National Cancer Institute

Expert-reviewed information summary about the treatment of childhood Hodgkin lymphoma.

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.

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).

Childhood Hodgkin Lymphoma Treatment

General Information About Childhood Hodgkin Lymphoma

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:

  • Hodgkin lymphoma has a bimodal age distribution that differs geographically and ethnically in industrialized countries; the early peak occurs in the middle-to-late 20s and the second peak after age 50 years. In developing countries, the early peak occurs before adolescence.
  • The male-to-female ratio varies markedly by age. Children younger than 5 years show a strong male predominance (M:F = 5.3) and children aged 15 to 19 years show a slight female predominance (M:F = 0.8).
  • There are three distinct forms of Hodgkin lymphoma:
    • —occurs in individuals aged 14 years and younger. The childhood form of Hodgkin lymphoma increases in prevalence in association with larger family size and lower socioeconomic status. Early exposure to common infections in early childhood appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity.
    • —affects individuals aged 15 to 34 years. The young adult form is associated with a higher socioeconomic status in industrialized countries, increased sibship size, and earlier birth order. The lower risk of Hodgkin lymphoma observed in young adults with multiple older, but not younger, siblings, is consistent with the hypothesis that early exposure to viral infection (which the siblings bring home from school, for example) may play a role in the pathogenesis of the disease.
    • —most commonly presents in individuals aged 55 to 74 years.
  • A family history of Hodgkin lymphoma in siblings or parents has been associated with an increased risk of this disease. In a population-based study that evaluated risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex, the cumulative risk of Hodgkin lymphoma was 0.6%, representing a 3.3-fold increased risk compared with the general population risk. The risk in siblings was significantly higher than the risk in parents and/or offspring. The risk in sisters was higher than the risk in brothers or siblings of opposite sex. The lifetime risk of Hodgkin lymphoma was higher when first-degree relatives were diagnosed before age 30 years.

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 positivity is most commonly observed in tumors with mixed-cellularity histology and is almost never seen in patients with lymphocyte-predominant histology.
  • EBV positivity is more common in children younger than 10 years than in adolescents and young adults.
  • The incidence of EBV tumor cell positivity for Hodgkin lymphoma in developed countries ranges from 15% to 25% in adolescents and young adults. A high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma is seen in developing countries, and these cases are generally EBV-positive (approximately 80%).

EBV serologic status is not a prognostic factor for failure-free survival in pediatric and young adult Hodgkin lymphoma patients, 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:

  • Hodgkin lymphoma usually occurs at a younger age and with histologies other than nodular sclerosing in patients with primary immunodeficiencies.
  • The risk of Hodgkin lymphoma increases as much as 50-fold over the general population in patients with autoimmune lymphoproliferative syndrome.
  • Although it is not an AIDS-defining malignancy, the incidence of Hodgkin lymphoma appears to be increased in HIV-infected individuals, including children.

Clinical Presentation

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.

  • Approximately 80% of patients present with painless adenopathy, most commonly involving the supraclavicular or cervical area.
  • Mediastinal disease is present in about 75% of adolescents and young adults and may be asymptomatic. In contrast, only about 35% of young children with Hodgkin lymphoma have mediastinal involvement, in part, reflecting the tendency of these patients to have either mixed cellularity or lymphocyte-predominant histology.
  • Fifteen percent to 20% of patients will have noncontiguous extranodal involvement (stage IV). The most common sites of extranodal involvement are the lung, liver, bones, and bone marrow.
  • Nonspecific constitutional symptoms including fatigue, anorexia, weight loss, pruritus, night sweats, and fever occur in approximately 25% of patients.
  • Three specific constitutional (B) symptoms that have been correlated with prognosis—unexplained fever (temperature above 38.0°C orally), unexplained weight loss (10% of body weight within the 6 months preceding diagnosis), and drenching night sweats—are commonly used to assign risk in clinical trials.

Prognostic Factors

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:

  • Advanced stage of disease.
  • Presence of B symptoms.
  • Presence of bulky disease.
  • Extranodal extension.
  • Elevated erythrocyte sedimentation rate.
  • Leukocytosis (white blood cell count of 11,500/mm or higher).
  • Anemia (hemoglobin lower than 11.0 g/dL).
  • Male sex.
  • Response to initial treatment with chemotherapy.

Prognostic factors identified in selected multi-institutional studies include the following:

  • In the Society for Paediatric Oncology and Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]) GPOH-95 study, B symptoms, histology, and male sex were adverse prognostic factors for event-free survival on multivariate analysis.
  • In 320 children with clinically staged Hodgkin lymphoma treated in the Stanford-St. Jude-Dana Farber Cancer Institute consortium, male sex; stage IIB, IIIB, or IV disease; white blood cell count of 11,500/mm or higher; and hemoglobin lower than 11.0 g/dL were significant prognostic factors for inferior disease-free survival and overall survival (OS). Prognosis was also associated with the number of adverse factors.
  • In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome.
  • One single-institutional study showed that African American patients had a higher relapse rate than did white patients, but OS was similar.

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. 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. 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.

Cellular Classification and Biologic Correlates of Childhood Hodgkin Lymphoma

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. 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:

  • The Reed-Sternberg cell is a binucleated or multinucleated giant cell with a bilobed nucleus and two large nucleoli that give a characteristic owl's eye appearance.
  • The malignant Reed-Sternberg cell comprises only about 1% of the abundant reactive cellular infiltrate of lymphocytes, macrophages, granulocytes, and eosinophils in involved specimens.
  • Reed-Sternberg cells almost always express CD30, and approximately 70% of patients express CD15. CD20 is expressed in approximately 6% to 10% of cases, and generally Reed-Sternberg cells do not express B-cell antigens such as CD45, CD19, and CD79A.
  • In nodular lymphocyte-predominant Hodgkin lymphoma, the Reed-Sternberg cells are usually mononuclear with a markedly convoluted and lobated nucleus (popcorn cells). Also known as lymphocytic and histiocytic cells, this Reed-Sternberg–cell variant does not express CD30, but does express CD20, suggesting that it is biologically distinct from other subtypes of Hodgkin lymphoma.
  • Most cases of classical Hodgkin lymphoma are characterized by expression of TNF-R and their ligands, as well as an unbalanced production of T helper lymphocytes type 2 (Th2) cytokines and chemokines. Activation of TNF-R results in constitutive activation of nuclear factor kappa B in Reed-Sternberg cells, which may prevent apoptosis and provide a survival advantage.

Hodgkin lymphoma can be divided into the following two broad pathologic classes:

  • Classical Hodgkin lymphoma.
  • Nodular lymphocyte-predominant Hodgkin lymphoma.

Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma is divided into the following four subtypes:

  • Lymphocyte-rich classical Hodgkin lymphoma.
  • Nodular sclerosis Hodgkin lymphoma.
  • Mixed-cellularity Hodgkin lymphoma.
  • Lymphocyte-depleted Hodgkin lymphoma.

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:

  • Lymphocyte-rich classical Hodgkin lymphoma may have a nodular appearance, but immunophenotypic analysis allows distinction between this form of Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma. Lymphocyte-rich classical Hodgkin lymphoma cells express CD15 and CD30.
  • Nodular sclerosis Hodgkin lymphoma histology accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents but only 55% of cases in younger children in the United States. This subtype is distinguished by the presence of collagenous bands that divide the lymph node into nodules, which often contain an Reed-Sternberg cell variant called the lacunar cell. Some pathologists subdivide nodular sclerosis into two subgroups (NS-1 and NS-2) on the basis of the number of Reed-Sternberg cells present. Transforming growth factor-beta may be responsible for the fibrosis in the nodular sclerosis Hodgkin lymphoma subtype.

    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.

  • Mixed-cellularity Hodgkin lymphoma is more common in young children than in adolescents and adults, with mixed-cellularity Hodgkin lymphoma accounting for approximately 20% of cases in children younger than 10 years, but only approximately 9% of older children and adolescents aged 10 to 19 years in the United States. Reed-Sternberg cells are frequent in a background of abundant normal reactive cells (lymphocytes, plasma cells, eosinophils, and histiocytes). Interleukin-5 may be responsible for the eosinophilia in mixed-cellularity Hodgkin lymphoma. This subtype can be confused with non-Hodgkin lymphoma.
  • Lymphocyte-depleted Hodgkin lymphoma is rare in children. It is common in adult patients with HIV. This subtype is characterized by the presence of numerous large, bizarre malignant cells, many Reed-Sternberg cells, and few lymphocytes. Diffuse fibrosis and necrosis are common. Many cases previously diagnosed as lymphocyte-depleted Hodgkin lymphoma are now recognized as diffuse large B-cell lymphoma, anaplastic large cell lymphoma, or nodular sclerosis classical Hodgkin lymphoma with lymphocyte depletion.

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. 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:

  • Pediatric patients are more likely to have low-stage disease and no B symptoms or extranodal involvement than are adult patients. Patients with nodular lymphocyte-predominant Hodgkin lymphoma generally present with localized, nonbulky, peripheral lymphadenopathy that rarely involves the mediastinum. Almost all patients are asymptomatic.
  • Nodular lymphocyte-predominant Hodgkin lymphoma is characterized by molecular and immunophenotypic evidence of B-lineage differentiation with the following distinctive features:
    • Nodular lymphocyte-predominant Hodgkin lymphoma is characterized by large cells with multilobed nuclei, referred to as popcorn cells. These cells express B-cell antigens, such as CD19, CD20, CD22, and CD79A, and are negative for CD15 and may or may not express CD30.
    • The and oncogenes are both expressed in nodular lymphocyte-predominant Hodgkin lymphoma; they are not expressed in the cells of patients with classical Hodgkin lymphoma.
    • Reliable discrimination from non-Hodgkin lymphoma is problematic in diffuse subtypes with lymphocytic and histiocytic cells set against a diffuse background of reactive T-cells.
    • Nodular lymphocyte-predominant Hodgkin lymphoma can be difficult to distinguish from progressive transformation of germinal centers and/or T-cell–rich B-cell lymphoma.
  • Pediatric patients (aged <20 years) have better outcomes than do adult patients, even when controlled for other prognostic factors. Chemotherapy and/or radiation therapy produce excellent long-term progression-free survival and overall survival in patients with nodular lymphocyte-predominant Hodgkin lymphoma; however, late recurrences have been reported up to 10 years after initial therapy.; []
  • Deaths observed among individuals with nodular lymphocyte-predominant Hodgkin lymphoma are more frequently related to treatment complications and/or the development of subsequent neoplasms (including non-Hodgkin lymphoma) than in refractory disease, underscoring the importance of judicious use of chemotherapy and radiation therapy at initial presentation and after recurrent disease.

Diagnosis and Staging Information for Childhood Hodgkin Lymphoma

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.

Pretreatment Staging

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:

  • Detailed history of systemic symptoms.
  • Physical examination.
  • Laboratory studies.
  • Anatomic imaging including chest x-ray and computed tomography (CT) scan of the neck, chest, abdomen, and pelvis.
  • Functional imaging including positron emission tomography (PET) scan.

Systemic symptoms

The following three specific constitutional symptoms (B symptoms) correlate with prognosis and are considered in assignment of stage:

  • Unexplained fever with temperatures above 38.0°C orally.
  • Unexplained weight loss of 10% within the 6 months preceding diagnosis.
  • Drenching night sweats.

Additional Hodgkin-associated constitutional symptoms without prognostic significance include the following:

  • Pruritus.
  • Alcohol-induced nodal pain.

Physical examination

  • All node-bearing areas, including the Waldeyer ring, should be assessed by careful physical examination.
  • Enlarged nodes should be measured to establish a baseline for evaluation of therapy response.

Laboratory studies

  • Hematological and chemical blood parameters show nonspecific changes that may correlate with disease extent.
  • Abnormalities of peripheral blood counts may include neutrophilic leukocytosis, lymphopenia, eosinophilia, and monocytosis.
  • Acute-phase reactants such as the erythrocyte sedimentation rate and C-reactive protein, if abnormal at diagnosis, may be useful in follow-up evaluation.

Anatomic imaging

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:

  • Contiguous nodal clustering or matting is highly suggestive of lymphomatous involvement.
  • Any focal mass lesion large enough to characterize in a visceral organ is considered lymphomatous involvement unless the imaging characteristics indicate an alternative etiology.
  • Criteria for nodal involvement may vary by cooperative group or protocol.
    • Children's Oncology Group (COG) and EuroNet protocols consider lymph nodes abnormal if the long axis is greater than 2.0 cm, regardless of the short axis and PET avidity. Lymph nodes with a long axis measuring between 1.0 cm and 2.0 cm are only considered abnormal if they are part of a conglomerate of nodes and are fluorine F 18-fludeoxyglucose (18F-FDG) PET positive.
    • In the Society for Paediatric Oncology and Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]) study, nodal involvement was defined as node size greater than 2 cm in largest diameter. The node was not involved if it was less than 1 cm and was considered questionably involved if it was between 1 cm and 2 cm. The involvement decision was then based on all further clinical evidence available.

Functional imaging

The recommended functional imaging procedure for initial staging is now PET, using the radioactive glucose analog, 18F-FDG. 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.

General concepts to consider in regard to defining lymphomatous involvement by 18F-FDG PET include the following:

  • Concordance between PET and CT data is generally high for nodal regions, but may be significantly lower for extranodal sites. In one study specifically analyzing pediatric Hodgkin lymphoma patients, assessment of initial staging comparing PET and CT data demonstrated concordance of approximately 86% overall. Concordance rates were significantly lower for the spleen, lung nodules, bone/bone marrow, and pleural and pericardial effusions. A meta-analysis of nine clinical studies showed that PET-CT achieved high sensitivity (96.9%) and high specificity (99.7%) in detecting bone marrow involvement in newly diagnosed patients with Hodgkin lymphoma.
  • Integration of data acquired from PET scans can lead to changes in staging.
  • Staging criteria using PET and CT scan information is protocol dependent, but generally areas of PET positivity that do not correspond to an anatomic lesion by clinical examination or CT scan size criteria should be disregarded in staging.
  • A suspected anatomic lesion that is PET-negative should not be considered involved unless proven by biopsy.

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:

  • If possible, the diagnosis should be established by biopsy of one or more peripheral lymph nodes. Aspiration cytology alone is not recommended because of the lack of stromal tissue, the small number of cells present in the specimen, and the difficulty of classifying Hodgkin lymphoma into one of the subtypes.
  • An image-guided biopsy may be used to obtain diagnostic tissue from intra-thoracic or intra-abdominal lymph nodes. On the basis of the involved sites of disease, alternative noninvasive procedures that may be considered include thoracoscopy, mediastinoscopy, and laparoscopy. Thoracotomy or laparotomy is rarely needed to access diagnostic tissue. The likelihood of obtaining sufficient tissue should be carefully considered when selecting a biopsy procedure.
  • Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation. After careful planning with anesthesia, peripheral lymph node biopsy or image-guided core-needle biopsy of mediastinal lymph nodes may be feasible using light sedation and local anesthesia before proceeding to more invasive procedures.
  • If airway compromise precludes the performance of a diagnostic operative procedure, preoperative treatment with steroids or low-dose, localized radiation therapy should be considered. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risks associated with general anesthesia or heavy sedation are alleviated. Treatment with steroids will make the PET-CT scan unreliable.
  • Because bone marrow involvement is relatively rare in pediatric Hodgkin lymphoma patients, bilateral bone marrow biopsy should be performed only in patients with advanced disease (stage III or stage IV) and/or B symptoms. In support of this, a meta-analysis of nine clinical studies including both pediatric and adult patients showed that PET-CT achieved high sensitivity (96.9%) and high specificity (99.7%) in detecting bone marrow involvement in newly diagnosed patients with Hodgkin lymphoma. (Refer to the Stage Information for Adult HL section in the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) In a consensus statement based on these studies, this group no longer recommends bone marrow biopsy in the initial evaluation of adults with Hodgkin lymphoma, with PET-CT being used instead to identify bone marrow involvement.

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 . Extralymphatic disease can cause confusion in staging. For example, the designation 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.

Risk Stratification

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.

Chart showing the variation in risk stratification across pediatric Hodgkin study groups and protocols.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.

Response Assessment

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.

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.

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.

Results of selected trials using interim response to titrate therapy

  • The Pediatric Oncology Group used a response-based therapy approach consisting of dose-dense ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide-prednisone, cyclophosphamide) for intermediate-stage and advanced-stage patients, in combination with 21 Gy involved-field radiation therapy (IFRT). The dose-dense approach permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response on CT imaging after three ABVE-PC cycles. Five-year event-free survival (EFS) was comparable for rapid early responders (86%; treated with three cycles of ABVE-PC) and slow early responders (83%; treated with five cycles of ABVE-PC). All patients received 21 Gy of regional radiation therapy.
  • The Children's Cancer Group (CCG) () evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen followed by a sex-tailored consolidation for pediatric patients with stage IIB, IIIB with bulky disease, and IV Hodgkin lymphoma. For rapid early responding girls, an additional four courses of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine) (without IFRT) was given in an effort to reduce breast cancer risk. Rapid early responding boys received two cycles of ABVD followed by IFRT. Slow early responders received four additional courses of BEACOPP and IFRT. Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four BEACOPP cycles and 5-year EFS among the cohort was 94% (median follow-up, 6.3 years).
  • The COG trial also used interim response to titrate therapy. (Refer to the Results from selected clinical trials section of this summary for more information.)

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:

  • Defining complete response.
    • The International Working Group (IWG) defined complete response for adults with Hodgkin lymphoma in terms of complete metabolic response as assessed by 18F-FDG PET, even when a persistent mass is present. These criteria were endorsed in the Lugano Classification, with the recommendation for using a 5-point scale in assessing response. COG protocols have adopted this approach for defining complete response.
    • Previous studies have varied in the use of findings from clinical exam, anatomic imaging, and functional imaging to assess response. Although complete response can be defined as absence of disease by clinical examination and/or imaging studies, complete response in Hodgkin lymphoma trials is often defined by a greater than 80% reduction of disease and a change from initial positivity to negativity on functional imaging. This definition is necessary in Hodgkin lymphoma because fibrotic residual disease is common, particularly in the mediastinum. In some studies, such patients are designated as having an unconfirmed complete response.
    • The Euronet Hodgkin lymphoma trials use a similar early response assessment definition of PET positivity, which is a Deauville score of greater than 3 after two cycles of OEPA (vincristine [Oncovin], etoposide, prednisone, doxorubicin [Adriamycin]). However, the definition for late response assessment after all chemotherapy is a Deauville score of greater than 1.
    • The definition of complete response varies by protocol/cooperative group. GPOH studies use very stringent criteria that includes at least 95% reduction in tumor volume or less than 2 mL residual volume on CT, as patients achieving these metrics will have radiation therapy omitted. This is in contrast to the COG high-risk Hodgkin lymphoma initial therapeutics clinical trial, which uses 18F-FDG PET assessment graded by a 5-point visual scale or Deauville criteria after two chemotherapy cycles to define a rapid early-responding lesion for which radiation will be omitted. A mass of any size is permitted for a complete response designation if the PET is negative.
  • Timing of PET scanning after completing therapy.
    • Timing of PET scanning after completing therapy is an important issue. For patients treated with chemotherapy alone, PET scanning is ideally performed a minimum of 3 weeks after the completion of therapy, while patients whose last treatment modality was radiation therapy should not undergo PET scanning until 8 to 12 weeks postradiation.
    • A COG study evaluated surveillance CT and detection of relapse in intermediate-stage and advanced-stage Hodgkin lymphoma. Most relapses occurred within the first year after therapy or were detected based on symptoms, laboratory, or physical findings. The method of detection of late relapse, whether by imaging or clinical change, did not affect overall survival. Routine use of CT at the intervals used in this study did not improve outcome. The concept of reduced frequency of imaging has been supported by other investigations.
    • Caution should be used in making the diagnosis of relapsed or refractory disease based solely on anatomic and functional imaging because false-positive results are not uncommon. Consequently, pathologic confirmation of refractory or recurrent disease is recommended before modification of therapeutic plans.

Treatment for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma

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:

Treatment Approaches

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 designation

  • Favorable clinical features include localized nodal involvement in the absence of B symptoms and bulky disease. Risk factors considered in other studies include the number of involved nodal regions, the presence of hilar adenopathy, the size of peripheral lymphadenopathy, and extranodal extension.
  • Unfavorable clinical features include the presence of B symptoms, bulky mediastinal or peripheral lymphadenopathy, extranodal extension of disease, and advanced (stages IIIB–IV) disease. Bulky mediastinal lymphadenopathy is designated when the ratio of the maximum measurement of mediastinal lymphadenopathy to intrathoracic cavity on an upright chest radiograph equals or exceeds 33%.
  • Localized disease (stages I, II, and IIIA) with unfavorable features may be treated similarly to advanced-stage disease in some treatment protocols or treated with therapy of intermediate intensity.
  • Inconsistency in risk categorization across studies often makes comparison of study outcomes challenging.

Risk-adapted treatment paradigms

  • No single treatment approach is ideal for all pediatric and young adult patients because of the differences in age-related developmental status and sex-related sensitivity to chemotherapy toxicity.
  • The general treatment strategy that is used to treat children and adolescents with Hodgkin lymphoma is chemotherapy for all patients, with or without radiation. The number of cycles and intensity of chemotherapy may be determined by the rapidity and degree of response, as is the radiation dose and volume.
  • Ongoing trials for patients with favorable disease presentations are evaluating the effectiveness of treatment with fewer cycles of combination chemotherapy alone that limit doses of anthracyclines and alkylating agents.
  • Contemporary trials for patients with intermediate/unfavorable disease presentations are testing if chemotherapy and radiation therapy can be limited in patients who achieve a rapid early response to dose-intensive chemotherapy regimens.
  • Sex-based regimens consider that male patients are more vulnerable to gonadal toxicity from alkylating agent chemotherapy and that female patients have a substantial risk of breast cancer after chest radiation. However, the cardiovascular risk to males after chest radiation suggests that limiting radiation exposure is also desirable in males.

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:

  • Although standard therapy for children with nodular lymphocyte-predominant Hodgkin lymphoma is chemotherapy plus LD-IFRT, there are reports in which patients have been treated with chemotherapy alone or with complete resection of isolated nodal disease without chemotherapy. Surgical resection of localized disease produces a prolonged disease-free survival in a substantial proportion of patients obviating the need for immediate cytotoxic therapy.
  • Results from a single-arm Children's Oncology Group (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.[]

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. 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.

Radiation Therapy

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.

Volume considerations

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:

  • Regional RT fields (e.g., mantle, subtotal, or total nodal) are now historic and have been replaced by involved-nodal RT (INRT) or ISRT, or rarely, IFRT in select situations such as adolescents and young adults treated with radiation alone for nodular lymphocyte-predominant Hodgkin lymphoma (refer to Table 4).
  • Involved-nodal RT (INRT), introduced by the European Organization for Research and Treatment of Cancer Lymphoma Group and the Groupe d'Etude des Lymphomes de l'Adulte, remains investigational, although initial clinical data are emerging. This approach defines the treatment volume using the prechemotherapy positron emission tomography (PET)–computed tomography (CT) scan that is obtained with the patient positioned in a similar manner to the position that will be used at the time of RT. This volume is later contoured onto the postchemotherapy-planning CT scan. The final treatment volume only includes the initially involved nodes with a margin, typically 2 cm.
  • Involved-site RT (ISRT) is an evolving approach to be used for patients when optimal prechemotherapy imaging (PET-CT in a position similar to what will be used at the time of RT) is not available to the radiation oncologist. Because the delineation of the area of involvement is less precise, a somewhat larger treatment volume is contoured than for INRT, specifically the whole nodal basin where the lymphoma was located before chemotherapy was given. The exact size of this volume will depend on the individual case scenario.
  • Modified involved-field RT (mIFRT) is the term used in the Euronet-PHL-C1 trial to describe treatment volumes that contain the involved lymph node(s) as seen before chemotherapy plus radiation planning margins of 1 cm to 2 cm, depending on the area of involvement. These volumes are comparable to ISRT fields, although the development preceded the widespread availability of CT-based planning. The subsequent Euronet-PHL-C2 trial employs INRT.
  • Targeted therapy involves restricting RT to areas of initial bulky disease, slowly responding disease (based on PET avidity with a Deauville score of greater than 3 after initial cycles of chemotherapy, usually two cycles), or postchemotherapy residual disease (that has been variously defined but is currently based on residual PET avidity with a Deauville score of greater than 2).

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.

Radiation dose

The dose of radiation is also variously defined and often protocol-specific. General considerations regarding radiation dose include the following:

  • Doses of 15 Gy to 25 Gy are typically used, with modifications based on patient age, the presence of bulky or residual (postchemotherapy) disease, and normal tissue concerns.
  • Some protocols have prescribed a boost of 5 Gy to 10 Gy in regions with suboptimal response to chemotherapy.

Technical considerations

Technical considerations for the use of radiation therapy to treat Hodgkin lymphoma include the following:

  • A linear accelerator with a beam energy of 6 mV is desirable because of its penetration, well-defined edge, and homogeneity throughout an irregular treatment field.
  • Individualized immobilization devices are preferable for young children to ensure accuracy and reproducibility.
  • Attempts should be made to exclude or position breast tissue under the lung/axillary shielding.
  • When the decision is made to include some or all of a critical organ (such as liver, kidney, or heart) in the radiation field, then normal tissue constraints are critical depending on the chemotherapy used and patient age. An untested indication for whole-heart irradiation (~10 Gy) is frank pericardial involvement with tumor.
  • Whole-lung irradiation (~10 Gy), with partial transmission blocks or intensity modulation, is a consideration in the setting of overt pulmonary nodules that have not achieved a CR. For example, the GPOH HD-95, GPOH 2002, and EuroNet-PHL-C1 trials administered ipsilateral whole-lung RT to patients who had not achieved a CR in the lungs to the first two cycles of chemotherapy. and used whole-lung RT in patients with pulmonary nodules at diagnosis, with the latter protocol randomly assigning some patients on the basis of response.
  • Three-dimensional conformal radiation therapy (3-D CRT) or intensity-modulated radiation therapy (IMRT) are standard techniques in the treatment of lymphoma. Appropriate CT-based image guided treatment planning and delivery is standard, preferably with fusion of staging CT and PET imaging with RT planning CT datasets to delineate the target volumes.
  • Data are accumulating in regard to the efficacy of IMRT and the decrease in median dose to normal surrounding tissues. Some uncertainty exists about the potential for increased late effects from IMRT, particularly secondary malignancy, because with IMRT, a larger area of the body receives a low dose compared with conventional techniques (although the mean dose to a volume may be decreased).
  • Proton therapy is currently being investigated and may further decrease the mean dose to the surrounding normal tissue compared with IMRT or 3-D CRT, without increasing the volume of normal tissue receiving lower-dose radiation.

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:

  • The treatment approach for pediatric Hodgkin lymphoma should focus on maximizing disease control and minimizing risks for late toxicity associated with both RT and chemotherapy.
  • The use of LD-IFRT or ISRT in pediatric Hodgkin lymphoma permits reduction in duration or intensity of chemotherapy and thus dose-related toxicity of anthracyclines, alkylating agents, and bleomycin that may preserve cardiopulmonary and gonadal function and reduce the risk of secondary leukemia.
  • Radiation has been used as an adjunct to multiagent chemotherapy in clinical trials for intermediate- and high-risk pediatric Hodgkin lymphoma with the goal of reducing risk of relapse in initially involved sites and preventing toxicity associated with second-line therapy.
  • Compared with chemotherapy alone, adjuvant radiation has, in most studies, produced a superior EFS for children with intermediate- and high-risk Hodgkin lymphoma who achieve a CR to multiagent chemotherapy, but it does not clearly improve OS because of the success of second-line therapy. However, the intermediate-risk Hodgkin lymphoma study () did not show a benefit for IFRT in patients who achieved a rapid and CR to chemotherapy. Four-year EFS was 87.9% for rapid responders who were randomly assigned to IFRT versus 84.3% ( = .11) for rapid responders who were not assigned to IFRT. OS was 98.8% in both groups. Adjuvant radiation therapy may be associated with an increased risk of late effects or mortality.
  • Radiation consolidation may facilitate local disease control in individuals with refractory or recurrent disease, especially in those who have limited or bulky sites of disease progression/recurrence, or persistent disease that does not completely respond to chemotherapy.

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:

  • Children and adolescents with low-risk Hodgkin lymphoma (stages I, IIA, IIIA1) treated with IFRT (25.5 Gy) after CR to two cycles of DBVE (doxorubicin, bleomycin, vincristine, and etoposide) had outcomes comparable to those treated with four cycles of DBVE and IFRT (25.5 Gy). This response-dependent approach permitted reduction in chemotherapy exposure in 45% of patients.
  • A dose-dense, early response–based treatment approach with ABVE-PC permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response after three ABVE-PC cycles.[]
  • Five-year EFS was comparable for rapid early responders (86%) and slow early responders (83%) treated with three and five cycles of ABVE-PC, respectively, followed by 21 Gy radiation. Patients who received dexrazoxane had more hematological and pulmonary toxicity.
  • Although etoposide is associated with an increased risk of therapy-related acute myeloid leukemia with 11q23 abnormalities, the risk is very low in those treated with ABVE or ABVE-PC without dexrazoxane.

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:

  • Among patients who achieved a CR to initial therapy, the projected 10-year EFS (in an ) was 91% for those randomly assigned to receive LD-IFRT and 83% for those randomly assigned to receive no further therapy.
  • Estimates for OS did not differ between the randomized groups as a result of successful treatment after relapse (10-year OS rates were 97% for IFRT and 96% for no further therapy in the ).

Another CCG Study () 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.[] 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:

  • Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four cycles of BEACOPP.
  • The 5-year EFS was 94%, with a median follow-up time of 6.3 years.
  • Results support that early intensification followed by less intense response-based therapy results in high EFS.

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:

  • Substitution of nonalkylating agent chemotherapy (e.g., methotrexate or etoposide) as an alternative to alkylating agent chemotherapy results in an inferior EFS among patients with unfavorable clinical presentations.
  • The combination of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) is an effective regimen (10-year EFS, 89%) for favorable-risk (low stage without B symptoms or bulky disease) children and adolescents with Hodgkin lymphoma when used in combination with response-based LD-IFRT (15–25.5 Gy).
  • Patients with favorable-risk Hodgkin lymphoma treated with four cycles of VAMP chemotherapy alone who achieved an early CR had a comparable 5-year EFS to those treated with four cycles of VAMP chemotherapy plus 25.5 Gy IFRT (89% vs. 88%).

The COG 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:

  • Early response was an important prognostic factor. Overall EFS was 85.0% and significantly ( < .001) higher for rapid early responders (86.9%) than was for slow early responders (77.4%). OS was 97.8% and significantly ( < .001) higher for rapid early responders (98.5%) than was for slow early responders (95.3%).
  • Approximately 45% of patients were rapid early responders and achieved CR by the end of chemotherapy. For this population, EFS did not differ significantly ( = .11) among those who were randomly assigned to IFRT (87.9%) versus no IFRT (84.3%). OS for those receiving IFRT was 98.8% (95% confidence interval [CI], 96.8%–99.5%) and OS for those receiving chemotherapy alone was 98.8% (95% CI, 96.9%–99.6%).
  • Approximately 20% of patients were slow early responders. For this population, EFS did not differ significantly ( = .11) among those who were randomly assigned to DECA (79.3%) versus no DECA (75.2%).
  • Study results confirm the prognostic significance of early chemotherapy response and support the safety of avoidance of IFRT based on rapid early response with CR by the end of chemotherapy.
  • An analysis of patterns of failure among patients who relapsed on the study demonstrated that first relapses more commonly occurred within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.

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.

Key findings from these trials include the following:

  • Substitution of cyclophosphamide for mechlorethamine in the MOPP combination results in a low risk of secondary myelodysplasia/leukemia.
  • Omission of procarbazine from the OPPA combination and substitution of methotrexate for procarbazine in the COPP combination (OPA/COMP) results in a substantially inferior EFS.
  • Substitution of etoposide for procarbazine in the OPPA combination (OEPA) in boys produces comparable EFS to that of girls treated with OPPA and is associated with hormonal parameters, suggesting lower risk of gonadal toxicity.
  • Omission of radiation for patients completely responding (defined as complete resolution or only minor residuals in all previously involved regions using clinical examination and anatomic imaging) to risk- and sex-based OEPA or OPPA/COPP chemotherapy results in a significantly lower EFS in intermediate- and high-risk patients compared with irradiated patients (79% vs. 91%), but no difference among nonirradiated and irradiated patients assigned to the favorable-risk group.
  • Substitution of dacarbazine for procarbazine (OEPA-COPDAC) in boys produces comparable results to standard OPPA-COPP in girls when used in combination with IFRT for intermediate- and high-risk patients.[]

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

The following is an example of a national and/or institutional clinical trial that is currently being conducted or is under analysis. Information about ongoing clinical trials is available from the NCI website.

  • (Adcetris [Brentuximab Vedotin], Combination Chemotherapy, and Radiation Therapy in Treating Younger Patients With Stage IIB, IIIB, and IV Hodgkin Lymphoma): A clinical trial at St. Jude Children’s Research Hospital is evaluating the safety of brentuximab vedotin, etoposide, prednisone, and doxorubicin hydrochloride (two cycles of AEPA) and cyclophosphamide, brentuximab vedotin, prednisone, and dacarbazine (two cycles of CAPDac), and the efficacy (early CR) after the two cycles of AEPA chemotherapy in high-risk patients with Hodgkin lymphoma (stages IIB, IIIB, IVA, and IVB.) The study will compare EFS in high-risk Hodgkin lymphoma patients treated with AEPA/CAPDac with the historical control, unfavorable-risk 2 arm of the St. Jude HOD99 study.
  • (A Randomized Phase III Study of Brentuximab Vedotin [SGN-35] for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma in Children and Adolescents): AHOD1331 is a randomized phase III clinical trial comparing brentuximab vedotin and combination chemotherapy to combination chemotherapy alone in treating younger patients (aged 2 to 18 years) with newly diagnosed high-risk Hodgkin lymphoma. The chemotherapy used with brentuximab vedotin is AVE-PC (doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide). The chemotherapy-alone arm uses the same agents and additionally incorporates bleomycin (ABVE-PC). Those patients who remain fluorine F 18-fludeoxyglucose PET positive after two cycles receive response-based ISRT.

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. 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. 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.[]

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/m. (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/m to 300 mg/m. Subsequent need for mediastinal radiation can further enhance the risk of a variety of late cardiac events. 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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I childhood Hodgkin lymphoma, stage II childhood Hodgkin lymphoma, stage III childhood Hodgkin lymphoma and stage IV childhood Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Treatment of Primary Refractory or Recurrent Hodgkin Lymphoma in Children and Adolescents

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:[]

  • The presence of B symptoms (fever, weight loss, and night sweats) and extranodal disease.
  • Early relapse (occurring between 3–12 months from the end of therapy).
  • Inadequate response to initial second-line therapy.

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.

Key concepts in regard to treatment of refractory or recurrent Hodgkin lymphoma in children and adolescents are as follows:

  • Chemotherapy: Chemotherapy is the recommended second-line therapy, with the choice of specific agents, dose-intensity, and number of cycles determined by the initial therapy, disease characteristics at progression/relapse, and response to second-line therapy.

    Agents used alone or in combination regimens in the treatment of refractory or recurrent Hodgkin lymphoma include the following:

    • ICE (ifosfamide, carboplatin, and etoposide).
    • Ifosfamide and vinorelbine with or without bortezomib.[]; []
    • Vinorelbine and gemcitabine.
    • IEP/ABVD/COPP (ifosfamide, etoposide, prednisone/doxorubicin, bleomycin, vinblastine, dacarbazine/cyclophosphamide, vincristine, procarbazine, prednisone).
    • Etoposide, prednisolone, ifosfamide, and cisplatin (EPIC).
    • APE (cytosine arabinoside, cisplatin, and etoposide).
    • MIED (high-dose methotrexate, ifosfamide, etoposide, and dexamethasone).
    • Rituximab (for patients with CD20-positive disease) alone or in combination with second-line chemotherapy.
    • Brentuximab vedotin. Brentuximab vedotin has been evaluated in adults with Hodgkin lymphoma. (Refer to the Recurrent Adult HL section in the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.)
      • A phase I study in adults with CD30-positive lymphomas identified a recommended phase II dose of 1.8 mg/kg on an every 3-week schedule and showed an objective response rate of 50% (6 of 12 patients) at the recommended phase II dose.[]
      • A phase II trial in adults with Hodgkin lymphoma (N = 102) who relapsed after autologous hematopoietic stem cell transplantation (HSCT) showed a complete remission rate of 34% and a partial remission rate of 40%. Patients who achieved a complete remission (n = 34) had a 3-year progression-free survival (PFS) rate of 58% and a 3-year overall survival (OS) rate of 73%, with only 6 of 34 patients proceeding to allogeneic HSCT while in remission. Further follow-up demonstrated a 5-year OS rate of 41% and a PFS rate of 22%. However, patients who achieved a complete remission (38%) had a 5-year OS rate of 64% and a PFS rate of 52%.[] The number of pediatric patients treated with brentuximab vedotin is not sufficient to determine whether they respond differently than adult patients.
      • The U.S. Food and Drug Administration (FDA) indications for brentuximab vedotin in adult patients are as follows: (1) classical Hodgkin lymphoma after failure of autologous HSCT or after failure of at least two previous multiagent chemotherapy regimens in patients who are not autologous HSCT candidates, and (2) classical Hodgkin lymphoma at high risk of relapse or progression as postautologous HSCT consolidation.

      There are ongoing trials to determine the toxicity and efficacy of combining brentuximab vedotin with chemotherapy.

  • Chemotherapy followed by autologous hematopoietic cell transplantation (HCT): Myeloablative chemotherapy with autologous HCT is the recommended approach for patients who develop refractory disease during therapy or relapsed disease within 1 year after completing therapy. ; []; [] (Refer to the Autologous HCT section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.) In addition, this approach is also recommended for those who recur with extensive disease after the first year of completing therapy or for those who recur after initial therapy that included intensive (alkylating agents and anthracyclines) multiagent chemotherapy and radiation therapy.
    • Autologous HCT has been preferred for patients with relapsed Hodgkin lymphoma because of the historically high transplant-related mortality (TRM) associated with allogeneic transplantation. After autologous HCT, the projected survival rate is 45% to 70% and PFS is 30% to 89%.; []
    • Brentuximab vedotin as maintenance therapy given for 1 year after autologous HCT in adult patients with high risk of relapse or progression was demonstrated in a randomized, placebo-controlled, phase III trial to improve PFS.
    • The most commonly utilized preparative regimen for peripheral blood stem cell transplant is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan) or CBV regimen (cyclophosphamide, carmustine, etoposide).; []; []
    • Carmustine may produce significant pulmonary toxicity.
    • Other noncarmustine-containing preparative regimens have been utilized, including high-dose busulfan, etoposide, and cyclophosphamide.
    • Adverse prognostic features for outcome after autologous HCT include extranodal disease at relapse, mediastinal mass at time of transplant, advanced stage at relapse, primary refractory disease, and a positive positron emission tomography scan before autologous HCT.
  • Chemotherapy followed by allogeneic HCT: For patients who fail after autologous HCT or for patients with chemoresistant disease, allogeneic HCT has been used with encouraging results. Investigations of reduced-intensity allogeneic transplantation that typically use fludarabine or low-dose total body irradiation to provide a nontoxic immunosuppression have demonstrated acceptable rates of TRM. (Refer to the Allogeneic HCT section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
  • LD-IFRT: LD-IFRT to sites of recurrent disease may enhance local control if these sites have not been previously irradiated. LD-IFRT is generally administered after high-dose chemotherapy and stem cell rescue.

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.

  • In one large series of patients, 5-year OS after primary refractory Hodgkin lymphoma was attained with aggressive second-line therapy (high-dose chemoradiation therapy) and autologous HCT in 49%.
  • In a Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) study, patients with primary refractory Hodgkin lymphoma (progressive disease on therapy or relapse within 3 months from the end of therapy) had 10-year event-free survival (EFS) and OS rates of 41% and 51%, respectively.
  • A study of 53 adolescent patients of the same types as those who participated in the GPOH study had similar results for EFS and OS. Chemosensitivity to standard-dose second-line chemotherapy predicted a better survival (66% OS), and those who remained refractory did poorly (17% OS).
  • Another group has reported the PFS post-HCT for chemosensitive patients as 80% compared with 0% for those with chemoresistant disease.

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.[]

Treatment Options Under Clinical Evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted or are under analysis. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent/refractory childhood Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

Special Considerations for the Treatment of Children With Cancer

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:

  • Primary care physicians.
  • Pediatric surgeons.
  • Radiation oncologists.
  • Pediatric medical oncologists and hematologists.
  • Rehabilitation specialists.
  • Pediatric nurse specialists.
  • Social workers.
  • Child life professionals.
  • Psychologists.

(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.

Late Effects from Childhood/Adolescent Hodgkin Lymphoma Therapy

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

  • Gonadal radiation and alkylating agent chemotherapy may produce testicular Leydig cell or germ cell dysfunction, with risk related to cumulative dose of both modalities.
  • Hypoandrogenism associated with Leydig cell dysfunction may manifest as lack of sexual development; small, atrophic testicles; and sexual dysfunction. Hypoandrogenism also increases the risk of osteoporosis and metabolic disorders associated with chronic disease.
  • Infertility caused by azoospermia is the most common manifestation of gonadal toxicity. Some pubertal male patients will have impaired spermatogenesis before they begin therapy.
  • The prepubertal testicle is likely equally or slightly less sensitive to chemotherapy compared with the pubertal testicle. Pubertal status is not protective of chemotherapy-associated gonadal toxicity.
  • Testicular Leydig cells are relatively resistant to treatment toxicity compared with testicular germ cells. Survivors who are azoospermic after gonadal toxic therapy may maintain adequate testosterone production.
  • Chemotherapy regimens that include no alkylating agents such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), ABVE (doxorubicin [Adriamycin], bleomycin, vincristine, etoposide), OEPA (vincristine [Oncovin], etoposide, prednisone, doxorubicin [Adriamycin]), or VAMP (vincristine, doxorubicin [Adriamycin], methotrexate, prednisone) are not associated with male infertility.
  • Chemotherapy regimens that include more than one alkylating agent, usually procarbazine in conjunction with cyclophosphamide (i.e., COPP [cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine]), chlorambucil, or nitrogen mustard (MOPP) confer a high risk of permanent azoospermia if treatment exceeds three cycles.
  • Investigations evaluating germ cell function in relation to single alkylating agent exposure suggest that the incidence of permanent azoospermia will be low if the cyclophosphamide dose is less than 7.5 g/m.

(Refer to the Testis section of the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Female Gonadal Toxicity

  • Because ovarian hormone production is linked to the maturation of primordial follicles, depletion of follicles by alkylating agent chemotherapy can potentially affect both fertility and ovarian hormone production.
  • Because of their greater complement of primordial follicles, the ovaries of young and adolescent girls are less sensitive to the effects of alkylating agents than are the ovaries of older women. In general, girls maintain ovarian function at higher cumulative alkylating agent doses compared with the germ cell function maintained in boys.
  • Most females treated with contemporary risk-adapted therapy will have menarche (if prepubertal at treatment) or regain normal menses (if pubertal at treatment) unless pelvic radiation therapy is given without oophoropexy. Current regimens used in pediatric oncology are tailored to minimize the risk of ovarian failure. Data presented below related to pediatric treatment before 1987 or adult trials in Europe (European Organisation for Research and Treatment of Cancer H1–H9 trials) are not likely reflective of the expected reproductive outcomes in the current era.
  • Ovarian transposition to a lateral or medial region from the planned radiation volume may preserve ovarian function in young and adolescent girls who require pelvic radiation therapy for lymphoma.
  • The risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation or dose-intensive alkylating agents for myeloablative conditioning before hematopoietic cell transplantation. The risk of ovarian failure after treatment with contemporary regimens using lower cumulative doses of cyclophosphamide without procarbazine is anticipated to be lower.
  • In the Childhood Cancer Survivor Study (CCSS), investigators observed that Hodgkin lymphoma survivors were among the highest risk groups for acute ovarian failure and early menopause. In this cohort, the cumulative incidence of nonsurgical premature menopause among survivors treated with alkylating agents and abdominal or pelvic radiation approached 30%. These patients were treated before 1986, usually with substantially higher doses of alkylating agents than are used in current regimens in the Children's Oncology Group, Euronet, or other consortiums.
  • A German study demonstrated that parenthood for female survivors of Hodgkin lymphoma was similar to that of the general population, although parenthood was lower for survivors who received pelvic radiation therapy.

(Refer to the Ovary section of the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Thyroid Abnormalities

  • Abnormalities of the thyroid gland, including hypothyroidism, hyperthyroidism, and thyroid neoplasms have been reported to occur at a higher rate among survivors of Hodgkin lymphoma than in the general population.
  • Risk factors for hypothyroidism include increasing dose of radiation, female sex, and older age at diagnosis. CCSS investigators reported a 20-year actuarial risk of 30% of developing hypothyroidism in Hodgkin survivors treated with 3,500 cGy to 4,499 cGy and 50% for subjects whose thyroid received 4,500 cGy or more.
  • Hypothyroidism develops most often in the first 5 years after treatment, but new cases have been reported to emerge more than 20 years after the diagnosis.
  • Hyperthyroidism has been observed after treatment for Hodgkin lymphoma, with a clinical picture similar to that of Graves disease. Higher radiation dose has been associated with greater risk of hyperthyroidism.
  • Thyroid neoplasms, both benign and malignant, have been reported with increased frequency after neck irradiation. The incidence of nodules varies substantially across studies (2%–65%) depending on the length of follow-up and detection methods used.

    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.)

Cardiac Toxicity

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.

Radiation-associated cardiovascular toxicity

  • Late effects of radiation to the heart may include the following:
    • Delayed pericarditis.
    • Pancarditis including pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
    • Cardiomyopathy.
    • Coronary artery disease.
    • Functional valve injury.
    • Conduction defects.

    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.

  • Modern radiation techniques allow a reduction in the volume of cardiac tissue incidentally exposed to higher radiation doses. It is anticipated that this will reduce the risk of adverse cardiac events.
  • Austrian-German investigators evaluated the development of cardiac disease (via patient self-report supplemented by physician report) in a cohort of 1,132 pediatric Hodgkin lymphoma survivors monitored for a median of 20 years. The 25-year cumulative incidence of heart disease increased with higher mediastinal radiation doses: 3% (unirradiated), 5% (20 Gy), 6% (25 Gy), 10% (30 Gy), and 21% (36 Gy). Valve defects were most common, followed by coronary artery disease, cardiomyopathy, rhythm disorders, and pericardial abnormalities.
  • In a study of adult survivors of Hodgkin lymphoma, vigorous exercise lowered the risk of cardiovascular events, independent of the treatment received.

Anthracycline-related cardiac toxicity

  • Late complications related to anthracycline injury may include subclinical left ventricular dysfunction, cardiomyopathy, and congestive heart failure.
  • Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, cumulative doses higher than 200 mg/m to 300 mg/m, younger age at time of exposure, and increased time from exposure.
  • Prevention or amelioration of anthracycline-induced cardiomyopathy is important because the continued usage of anthracyclines is required in cancer therapy in more than one-half of children with newly diagnosed cancer.
  • Dexrazoxane (a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent) has been shown to prevent heart damage in adults and children treated with anthracyclines. Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy.
  • Studies of cancer survivors treated with anthracyclines have not demonstrated the benefit of enalapril in preventing progressive 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.)

Subsequent Neoplasms

  • A number of series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published. Many of the patients included in these series received high-dose radiation therapy and high-dose alkylating agent chemotherapy regimens, which are no longer used.
  • Subsequent neoplasms comprise two distinct groups: chemotherapy-related myelodysplasia and acute myeloid leukemia (AML) and solid neoplasms that are predominately radiation related.
  • Secondary hematological malignancy (most commonly AML and myelodysplasia) is related to the use of alkylating agents, anthracycline, and etoposide and exhibit a brief latency period (<10 years from the primary cancer). This excess risk is largely related to cases of myelodysplasia and secondary AML. A single-study experience suggests that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity. Clinical trials using dexrazoxane in childhood leukemia have not observed an excess risk of subsequent neoplasms.
  • Chemotherapy-related myelodysplasia and AML are less prevalent following contemporary therapy because of the restriction of cumulative alkylating agent doses.
  • Solid neoplasms most often involve the skin, breast, thyroid, gastrointestinal tract, lung, and head and neck, with risk increasing with radiation dose.
  • The risk of a secondary solid tumor escalates with the passage of time after diagnosis of Hodgkin lymphoma, with a latency of 20 years or more.
  • Breast cancer is the most common therapy-related solid subsequent neoplasm after Hodgkin lymphoma. The absolute excess risk ranges from 18.6 to 79 per 10,000 person-years, and the cumulative incidence ranges from 12% to 26%, 25 to 30 years after radiation exposure.
  • High risk of breast cancer has been found to increase as early as 8 years from radiation exposure, is rare before age 25 years, and continues to increase with time from exposure. Importantly, breast cancer in female childhood cancer survivors typically develops at least 25 years earlier than that of primary breast cancer in the general population and often years before the implementation of population-based screening.
  • The cumulative incidence of breast cancer by age 40 to 45 years ranges from 13% to 20%, compared with a 1% risk for women in the general population. This risk is similar to what is observed for women with a gene mutation, where, by age 40 years, the cumulative incidence of breast cancer ranges from 10% to 19%.
  • The risk for breast cancer in female survivors of Hodgkin lymphoma is directly related to the dose of radiation therapy received over a range from 4 Gy to 40 Gy. Female patients treated with both radiation therapy and alkylating agent chemotherapy have a lower RR for developing breast cancer than women receiving radiation therapy alone. CCSS investigators also demonstrated that breast cancer risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries. The protective effect of alkylating chemotherapy and ovarian radiation is believed to be mediated through induction of premature menopause, suggesting that hormone stimulation contributes to the development of radiation-induced breast cancer.
  • A study of women survivors who received chest radiation for Hodgkin lymphoma showed that one of the most important factors in obtaining breast cancer screening per guidelines was recommendation from their treating physician. Standard guidelines for routine breast screening are available. The COG guidelines recommend annual screening with magnetic resonance imaging and mammograms for women beginning 8 years after treatment or at age 25 years, whichever is later.

(Refer to the Subsequent Neoplasms section of the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)

Changes to This Summary (08/31/2017)

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.

Treatment of Primary Refractory or Recurrent Hodgkin Lymphoma in Children and Adolescents

Added text about the APEC1621 (NCT03155620) trial as a treatment option under clinical evaluation for refractory or recurrent Hodgkin lymphoma in children and adolescents.

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.

About This PDQ Summary

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:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

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:

  • Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
  • Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
  • Thomas G. Gross, MD, PhD (National Cancer Institute)
  • Melissa Maria Hudson, MD (St. Jude Children's Research Hospital)
  • Kenneth L. McClain, MD, PhD (Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital)
  • Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
  • Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to 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 . Available at: Accessed . [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 on the Managing Cancer Care page.

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