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Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For Hodgkin lymphoma, the 5-year survival rate has increased over the same time from 81% to more than 95% for children and adolescents. Childhood and adolescent cancer survivors require close monitoring because late effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Overview of Childhood Hodgkin Lymphoma
Childhood Hodgkin lymphoma is one of the few pediatric malignancies that shares aspects of its biology and natural history with an adult cancer. When treatment approaches for children were modeled after those used for adults, substantial morbidities resulted from the unacceptably high radiation doses. Thus, new strategies utilizing chemotherapy and lower-dose radiation were developed. Approximately 90% to 95% of children with Hodgkin lymphoma can be cured, prompting increased attention to devising therapy that lessens long-term morbidity for these patients. Contemporary treatment programs use a risk-based and response-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field or involved-site radiation therapy. Prognostic factors used in determining chemotherapy intensity include stage, presence or absence of B symptoms (fever, weight loss, and night sweats), and/or bulky disease.
Hodgkin lymphoma comprises 6% of childhood cancers. In the United States, the incidence of Hodgkin lymphoma is age related and is highest among adolescents aged 15 to 19 years (29 cases per 1 million per year), with children ages 10 to 14 years, 5 to 9 years, and 0 to 4 years having approximately threefold, eightfold, and 30-fold lower rates, respectively. In developing countries, there is a similar rate in young adults but a much higher incidence in childhood.
Hodgkin lymphoma has the following unique epidemiological features:
Epstein-Barr virus and Hodgkin lymphoma
Epstein-Barr virus (EBV) has been implicated in the causation of Hodgkin lymphoma. A large proportion of patients with Hodgkin lymphoma have high EBV titers, suggesting that an enhanced activation of EBV may precede the development of Hodgkin lymphoma in some patients. EBV genetic material can be detected in Reed-Sternberg cells from some patients with Hodgkin lymphoma.
The incidence of EBV-associated Hodgkin lymphoma also shows the following distinct epidemiological features:
EBV serologic status is not a prognostic factor for failure-free survival in pediatric and young adult Hodgkin lymphoma patients,[13,14,15,17,18] but plasma EBV DNA has been associated with an inferior outcome in adults. Patients with a previous history of serologically confirmed infectious mononucleosis have a fourfold increased risk of developing EBV-positive Hodgkin lymphoma; these patients are not at increased risk for EBV-negative Hodgkin lymphoma.
Immunodeficiency and Hodgkin lymphoma
Among individuals with immunodeficiency, the risk of Hodgkin lymphoma is increased, although it is not as high as the risk of non-Hodgkin lymphoma.
Characteristics of Hodgkin lymphoma presenting in the context of immunodeficiency are as follows:
The following presenting features of Hodgkin lymphoma result from direct or indirect effects of nodal or extranodal involvement and/or constitutional symptoms related to cytokine release from Reed-Sternberg cells.
As the treatment of Hodgkin lymphoma improved, factors associated with outcome became more difficult to identify. Several factors, however, continue to influence the success and choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and biologic aggressiveness are frequently collinear.
Pretreatment factors associated with an adverse outcome in one or more studies include the following:
Prognostic factors identified in selected multi-institutional studies include the following:
The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important and is being used in the research setting to determine subsequent therapy.[29,30,32] Positron emission tomography (PET) scanning is being evaluated as a method to assess early response in pediatric Hodgkin lymphoma. Fluorine F 18-fludeoxyglucose PET avidity after two cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[34,35,36] Further studies in children are required to assess the role of early response based on PET. The value of PET avidity to predict outcome and whether improved outcome can be achieved by altering the therapeutic strategy on the basis of early PET response is to be determined.
Prognostic factors will continue to change because of risk stratification and choice of therapy, with parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy used to stratify therapeutic assignment.
Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Reed-Sternberg cells) or large mononuclear cell variants (lymphocytic and histiocytic cells) in a background of inflammatory cells consisting of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts. The inflammatory cells are present in different proportions depending on the histologic subtype. It has been conclusively shown that Reed-Sternberg cells and/or lymphocytic and histiocytic cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from germinal center B cells.[1,2] The histologic features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines, chemokines, and products of the tumor necrosis factor receptors (TNF-R) family secreted by the Reed-Sternberg cells.
The hallmark of Hodgkin lymphoma is the Reed-Sternberg cell and its variants, which have the following features:
Hodgkin lymphoma can be divided into the following two broad pathologic classes:[9,10]
Classical Hodgkin Lymphoma
Classical Hodgkin lymphoma is divided into the following four subtypes:
These subtypes are defined according to the number of Reed-Sternberg cells, characteristics of the inflammatory milieu, and the presence or absence of fibrosis.
Characteristics of the histological subtypes of classical Hodgkin lymphoma include the following:
A study of over 600 patients with nodular sclerosis Hodgkin lymphoma from three different university hospitals in the United States showed that two haplotypes in the HLA class II region correlated with a 70% increased risk of developing nodular sclerosis Hodgkin lymphoma. Another haplotype was associated with a 60% decreased risk of developing Hodgkin lymphoma. It is hypothesized that these haplotypes are associated with atypical immune responses that predispose to Hodgkin lymphoma.
Nodular Lymphocyte-Predominant Hodgkin Lymphoma
The frequency of nodular lymphocyte-predominant Hodgkin lymphoma in the pediatric population ranges from 5% to 10% in different studies, with a higher frequency in children younger than 10 years compared with children aged 10 to 19 years. Nodular lymphocyte-predominant Hodgkin lymphoma is most common in males younger than 18 years.[15,16] A comprehensive review of nodular lymphocyte-predominant Hodgkin lymphoma addressing biology, evaluation, and treatment has been published.
Characteristics of nodular lymphocyte-predominant Hodgkin lymphoma include the following:
Staging and evaluation of disease status is undertaken at diagnosis and performed again early in the course of chemotherapy and at the end of chemotherapy.
The diagnostic and staging evaluation is a critical determinant in the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following:
The following three specific constitutional symptoms (B symptoms) correlate with prognosis and are considered in assignment of stage:
Additional Hodgkin-associated constitutional symptoms without prognostic significance include the following:
Anatomic information from CT is complemented by PET functional imaging, which is sensitive in determining initial sites of involvement, particularly in sites too small to be considered clearly involved by CT criteria.
Definition of bulky disease
Historically, the presence of bulky disease, especially mediastinal bulk, predicted an increased risk of local failure and resulted in the incorporation of bulk as an important factor in treatment assignment. The definition of bulk has varied across pediatric protocols and evolved over time with advances in diagnostic imaging technology. In North American protocols, the posteroanterior chest radiograph remains important because the criterion for bulky mediastinal lymphadenopathy is defined by the ratio of the diameter of the mediastinal lymph node mass to the maximal diameter of the rib cage on an upright chest radiograph; a ratio of 33% or higher is considered bulky. In contrast, the EuroNet-Pediatric Hodgkin Lymphoma Group defines mediastinal bulk by the volume of the largest contiguous lymph node mass being 200 mL or more on CT. These two definitions differ from the recently published consensus guidelines from the International Conference on Malignant Lymphomas Imaging Group (Lugano), where bulk is greater or equal to 10 cm unidimensionally on CT.
The criteria for bulky peripheral (nonmediastinal) lymphadenopathy have also varied over the years per cooperative group study protocols (usually exceeding 4–6 cm), and this disease characteristic has not been consistently used for treatment stratification. In contemporary U.S. protocols, bulky peripheral lymphadenopathy is defined as greater than 6 cm, with aggregates measured transversely. In EuroNet protocols, it is defined as a volume of greater than 200 mL. In contrast to mediastinal bulk, this disease characteristic has not been consistently used for treatment stratification.
Criteria for lymphomatous involvement by CT
Defining strict CT size criteria for the establishment of lymphomatous nodal involvement is complicated by a number of factors, such as overlap between benign reactive hyperplasia and malignant lymphadenopathy and obliquity of node orientation to the scan plane. Additional difficulties more specific to children include greater variability of normal nodal size with body region and age and the frequent occurrence of reactive hyperplasia.
General concepts to consider in regard to defining lymphomatous involvement by CT include the following:
The recommended functional imaging procedure for initial staging is now PET, using the radioactive glucose analog, 18F-FDG.[4,5] 18F-FDG PET identifies areas of tumor with increased metabolic activity, specifically anaerobic glycolysis. PET-CT, which integrates functional and anatomic tumor characteristics, is often used for staging and monitoring of pediatric patients with Hodgkin lymphoma. Residual or persistent 18F-FDG avidity has been correlated with prognosis and the need for additional therapy in posttreatment evaluation.[6,7,8,9]
General concepts to consider in regard to defining lymphomatous involvement by 18F-FDG PET include the following:
18F-FDG PET has limitations in the pediatric setting. Tracer avidity may be seen in a variety of nonmalignant conditions including thymic rebound commonly observed after completion of lymphoma therapy. 18F-FDG avidity in normal tissues, for example, brown fat of cervical musculature, may confound interpretation of the presence of nodal involvement by lymphoma.
Establishing the Diagnosis of Hodgkin Lymphoma
After a careful physiologic and radiographic evaluation of the patient, the least invasive procedure should be used to establish the diagnosis of lymphoma. However, this should not be interpreted to mean that a needle biopsy is the optimal methodology. Small fragments of lymphoma tissue are often inadequate for diagnosis, resulting in the need for second procedures that delay the diagnosis.
Key issues to consider in choosing the diagnostic approach include the following:
Ann Arbor Staging Classification for Hodgkin Lymphoma
Stage is determined by anatomic evidence of disease using CT scanning in conjunction with functional imaging. The staging classification used for Hodgkin lymphoma was adopted at the Ann Arbor Conference held in 1971  and revised in 1989 (refer to Table 1). Staging is independent of the imaging modality used.
Extralymphatic disease resulting from direct extension of an involved lymph node region is designated E. Extralymphatic disease can cause confusion in staging. For example, the designation E is not appropriate for cases of widespread disease or diffuse extralymphatic disease (e.g., large pleural effusion that is cytologically positive for Hodgkin lymphoma), which should be considered stage IV. If pathologic proof of noncontiguous involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Current practice is to assign a clinical stage on the basis of findings of the clinical evaluation; however, pathologic confirmation of noncontiguous extralymphatic involvement is strongly suggested for assignment to stage IV.
After the diagnostic and staging evaluation data are acquired, patients are further classified into risk groups for the purposes of treatment planning. The classification of patients into low-, intermediate-, or high-risk categories varies considerably among the different pediatric research groups, and often even between different studies conducted by the same group, as summarized in Figure 1.
Figure 1. Variation in risk stratification across pediatric Hodgkin study groups and protocols. E, extranodal extension; X, bulky disease (peripheral >6 cm and mediastinal bulk); mX, mediastinal bulk (≥0.33 mediastinal to thoracic ratio); ns, nodal site; TG, treatment group; TL, treatment level; RF, risk factors: erythrocyte sedimentation rate (ESR) ≥30 mm/hour and/or bulk ≥200 mL. (*) EuroNet-PHL-C1 was amended in 2012: Low-risk (TG1) patients with ESR ≥30 mm/hour and/or bulk ≥200 mL were treated in TG2 (intermediate risk). Christine Mauz-Körholz, Monika L. Metzger, Kara M. Kelly, Cindy L. Schwartz, Mauricio E. Castellanos, Karin Dieckmann, Regine Kluge, and Dieter Körholz, Pediatric Hodgkin Lymphoma, Journal of Clinical Oncology, volume 33, issue 27, pages 2975–2985. Reprinted with permission. © (2015) American Society of Clinical Oncology. All rights reserved.
Although all major research groups classify patients according to clinical criteria, such as stage and presence of B symptoms, extranodal involvement, or bulky disease, comparison of outcomes across trials is further complicated because of differences in how these individual criteria are defined.
Further refinement of risk classification may be performed through assessment of response after initial cycles of chemotherapy or at the completion of chemotherapy.
Interim response assessment
The interim response to initial therapy, which may be assessed on the basis of volume reduction of disease, functional imaging status, or both, is an important prognostic variable in both early- and advanced-stage pediatric Hodgkin lymphoma.[19,20]
Definitions for interim response are variable and protocol specific but can range from volume reductions of greater than 50% to the achievement of a complete response with a volume reduction of greater than 95% by anatomic imaging or resolution of 18F-FDG PET avidity.[3,21,22]
The rapidity of response to early therapy has been used in risk stratification to tailor therapy in an effort to augment therapy in higher-risk patients or to reduce the late effects while maintaining efficacy.[22,23,24]
Results of selected trials using interim response to titrate therapy
End of chemotherapy response assessment
Restaging is carried out upon the completion of all planned initial chemotherapy and may be used to determine the need for consolidative radiation therapy. Key concepts to consider include the following:
Historical Overview of Treatment for Hodgkin Lymphoma
Long-term survival has been achieved in children and adolescents with Hodgkin lymphoma using radiation, multiagent chemotherapy, and combined-modality therapy. In selected cases of localized lymphocyte-predominant Hodgkin lymphoma, complete surgical resection may be curative and obviate the need for cytotoxic therapy.
Treatment options for children and adolescents with Hodgkin lymphoma include the following:
Contemporary treatment for pediatric Hodgkin lymphoma uses a risk-adapted and response-based paradigm that assigns the length and intensity of therapy based on disease-related factors such as stage, number of involved nodal regions, tumor bulk, the presence of B symptoms, and early response to chemotherapy by functional and anatomic imaging. Age, sex, and histological subtype may also be considered in treatment planning.
Risk-adapted treatment paradigms
Histology-based therapy (stage I nodular lymphocyte-predominant Hodgkin lymphoma)
Histological subtype may direct therapy in patients with stage I completely resected, nodular lymphocyte-predominant Hodgkin lymphoma, whose initial treatment may be surgery alone.
This histology-based treatment approach is supported by the following findings from the literature:
Advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma is very rare, and there is no consensus regarding the optimal treatment, although outcomes for patients are excellent. In a retrospective review of 41 cases of advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma, many different chemotherapy regimens were used, some including rituximab. OS was 98%, with the only death being from secondary malignancy.[Level of evidence: 3iiiA]
A summary of treatment approaches for nodular lymphocyte-predominant Hodgkin lymphoma can be found in Table 9. Both children and adults treated for nodular lymphocyte-predominant Hodgkin lymphoma have a favorable outcome, particularly when the disease is localized (stage I), as it is for most patients.[23,24,26,28] Death among long-term survivors of nodular lymphocyte-predominant Hodgkin lymphoma is more likely to result from treatment-related toxicity (both acute and long-term) than from lymphoma.[29,30]
As discussed in the previous sections, most newly diagnosed children will be treated with risk-adapted chemotherapy alone or in combination with consolidative radiation therapy (RT). RT volumes can have variable and protocol-specific definitions, but generally encompass lymph node regions initially involved at the time of diagnosis, without extensive inclusion of uninvolved regions. RT field reductions are made to account for tumor regression with chemotherapy.
With advancements in systemic therapy, RT field definitions have evolved and become increasingly restricted. RT is no longer needed to sterilize all disease. Advancements in radiologic imaging allow more precise radiation target definition. Historically, concerns about the symmetry of growth in young children with unilateral disease involvement often prompted treatment of the contralateral tissues. With contemporary treatments using lower radiation doses (15 to 21 Gy) and reduced volumes (involved-site RT [ISRT]), treatment of contralateral uninvolved sites is not necessary.
General trends in radiation treatment volume are summarized as follows:
Visual PET criteria are scored according to uptake involved by lymphoma from the Deauville 5-point scale, from 1 to 5, as described in Table 2. The Children's Oncology Group and Euronet definitions of PET response of lymph nodes or nodal masses are described in Table 3.
A breast-sparing radiation therapy plan using proton therapy is being evaluated to determine if there is a statistically significant reduction in dose. Long-term results are awaited.
Considerations in ISRT or INRT Treatment Planning
Radiation therapy planning that uses CT scans obtained during the simulation procedure is a requirement for contemporary INRT or ISRT. Fusion of staging imaging (CT or PET-CT) with the planning CT dataset can facilitate delineation of the treatment volume. RT planning scans that encompass the full extent of organs at risk (e.g., lungs) are important so that normal tissue exposures can be calculated accurately.
Definitions that are important in planning radiation therapy include the following:
The treatment volume for unfavorable or advanced disease is somewhat variable and often protocol-specific. Large-volume RT may compromise organ function and limit the intensity of second-line therapy if relapse occurs. In patients with intermediate or advanced disease, who often have multifocal/extranodal disease, the current standard of therapy includes postchemotherapy ISRT that limits radiation exposure to large portions of the body.[14,38]
The dose of radiation is also variously defined and often protocol-specific. General considerations regarding radiation dose include the following:
Technical considerations for the use of radiation therapy to treat Hodgkin lymphoma include the following:
Role of LD-ISRT in childhood and adolescent Hodgkin lymphoma
Because all children and adolescents with Hodgkin lymphoma receive chemotherapy, a question commanding significant attention is whether patients who achieve a rapid early response or a CR to chemotherapy require RT. Conversely, the judicious use of LD-ISRT may permit a reduction in the intensity or duration of chemotherapy below toxicity thresholds that would not be possible if single modality chemotherapy were used, thus decreasing overall acute and late toxicities.
Key points to consider in regard to the role of radiation in pediatric Hodgkin lymphoma include the following:
Finally, an inherent assumption is made in a trial comparing chemotherapy alone versus chemotherapy and radiation that the effect of radiation on EFS will be uniform across all patient subgroups. However, it is not clear how histology, presence of bulky disease, presence of B symptoms, or other variables affect the efficacy of postchemotherapy radiation.
All of the agents in original MOPP and ABVD regimens continue to be used in contemporary pediatric treatment regimens. COPP (substituting cyclophosphamide for mechlorethamine) has almost uniformly replaced MOPP as the preferred alkylator regimen in most frontline trials. Etoposide has been incorporated into treatment regimens as an effective alternative to alkylating agents in an effort to reduce gonadal toxicity and enhance antineoplastic activity.
Combination chemotherapy regimens used in contemporary trials are summarized in Table 5.
Results from selected clinical trials
North American cooperative and consortium trials
The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy utilizing ABVE (doxorubicin [Adriamycin], bleomycin, vincristine, and etoposide)  for favorable low-stage patients and dose-dense ABVE-PC (prednisone and cyclophosphamide) for unfavorable advanced-stage patients in combination with 21 Gy IFRT.
Key findings from these trials include the following:
The Children's Cancer Group (CCG) undertook a randomized controlled trial comparing survival outcomes in children treated with risk-adapted COPP/ABV hybrid chemotherapy alone with those treated with COPP/ABV hybrid chemotherapy plus LD-IFRT. The study was closed early because of a significantly higher number of relapses among patients treated with chemotherapy alone. Long-term results include the following:[14,19]
Another CCG Study (COG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP regimen followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[Level of evidence: 2Dii] For rapid early responding girls, an additional four courses of COPP/ABV (without IFRT) were given. Rapid early responding boys received two cycles of ABVD followed by IFRT. Slow early responders received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girl's therapy was intended to reduce the risk of breast cancer. Key findings from this trial include the following:
The Stanford, St. Jude Children's Research Hospital, and Boston Consortium administered a series of risk-adapted trials over the last 20 years. Key findings include the following:
The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulk disease, and IA or IIA with bulk disease. All patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation.
Key 4-year OS and EFS outcomes from this trial include the following:
German multicenter trials
In the last 30 years, German investigators have implemented a series of risk-adapted trials evaluating sex-based treatments featuring multiagent chemotherapy with vincristine, prednisone, procarbazine, and doxorubicin (OPPA)/COPP and IFRT.
Accepted Risk-Adapted Treatment Strategies for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma
Contemporary trials for pediatric Hodgkin lymphoma involve a risk-adapted, response-based treatment approach that titrates the length and intensity of chemotherapy and dose of radiation based on disease-related factors including stage, number of involved nodal regions, tumor bulk, the presence of B symptoms, and early response to chemotherapy as determined by functional imaging. In addition, vulnerability related to age and sex is also considered in treatment planning.
Classical Hodgkin lymphoma low-risk disease
Table 6 summarizes the results of contemporary treatment approaches used for low-risk Hodgkin lymphoma.
Classical Hodgkin lymphoma intermediate-risk disease
Table 7 summarizes the results of contemporary treatment approaches used for intermediate-risk Hodgkin lymphoma.
Classical Hodgkin lymphoma high-risk disease
Table 8 summarizes the results of contemporary treatment approaches used for high-risk Hodgkin lymphoma.
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
Nodular lymphocyte-predominant Hodgkin lymphoma
The use of combination chemotherapy and/or radiation therapy can achieve excellent long-term progression-free survival and OS in patients with nodular lymphocyte-predominant Hodgkin lymphoma.[26,55,56] Late recurrences have been reported and are typically responsive to re-treatment. Because deaths observed among individuals with this histological subtype are frequently related to complications from cytotoxic therapy, risk-adapted treatment assignment is particularly important for limiting exposure to agents with established dose-related toxicities.[55,56]Table 9 summarizes the results of contemporary treatment approaches used for nodular lymphocyte-predominant Hodgkin lymphoma, some of which feature surgery alone for completely resected disease and limited cycles of chemotherapy with or without LD-IFRT. Because of the relative rarity of this subtype, most trials are limited by small cohort numbers and nonrandom allocation of treatment. Results from a single-arm COG trial provide data to support the strategy of observation after surgical resection and treatment with limited chemotherapy for children with favorable stage IA or IIA Hodgkin lymphoma. Among 178 patients treated with surgical resection alone of single-node disease (n = 52), chemotherapy alone after complete response to three cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy (n = 115), or chemotherapy with LD-IFRT (21 Gy) after incomplete response to AV-PC chemotherapy (n = 11), the 5-year EFS was 85.5%, and the OS was 100%. Five-year EFS was 77% for patients observed after total resection and 88.8% for patients treated with AV-PC chemotherapy.[Level of evidence: 1iiDi]
Treatment of Adolescents and Young Adults with Hodgkin Lymphoma
The treatment approach used for adolescents and young adults with Hodgkin lymphoma may vary based on community referral patterns and age restrictions at pediatric cancer centers. In patients with high-risk disease, the standard of care in adult oncology practices typically involves at least six cycles of ABVD chemotherapy that would deliver a cumulative anthracycline dose of 300 mg/m2.[57,58] (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) In late-health outcomes studies of pediatric cancer survivors, the risk of anthracycline cardiomyopathy has been shown to exponentially increase after exposure to cumulative anthracycline doses of 250 mg/m2 to 300 mg/m2.[59,60] Subsequent need for mediastinal radiation can further enhance the risk of a variety of late cardiac events.[59,60,61] In an effort to optimize disease control and preserve both cardiac and gonadal function, pediatric regimens for low-risk disease most often feature a restricted number of cycles of ABVD derivative combinations, whereas alkylating agents and etoposide are integrated into anthracycline-containing regimens for those with intermediate- and high-risk disease.
Participation in a clinical trial should be considered for adolescent and young adult patients with Hodgkin lymphoma. Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The excellent response to frontline therapy among children and adolescents with Hodgkin lymphoma limits opportunities to evaluate second-line (salvage) therapy. Because of the small number of patients that fail primary therapy, no uniform second-line treatment strategy exists for this patient population. Adverse prognostic factors after relapse include the following:[Level of evidence: 3iiA]
Children with localized favorable (relapse ≥12 months after completing therapy) disease recurrences whose original therapy involved reduced cycles of risk-adapted therapy or with chemotherapy alone and/or low-dose involved-field radiation therapy (LD-IRFT) consolidation have a high likelihood of achieving long-term survival after treatment with more intensive conventional chemotherapy.[5,6]
Key concepts in regard to treatment of refractory or recurrent Hodgkin lymphoma in children and adolescents are as follows:
Agents used alone or in combination regimens in the treatment of refractory or recurrent Hodgkin lymphoma include the following:
There are ongoing trials to determine the toxicity and efficacy of combining brentuximab vedotin with chemotherapy.
Patients treated with HCT may experience relapse as late as 5 years after the procedure; they should be monitored for relapse and late treatment sequelae.
Response Rates for Primary Refractory Hodgkin Lymphoma
Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with autologous HCT and radiation. However, intensification of therapy followed by HCT consolidation has been reported to achieve long-term survival in some studies.
Second Relapse After Initial Treatment With Autologous HCT
In a phase II study, patients (median age, 26.5 years) who had relapsed or refractory disease after autologous HCT received brentuximab vedotin, with an objective response rate of 73% and a complete remission rate of 34%. Patients who achieved a complete remission (n = 34) had a 3-year PFS rate of 58% and a 3-year OS rate of 73%, with only 6 of 34 patients proceeding to allogeneic SCT while in remission.[Level of evidence: 2A]
Treatment Options Under Clinical Evaluation
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Children and adolescent survivors of Hodgkin lymphoma may be at risk for numerous late complications of treatment related to radiation, specific chemotherapeutic exposures, and surgical staging. Adverse treatment effects may impact oral/dental health; musculoskeletal growth and development; endocrine, reproductive, cardiovascular and pulmonary function; and risk of secondary carcinogenesis. In the past 30 to 40 years, pediatric Hodgkin lymphoma therapy has changed dramatically to proactively limit exposure to radiation and chemotherapeutic agents, such as anthracyclines, alkylating agents, and bleomycin. When counseling individual patients about the risk for specific treatment complications, the era of treatment should be considered.
Table 10 summarizes late health effects observed in Hodgkin lymphoma survivors, followed by a limited discussion of the common late effects. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)
Male Gonadal Toxicity
(Refer to the Testis section of the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Female Gonadal Toxicity
(Refer to the Ovary section of the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
The relative risk (RR) of thyroid cancer is increased among Hodgkin lymphoma survivors (approximately 18-fold for the CCSS Hodgkin lymphoma cohort compared with the general population). Risk factors for the development of thyroid nodules in Hodgkin lymphoma survivors reported by CCSS include time since diagnosis of more than 10 years (RR, 4.8; 95% confidence interval [CI], 3.0–7.8), female sex (RR, 4.0; 95% CI, 2.5–6.7), and radiation dose to thyroid higher than 25 Gy (RR, 2.9; 95% CI, 1.4–6.9). The absolute risk of thyroid cancer is relatively low, with approximately 1% of the CCSS Hodgkin cohort developing thyroid cancer, with a median follow-up of approximately 15 years.
A single-institution Hodgkin lymphoma survivor cohort that included both adult and pediatric cases showed a cumulative incidence of thyroid cancer at 10 years from diagnosis of 0.26%, increasing to approximately 3% at 30 years from diagnosis. In this cohort, age younger than 20 years at Hodgkin lymphoma diagnosis and female sex were significantly associated with thyroid cancer.
(Refer to the Thyroid Gland section of the PDQ summary on Late Effects of Treatment for Childhood Cancer summary for more information.)
Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk for long-term cardiac toxicity. The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. The pathogenesis of injury differs, however, with radiation primarily affecting the fine vasculature of the heart, and anthracyclines directly damaging myocytes.[22,23,24]
Radiation-associated cardiovascular toxicity
The risks to the heart are related to the amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, and latency period.
Anthracycline-related cardiac toxicity
(Refer to the Late Effects of the Cardiovascular System section of the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
(Refer to the Subsequent Neoplasms section of the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Editorial changes were made to this summary.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Hodgkin Lymphoma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/child-hodgkin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389170]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2018-08-22
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