a family-based exome-wide association study of maternal genetic effects among Hispanics with childhood B-cell ALL using the Illumina Infinium HumanExome BeadChip. A discovery cohort of 312 Guatemalan and Hispanic American families and an independent replication cohort of 152 Hispanic American families were used. RESULTS: Three maternal single-nucleotide polymorphisms (SNPs) approached the study threshold for significance after correction for multiple testing (P<1.0 × 10-6 ): MTL5 rs12365708 (testis expressed metallothionein-like protein [tesmin]) (relative risk [RR], 2.62; 95% confidence interval [95% CI], 1.61-4.27 [P = 1.8 × 10-5 ]); ALKBH1 rs6494 (AlkB homolog 1, histone H2A dioxygenase) (RR, 3.77; 95% CI, 1.84-7.74 [P = 3.7 × 10-5 ]); and NEUROG3 rs4536103 (neurogenin 3) (RR, 1.75; 95% CI, 1.30-2.37 [P = 1.2 × 10-4 ]). Although effect sizes were similar, these SNPs were not nominally significant in the replication cohort in the current study. In a meta-analysis comprised of the discovery cohort and the replication cohort, these SNPs were still not found to be statistically significant after correction for multiple comparisons (rs12365708: pooled RR, 2.27 [95% CI, 1.48-3.50], P = 1.99 × 10-4 ; rs6494: pooled RR, 2.31 [95% CI, 1.38-3.85], P = .001; and rs4536103: pooled RR, 1.67 [95% CI, 1.29-2.16] P = 9.23 × 10-5 ). CONCLUSIONS: In what to the authors' knowledge is the first family-based based exome-wide association study to investigate maternal genotype effects associated with childhood ALL, the results did not implicate a strong role of maternal genotype on disease risk among Hispanics; however, 3 maternal SNPs were identified that may play a modest role in susceptibility. Cancer 2016;122:3697-704. © 2016 American Cancer Society.

A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study.

A Children's Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59-83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61-95%; p = 0.32). Although not statistically different, results suggest IVB may be a promising combination.

Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031.

PURPOSE: The Children's Oncology Group study AHOD0031, a randomized phase III study, was designed to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. To avoid treatment-associated risks that compromise long-term health and to maintain high cure rates, dose-intensive chemotherapy with limited cumulative doses was used. PATIENTS AND METHODS: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation. Rapid early responders (RERs) received two additional ABVE-PC cycles, followed by complete response (CR) evaluation. RERs with CR were randomly assigned to involved-field radiotherapy (IFRT) or no additional therapy; RERs with less than CR were nonrandomly assigned to IFRT. Slow early responders (SERs) were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All SERs were assigned to receive IFRT. RESULTS: Among 1,712 eligible patients, 4-year event-free survival (EFS) was 85.0%: 86.9% for RERs and 77.4% for SERs (P < .001). Four-year overall survival was 97.8%: 98.5% for RERs and 95.3% for SERs (P < .001). Four-year EFS was 87.9% versus 84.3% (P = .11) for RERs with CR who were randomly assigned to IFRT versus no IFRT, and 86.7% versus 87.3% (P = .87) for RERs with positron emission tomography (PET) -negative results at response assessment. Four-year EFS was 79.3% versus 75.2% (P = .11) for SERs who were randomly assigned to DECA versus no DECA, and 70.7% versus 54.6% (P = .05) for SERs with PET-positive results at response assessment. CONCLUSION: This trial demonstrated that early response assessment supported therapeutic titration (omitting radiotherapy in RERs with CR; augmenting chemotherapy in SERs with PET-positive disease). Strategies directed toward improved response assessment and risk stratification may enhance tailoring of treatment to patient characteristics and response.