Radiation Therapy Across Pediatric Hodgkin Lymphoma Research Group Protocols: A Report From the Staging, Evaluation, and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma (CAYAHL) Group

Abstract

Radiation therapy (RT) has played a central role in the management of Hodgkin lymphoma (HL) for more than 50 years. Palliative RT was replaced with large fields delivered with curative treatment intent during the 1950s and 1960s.1Kaplan HS Rosenberg SA. The management of Hodgkin's disease.Cancer. 1975; 36: 796-803Crossref PubMed Scopus (68) Google Scholar Over time, combined modality therapy (CMT) with chemotherapy followed by consolidative RT has increased cure rates while often using less intensive chemotherapy regimens and smaller RT fields at lower doses. The 10-year overall survival now exceeds 85% with CMT for pediatric patients with HL. Efforts continue to improve cure rates in the highest-risk patients, but the goal of contemporary HL therapy is now largely focused on reducing the late adverse effects of treatment using risk- and response-adapted therapies without compromising outcomes.2Wolden SL Chen L Kelly KM et al.Long-term results of CCG 5942: A randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin's lymphoma—A report from the Children's Oncology Group.J Clin Oncol. 2012; 30: 3174-3180Crossref PubMed Scopus (127) Google Scholar,3Jhawar SR Rivera-Núñez Z Drachtman R Cole PD Hoppe BS Parikh RR. Association of combined modality therapy vs chemotherapy alone with overall survival in early-stage pediatric Hodgkin lymphoma.JAMA Oncol. 2019; 5: 689-695Crossref PubMed Scopus (11) Google Scholar Substantial heterogeneity exists between national and international clinical trial protocols for pediatric and adult HL regarding optimal RT utilization. This contributes to disparate recommendations regarding indications for RT, sites requiring RT, field design, dose, permissible modalities, and motion management strategies. The Staging, Evaluation, and Response Criteria Harmonization for Childhood, Adolescent, and Young Adult Hodgkin Lymphoma initiative was formed in 2011 to promote collaboration among an international group of pediatric HL investigators who actively participate in cooperative group clinical trials. The aim of this team is to develop a unified framework to approach staging, response assessment, and treatment efficacy across pediatric HL clinical trial groups to enhance the design and execution of clinical trials. In this report, our purpose is to review and detail critical aspects of RT delivery that should be considered by pediatric, medical, and radiation oncologists interested in developing future HL trials. Historically, RT utilization was not a research question because all children and adults received RT either alone or combined with chemotherapy. Contemporary studies where all patients received RT were generally limited to stage I/II patients for whom the prechemotherapy extent of disease could be encompassed within reasonable RT fields.4Tebbi CK Mendenhall N London WB et al.Treatment of stage I, IIA, IIIA1 pediatric Hodgkin disease with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: A Pediatric Oncology Group (POG) study.Pediatr Blood Cancer. 2006; 46: 198-202Crossref PubMed Scopus (49) Google Scholar,5Donaldson SS Link MP Weinstein HJ et al.Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease.J Clin Oncol. 2007; 25: 332-337Crossref PubMed Scopus (106) Google Scholar Of note, some trials from earlier eras included higher-risk patients with stage III/IV disease who were treated with much larger fields.6Friedmann AM Hudson MM Weinstein HJ et al.Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation.J Clin Oncol. 2002; 20: 3088-3094Crossref PubMed Scopus (67) Google Scholar, 7Hudson MM Krasin M Link MP et al.Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease.J Clin Oncol. 2004; 22: 4541-4550Crossref PubMed Scopus (70) Google Scholar, 8Schwartz CL Constine LS Villaluna D et al.A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: The results of P9425. Blood. 2009;114:2051-2059.Erratum in: Blood. 2016; 128: 605PubMed Google Scholar, 9Mauz-Körholz C Hasenclever D Dörffel W et al.Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: The GPOH-HD-2002 study.J Clin Oncol. 2010; 28: 3680-3686Crossref PubMed Scopus (174) Google Scholar In these trials, the study questions generally focused on treatment intensity, but all patients received combined modality therapy. For example, Hudson et al compared the efficacy of lower doses of involved-field RT (IFRT) of 15.5 Gy for patients with a complete response (CR) after chemotherapy compared with 25.5 Gy after a partial response (PR).7Hudson MM Krasin M Link MP et al.Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease.J Clin Oncol. 2004; 22: 4541-4550Crossref PubMed Scopus (70) Google Scholar The optimization of treatment intensity in HL necessitates a standardized and reproducible method of assessing treatment response. Definitions of response, however, vary according to the timepoint(s) of evaluation and the anatomic and metabolic criteria employed, and they diverge across individual clinical trials and national and international research consortia.10Roberts KB Younes A Hodgson DC et al.ACR Appropriateness Criteria® Hodgkin lymphoma-unfavorable clinical stage I and II.Am J Clin Oncol. 2016; 39: 384-395Crossref PubMed Scopus (3) Google Scholar,11Mauz-Körholz C Metzger ML Kelly KM et al.Pediatric Hodgkin lymphoma.J Clin Oncol. 2015; 33: 2975-2985Crossref PubMed Scopus (94) Google Scholar Interim response has been used to identify rapid early responders who may potentially receive less intensive therapy without compromising outcomes, whereas slow responders may benefit from treatment intensification.6Friedmann AM Hudson MM Weinstein HJ et al.Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation.J Clin Oncol. 2002; 20: 3088-3094Crossref PubMed Scopus (67) Google Scholar,12Dörffel W Rühl U Lüders H et al.Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95.J Clin Oncol. 2013; 31: 1562-1568Crossref PubMed Scopus (92) Google Scholar,13Metzger ML Weinstein HJ Hudson MM et al.Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma.JAMA. 2012; 307: 2609-2616Crossref PubMed Scopus (74) Google Scholar Earlier studies employed computed tomography (CT) for response assessment, but over time, functional imaging has been increasingly used (Gallium or fluorodeoxyglucose [FDG] positron emission tomography [PET]).10Roberts KB Younes A Hodgson DC et al.ACR Appropriateness Criteria® Hodgkin lymphoma-unfavorable clinical stage I and II.Am J Clin Oncol. 2016; 39: 384-395Crossref PubMed Scopus (3) Google Scholar Some more recent studies have even relied solely on metabolic response by functional imaging to assess response (NCT03907488, NCT03755804). Over time, more intensive chemotherapy regimens were implemented to mitigate the need for large RT fields, particularly in patients with advanced disease. Successive trials demonstrated the increasing effectiveness of chemotherapy in improving relapse-free survival. Despite these advances, however, selected patients still relapsed, and identification of high-risk patients who may benefit from treatment intensification is an important need. For example, patients with bulky disease and less than CR were identified to have a higher risk of relapse with chemotherapy alone in multiple reports.12Dörffel W Rühl U Lüders H et al.Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95.J Clin Oncol. 2013; 31: 1562-1568Crossref PubMed Scopus (92) Google Scholar,14Kelly KM Sposto R Hutchinson R et al.BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: A report from the Children's Oncology Group.Blood. 2011; 117: 2596-2603Crossref PubMed Scopus (81) Google Scholar, 15Charpentier AM Friedman DL Wolden S et al.Predictive factor analysis of response-adapted radiation therapy for chemotherapy-sensitive pediatric Hodgkin lymphoma: Analysis of the Children's Oncology Group AHOD 0031 trial.Int J Radiat Oncol Biol Phys. 2016; 96: 943-950Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 16Kelly KM Cole PD Pei Q et al.Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): A report from the Children's Oncology Group.Br J Haematol. 2019; 187: 39-48Crossref PubMed Scopus (23) Google Scholar Ongoing reevaluation of the value of using RT in such high-risk patients, including those with bulky disease, is warranted. Several pediatric trials evaluated the benefit of RT in patients with a CR to chemotherapy and included both randomized and nonrandomized evaluations of omitting RT in complete responders with early stage unfavorable,2Wolden SL Chen L Kelly KM et al.Long-term results of CCG 5942: A randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin's lymphoma—A report from the Children's Oncology Group.J Clin Oncol. 2012; 30: 3174-3180Crossref PubMed Scopus (127) Google Scholar,12Dörffel W Rühl U Lüders H et al.Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95.J Clin Oncol. 2013; 31: 1562-1568Crossref PubMed Scopus (92) Google Scholar,17Friedman DL Chen L Wolden S et al.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.J Clin Oncol. 2014; 32: 3651-3658Crossref PubMed Scopus (148) Google Scholar early stage favorable,2Wolden SL Chen L Kelly KM et al.Long-term results of CCG 5942: A randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin's lymphoma—A report from the Children's Oncology Group.J Clin Oncol. 2012; 30: 3174-3180Crossref PubMed Scopus (127) Google Scholar,9Mauz-Körholz C Hasenclever D Dörffel W et al.Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: The GPOH-HD-2002 study.J Clin Oncol. 2010; 28: 3680-3686Crossref PubMed Scopus (174) Google Scholar,12Dörffel W Rühl U Lüders H et al.Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95.J Clin Oncol. 2013; 31: 1562-1568Crossref PubMed Scopus (92) Google Scholar,13Metzger ML Weinstein HJ Hudson MM et al.Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma.JAMA. 2012; 307: 2609-2616Crossref PubMed Scopus (74) Google Scholar,18Keller FG Castellino SM Chen L et al.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; 124: 3210-3219Crossref PubMed Scopus (24) Google Scholar and advanced disease.2Wolden SL Chen L Kelly KM et al.Long-term results of CCG 5942: A randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin's lymphoma—A report from the Children's Oncology Group.J Clin Oncol. 2012; 30: 3174-3180Crossref PubMed Scopus (127) Google Scholar,6Friedmann AM Hudson MM Weinstein HJ et al.Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation.J Clin Oncol. 2002; 20: 3088-3094Crossref PubMed Scopus (67) Google Scholar,12Dörffel W Rühl U Lüders H et al.Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95.J Clin Oncol. 2013; 31: 1562-1568Crossref PubMed Scopus (92) Google Scholar,14Kelly KM Sposto R Hutchinson R et al.BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: A report from the Children's Oncology Group.Blood. 2011; 117: 2596-2603Crossref PubMed Scopus (81) Google Scholar,19Weiner MA Leventhal B Brecher ML et al.Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: A Pediatric Oncology Group study.J Clin Oncol. 1997; 15: 2769-2779Crossref PubMed Scopus (155) Google Scholar The definition of CR varied across protocols, and later trials incorporated the use of functional imaging in addition to CT imaging. Although the investigational arm of these trials omitted RT in complete responders, patients with an incomplete response or PR still received RT. An example of this paradigm was the CCG 5942 study, in which patients with early favorable, early unfavorable, and advanced stage HL received risk-based chemotherapy followed by CT-based response assessment. Complete responders were randomized between consolidative RT and no further therapy. The results from this group of studies have been mixed, with some demonstrating that RT can be safely omitted without compromising progression-free survival in selected patients,6Friedmann AM Hudson MM Weinstein HJ et al.Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation.J Clin Oncol. 2002; 20: 3088-3094Crossref PubMed Scopus (67) Google Scholar,9Mauz-Körholz C Hasenclever D Dörffel W et al.Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: The GPOH-HD-2002 study.J Clin Oncol. 2010; 28: 3680-3686Crossref PubMed Scopus (174) Google Scholar,12Dörffel W Rühl U Lüders H et al.Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95.J Clin Oncol. 2013; 31: 1562-1568Crossref PubMed Scopus (92) Google Scholar, 13Metzger ML Weinstein HJ Hudson MM et al.Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma.JAMA. 2012; 307: 2609-2616Crossref PubMed Scopus (74) Google Scholar, 14Kelly KM Sposto R Hutchinson R et al.BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: A report from the Children's Oncology Group.Blood. 2011; 117: 2596-2603Crossref PubMed Scopus (81) Google Scholar,18Keller FG Castellino SM Chen L et al.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; 124: 3210-3219Crossref PubMed Scopus (24) Google Scholar,19Weiner MA Leventhal B Brecher ML et al.Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: A Pediatric Oncology Group study.J Clin Oncol. 1997; 15: 2769-2779Crossref PubMed Scopus (155) Google Scholar but others indicated a significant progression-free survival benefit in patients who received consolidative RT.2Wolden SL Chen L Kelly KM et al.Long-term results of CCG 5942: A randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin's lymphoma—A report from the Children's Oncology Group.J Clin Oncol. 2012; 30: 3174-3180Crossref PubMed Scopus (127) Google Scholar,6Friedmann AM Hudson MM Weinstein HJ et al.Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation.J Clin Oncol. 2002; 20: 3088-3094Crossref PubMed Scopus (67) Google Scholar,20Radford J Illidge T Counsell N et al.Results of a trial of PET-directed therapy for early-stage Hodgkin's lymphoma.N Engl J Med. 2015; 372: 1598-1607Crossref PubMed Scopus (457) Google Scholar The interpretation and comparison of results from these trials are complicated by the different risk groups included,6Friedmann AM Hudson MM Weinstein HJ et al.Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation.J Clin Oncol. 2002; 20: 3088-3094Crossref PubMed Scopus (67) Google Scholar,17Friedman DL Chen L Wolden S et al.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.J Clin Oncol. 2014; 32: 3651-3658Crossref PubMed Scopus (148) Google Scholar,18Keller FG Castellino SM Chen L et al.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; 124: 3210-3219Crossref PubMed Scopus (24) Google Scholar variable definitions of response, and systemic therapies used. Adaptive trials using interim response assessment have included the assignment of rapid early responders (who continue to have a CR at the end of chemotherapy) to CMT or chemotherapy-alone regimens.13Metzger ML Weinstein HJ Hudson MM et al.Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma.JAMA. 2012; 307: 2609-2616Crossref PubMed Scopus (74) Google Scholar,17Friedman DL Chen L Wolden S et al.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.J Clin Oncol. 2014; 32: 3651-3658Crossref PubMed Scopus (148) Google Scholar In the St. Jude–Stanford–Dana Farber trial, low-risk patients received 2 cycles of vincristine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy. Patients with a CR by both PET and CT received 2 additional cycles of VAMP and no RT, and partial responders received 2 more cycles of VAMP followed by RT.13Metzger ML Weinstein HJ Hudson MM et al.Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma.JAMA. 2012; 307: 2609-2616Crossref PubMed Scopus (74) Google Scholar In the AHOD 0031 trial, patients were treated with 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) chemotherapy followed by a CT-based response assessment, and responders then received 2 more cycles of ABVE-PC chemotherapy. After 4 cycles, complete responders by CT and functional imaging were randomized between consolidative RT and no further therapy.17Friedman DL Chen L Wolden S et al.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.J Clin Oncol. 2014; 32: 3651-3658Crossref PubMed Scopus (148) Google Scholar Adaptive trials where the chemotherapy regimen was adjusted based on response to therapy were also applied, wherein only sites with inadequate or incomplete response to systemic therapy were irradiated.12Dörffel W Rühl U Lüders H et al.Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95.J Clin Oncol. 2013; 31: 1562-1568Crossref PubMed Scopus (92) Google Scholar,14Kelly KM Sposto R Hutchinson R et al.BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: A report from the Children's Oncology Group.Blood. 2011; 117: 2596-2603Crossref PubMed Scopus (81) Google Scholar,16Kelly KM Cole PD Pei Q et al.Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): A report from the Children's Oncology Group.Br J Haematol. 2019; 187: 39-48Crossref PubMed Scopus (23) Google Scholar,17Friedman DL Chen L Wolden S et al.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.J Clin Oncol. 2014; 32: 3651-3658Crossref PubMed Scopus (148) Google Scholar For example, in the AHOD 0831 study, all patients were evaluated by PET/CT for response after 2 cycles of ABVE-PC chemotherapy. Any sites of disease that had not completely responded after 2 cycles were considered slow early responding sites. After completion of chemotherapy, all sites with either bulky disease at presentation or slow early response received consolidative RT.16Kelly KM Cole PD Pei Q et al.Response-adapted therapy for the treatment of children with newly diagnosed high risk Hodgkin lymphoma (AHOD0831): A report from the Children's Oncology Group.Br J Haematol. 2019; 187: 39-48Crossref PubMed Scopus (23) Google Scholar RT was historically administered to all sites of disease at diagnosis in pediatric and adult patients with all stages of disease. Today, this approach is essentially limited to only patients with stage I/II disease, as in the AHOD 0431 study, in which patients with stage IA/IIA disease with <3 sites of initial involvement with a PR to 3 cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide received IFRT to initially involved sites. This approach has been avoided in contemporary studies of high-risk patients with stage III/IV disease to limit the use of extensive RT fields and their subsequent late effects.2Wolden SL Chen L Kelly KM et al.Long-term results of CCG 5942: A randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin's lymphoma—A report from the Children's Oncology Group.J Clin Oncol. 2012; 30: 3174-3180Crossref PubMed Scopus (127) Google Scholar,6Friedmann AM Hudson MM Weinstein HJ et al.Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation.J Clin Oncol. 2002; 20: 3088-3094Crossref PubMed Scopus (67) Google Scholar, 7Hudson MM Krasin M Link MP et al.Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease.J Clin Oncol. 2004; 22: 4541-4550Crossref PubMed Scopus (70) Google Scholar, 8Schwartz CL Constine LS Villaluna D et al.A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: The results of P9425. Blood. 2009;114:2051-2059.Erratum in: Blood. 2016; 128: 605PubMed Google Scholar, 9Mauz-Körholz C Hasenclever D Dörffel W et al.Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: The GPOH-HD-2002 study.J Clin Oncol. 2010; 28: 3680-3686Crossref PubMed Scopus (174) Google Scholar,12Dörffel W Rühl U Lüders H et al.Treatment of children and adolescents with Hodgkin lymphoma without radiotherapy for patients in complete remission after chemotherapy: Final results of the multinational trial GPOH-HD95.J Clin Oncol. 2013; 31: 1562-1568Crossref PubMed Scopus (92) Google Scholar,14Kelly KM Sposto R Hutchinson R et al.BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: A report from the Children's Oncology Group.Blood. 2011; 117: 2596-2603Crossref PubMed Scopus (81) Google Scholar,17Friedman DL Chen L Wolden S et al.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.J Clin Oncol. 2014; 32: 3651-3658Crossref PubMed Scopus (148) Google Scholar,19Weiner MA Leventhal B Brecher ML et al.Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: A Pediatric Oncology Group study.J Clin Oncol. 1997; 15: 2769-2779Crossref PubMed Scopus (155) Google Scholar,21Kung FH Schwartz CL Ferree CR et al.POG 8625: A randomized trial comparing chemotherapy with chemoradiotherapy for children and adolescents with Stages I, IIA, IIIA1 Hodgkin Disease: A report from the Children's Oncology Group.J Pediatr Hematol Oncol. 2006; 28: 362-368Crossref PubMed Scopus (74) Google Scholar In the POG 9425 study, patients received regional RT fields, such as the mantle and paraortic fields with or without the pelvis if disease was within any of these nodal basins. These volumes effectively translated into subtotal lymphoid irradiation (STLI) or total lymphoid irradiation in patients with stage III/IV disease.8Schwartz CL Constine LS Villaluna D et al.A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: The results of P9425. Blood. 2009;114:2051-2059.Erratum in: Blood. 2016; 128: 605PubMed Google Scholar Alternatively, RT can be selectively administered only to sites presumed to be at a higher risk of relapse. This may include sites of bulky disease and sites of either slow response or PR. The rationale for this approach is that chemotherapy alone may eradicate nonbulky disease or sites in rapid early and CR, whereas unfavorable sites may benefit from treatment intensification, including consolidative RT. This tailored RT approach can lead to a significant reduction in the volume of normal tissues irradiated, particularly in patients with advanced stage disease. Irradiation of only high-risk sites may improve the therapeutic ratio by minimizing late toxicities through the selective avoidance of RT in patients with more favorable responses. Table 1 summarizes the inclusion criteria, treatment arms, RT indications, and accrual status of past and current pediatric HL trials.Table 1Contemporary pediatric Hodgkin lymphoma clinical trialsTrialCooperative groupInclusion criteriaAccrual statusTreatment arms/indications for RTPercentage treated with RTAHOD 0031COGStage I-IIB; I-IIAE; III-IVA; III-IVAE with/without bulk; IA/IIA with bulkCompletedAll received 4 cycles ABVE-PC•RER & CR: Randomized to ± IFRT•RER and PR: IFRT•SER: Randomized to ± DECA × 2 augmented therapy and all received IFRT. RER: >60% reduction in PPD for all target lesions. SER: <60% reduction in PPD for all target lesions. CR: >80% reduction in PPD and negative gallium or FDG-PET scan (less than mediastinal background blood pool).67.5%AHOD 0431COGStage IA/IIA (no bulk)LPHD not allowed.ClosedAll received 3 cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide.•If < PR: Off-protocol therapy•If PR: IFRT•If CR: Observation (Off-protocol therapy for high-risk relapse; IV, DECA, and IFRT for low-risk relapse). CR: Anatomic reduction ≥80% in PPD and FDG-PET-negative result. PR: Anatomic reduction >50% in PPD of measurable disease regardless of FDG-PET response.43.5%HOD05SJCRHStage IB; IIIA; and I-IIA with any of the following: Bulky LMA, E lesions, or ≥3 nodal sitesClosedAll receive 12 weeks Stanford V → ERA (after 8 weeks of chemotherapy)-adapted RT:•If CR and nonbulky: 15 Gy in 1.5 Gy/fx•If PR and/or mediastinal bulk: 25.5 Gy in 1.5 Gy/fx ERA defined by PET negative and > (CR) anatomic response or <75% (PR) anatomic response regardless of PET.∼100%HOD08SJCRHStage IA or IIA and nonbulky mediastinal (<33% mediastinal to thoracic ratio on CXR) and <3 LN regions and no E lesionClosedAll receive 8 weeks Stanford V, followed by ERA-adapted RT:25.5 Gy in 1.5Gy/fx RT to a site with <75% anatomic response or PET+, but omitted for >75% response and PET–.NRHLHR13SJCRHStage IIB, IIIB, IVA, or IVB; LPHD not allowedClosedERA driven by metabolic and anatomic response.•2 cycles AEPA → ERA → 4 cycles. CAPDac → ± ERA-adapted RT. RT given if ERA is Deauville 4-5 or anatomic response <75% from baseline.NRAHOD 0831COGStage IIIB-IVBClosedAll receive 2 cycles ABVE-PC.•If CR: 2 cycles ABVE-PC → Risk-adapted RT.•If PR/SD: 2 cycles Ifos/Vino→ 2 cycles. ABVE-PC → Risk-adapted RT.•If PD: Off-protocol therapy. CR: Deauville 1 or 2 PR: Deauville 3, 4, 5 with >50% decrease in PPD.76.2%AHOD 1331COGStage IIB with Bulk; IIIB; IVA; IVBOpenRandomized to 5 cycles ABVE-PC versus Bv-AVEPC → ERA-adapted ISRT.RER: Deauville 1,2, or 3.SER: Deauville 4, 5.CR: Deauville 1,2.PR: Deauville 3, 4, 5 at the end of treatment.NREuronet-PHL-C1EuroNetAll stages/risk categories; LPHD not allowedAll receive 2 cycles OEPA → ERA.TG1: RT unless CMR on ERA.TG2: 2 cycles COPDAC versus COPP → RT unless CMR on ERA.TG3: 4 cycles COPDAC versus COPP → RT unless CMR on ERA.ERA is defined by PET only (±) where adequate response = no initially involved PET+ areas remain positive.33.3%Euronet-PHL-C2EuroNetAll stages/risk categoriesLPHD not allowedOpenAll receive 2 cycles OEPA → ERATL-1: PET- → 1 cycle CO