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Home > Health Library > Childhood Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
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 for children and adolescents has increased over the same time from 81% to more than 95%.
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 unacceptably high radiation doses. Thus, new strategies using chemotherapy and lower-dose radiation were developed.
Approximately 90% to 95% of children with Hodgkin lymphoma can be cured, prompting increased attention to 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), bulky disease, extranodal involvement, and/or erythrocyte sedimentation rate.
Hodgkin lymphoma accounts for 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); children aged 10 to 14 years, 5 to 9 years, and 0 to 4 years have approximately threefold, eightfold, and 30-fold lower rates, respectively, than do adolescents. In developing countries, there is a similar incidence rate in young adults but a much higher incidence rate in childhood.
Hodgkin lymphoma has the following unique epidemiological features:
Early exposure to common infections in early childhood appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity.[7,8]
There are more males than females affected in the younger age cohort, especially in children younger than 10 years. EBV-associated Hodgkin lymphoma increases in prevalence in association with larger family size and lower socioeconomic status.
Nodular-sclerosing Hodgkin lymphoma is the most common subtype, followed by mixed cellularity.
Epstein-Barr virus (EBV) and Hodgkin lymphoma
EBV has been implicated in the etiology of some cases of Hodgkin lymphoma. Patients with Hodgkin lymphoma may have high EBV titers, suggesting that a previous infection with 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, most commonly in those with mixed-cellularity disease. In children and adolescents with intermediate-risk Hodgkin lymphoma, EBV DNA in cell-free blood correlated with the presence of EBV in the tumor; EBV DNA 8 days after the initiation of therapy predicted an inferior event-free survival (EFS).
The incidence of EBV-associated Hodgkin lymphoma also shows the following distinct epidemiological features:
EBV serologic status is not a prognostic factor for failure-free survival in young adult patients with Hodgkin lymphoma,[15,16,17,19,20] but plasma EBV DNA has been associated with an inferior outcome in adults. However, this is not the case in children, with better outcomes described for intermediate-risk patients with higher levels of EBV DNA at diagnosis, which also correlates with better outcomes for patients with mixed-cellularity disease treated with dose-dense chemotherapy (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide]). 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 of developing EBV-negative Hodgkin lymphoma.
Immunodeficiency and Hodgkin lymphoma
Among individuals with immunodeficiency, the risk of Hodgkin lymphoma is increased, although the risk of non-Hodgkin lymphoma is even higher.
Characteristics of Hodgkin lymphoma presenting in the context of immunodeficiency are as follows:
The following presenting features of Hodgkin lymphoma result from direct or indirect effects of nodal or extranodal involvement and/or constitutional symptoms related to cytokine release from Reed-Sternberg cells and cell signaling within the tumor microenvironment:
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.[30,31]
As the treatment of Hodgkin lymphoma improved, factors associated with outcome became more difficult to identify. Several factors, however, continue to influence the success and choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and biologic aggressiveness are frequently collinear.
Pretreatment factors associated with an adverse outcome in one or more studies include the following:
Prognostic factors identified in selected multi-institutional studies include the following:
A single-institution study showed that African American patients had a higher relapse rate than did White patients, but OS was similar. A Children's Oncology Group (COG) analysis showed no difference in EFS by race or ethnicity. However, compared with non-Hispanic White children, Hispanic and non-Hispanic Black children had an inferior OS because of an increased postrelapse mortality rate.[Level of evidence: 1iiA]
Response to initial chemotherapy
The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important.[38,39,42] Response evaluation in previous generations of trials relied on computed tomography and gallium uptake; more recent trials have employed positron emission tomography (PET) scanning 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.[44,45,46] Reduction in PET avidity after one cycle of chemotherapy was associated with a favorable EFS outcome in children with limited-stage classical Hodgkin lymphoma. Additional studies in children are ongoing to assess the role of early PET-based response in modifying therapy and predicting outcome.
Prognostic factors will continue to change because of risk stratification and choice of therapy, with parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy used to stratify therapeutic assignment.
Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Reed-Sternberg cells) or large mononuclear cell variants (lymphocytic and histiocytic cells) in a background of inflammatory cells consisting of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts. The inflammatory cells are present in different proportions depending on the histologic subtype. It has been conclusively shown that Reed-Sternberg cells and/or lymphocytic and histiocytic cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from germinal center B cells.[1,2]
The histologic features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines, chemokines, and products of the tumor necrosis factor receptors (TNF-R) family secreted by the Reed-Sternberg cells and cell signaling within the tumor microenvironment.[3,4,5]
The hallmark of Hodgkin lymphoma is the Reed-Sternberg cell and its variants, which have the following features:
Hodgkin lymphoma can be divided into the following two broad pathologic classes:[14,15]
Classical Hodgkin Lymphoma
Classical Hodgkin lymphoma is divided into four subtypes. These subtypes are defined according to the number of Reed-Sternberg cells, characteristics of the inflammatory milieu, and the presence or absence of fibrosis.
Characteristics of the four histological subtypes of classical Hodgkin lymphoma include the following:
This subtype is distinguished by the presence of collagenous bands that divide the lymph node into nodules, which often contain a Reed-Sternberg cell variant called the lacunar cell. Transforming growth factor-beta may be responsible for the fibrosis in the nodular-sclerosing Hodgkin lymphoma subtype.
A study of over 600 patients with nodular-sclerosing 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-sclerosing 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.
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 difficult to distinguish from non-Hodgkin lymphoma.
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-sclerosing 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 than in children aged 10 to 19 years. Nodular lymphocyte-predominant Hodgkin lymphoma is most common in males younger than 18 years.[20,21]
Characteristics of nodular lymphocyte-predominant Hodgkin lymphoma include the following:
Staging and evaluation of disease status is undertaken at diagnosis and performed again early in the course of chemotherapy and at the end of chemotherapy.
Diagnostic and Staging Evaluation
The diagnostic and staging evaluation is a critical determinant in the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following:
The following three specific constitutional symptoms (B symptoms) correlate with prognosis and are considered in assignment of stage:
Additional Hodgkin-associated constitutional symptoms without prognostic significance include the following:
Anatomical information from CT or MRI 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 or MRI criteria. Collaboration across international groups to harmonize definitions is ongoing.
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.
The criteria for bulky mediastinal and nonmediastinal disease are as follows:
Criteria for lymphomatous involvement by CT or MRI
Defining strict CT or MRI size criteria for lymphomatous nodal involvement is complicated by several factors, such as size overlap between what proves to be benign reactive hyperplasia versus malignant lymphadenopathy, the implication of nodal clusters, and obliquity of node orientation to the scan plane. Additional difficulties more specific to children include greater variability of normal nodal size and the frequent occurrence of reactive hyperplasia.
General concepts to consider in regard to defining lymphomatous involvement by CT or MRI include the following:
The recommended functional imaging procedure for initial staging is PET, using the radioactive glucose analog, 18F-FDG.[7,8] 18F-FDG PET identifies areas of tumor with increased metabolic activity, specifically anaerobic glycolysis. PET-CT, which integrates functional and anatomical 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 poor prognosis and the need for additional therapy in posttreatment evaluation.[9,10,11,12]; [Level of evidence: 2Diii]
General concepts to consider in regard to defining lymphomatous involvement by 18F-FDG PET include the following:
18F-FDG PET has limitations in the pediatric setting. Tracer avidity may be seen in a variety of nonmalignant conditions including thymic rebound commonly observed after completion of lymphoma therapy. 18F-FDG avidity in normal tissues, such as brown fat in the neck, may confound interpretation of the presence of nodal involvement by lymphoma.
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 COG and EuroNet definitions of PET response of lymph nodes or nodal masses are described in Table 3.
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.
If possible, the diagnosis should be established by biopsy of one or more peripheral lymph nodes. The likelihood of obtaining sufficient tissue should be carefully considered when selecting a biopsy procedure. Other issues to consider in choosing the diagnostic approach to lymph node biopsy include the following:
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 anatomical evidence of disease using CT or MRI 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 4). Staging is independent of the imaging modality used.
Extralymphatic disease resulting from direct extension of an involved lymph node region is designated E. Extralymphatic disease can cause confusion in staging. For example, the designation E is not appropriate for cases of widespread disease or diffuse extralymphatic disease (e.g., large pleural effusion that is cytologically positive for Hodgkin lymphoma), which should be considered stage IV. If pathologic proof of noncontiguous involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed.
Current practice is to assign a clinical stage on the basis of findings of the clinical evaluation; however, pathologic confirmation of noncontiguous extralymphatic involvement is strongly suggested for assignment to stage IV.
After the diagnostic and staging evaluation data are acquired, patients are further classified into risk groups for the purposes of treatment planning. The classification of patients into low-, intermediate-, or high-risk categories varies considerably among the different pediatric research groups, and often even between different studies conducted by the same group, as summarized in Figure 1.
Figure 1. Variation in risk stratification across pediatric Hodgkin study groups and protocols. E, extranodal extension; X, bulky disease (peripheral >6 cm and mediastinal bulk); mX, mediastinal bulk (≥0.33 mediastinal to thoracic ratio); ns, nodal site; TG, treatment group; TL, treatment level; RF, risk factors: erythrocyte sedimentation rate (ESR) ≥30 mm/hour and/or bulk ≥200 mL. (*) EuroNet-PHL-C1 was amended in 2012: Low-risk (TG1) patients with ESR ≥30 mm/hour and/or bulk ≥200 mL were treated in TG2 (intermediate risk). Christine Mauz-Körholz, Monika L. Metzger, Kara M. Kelly, Cindy L. Schwartz, Mauricio E. Castellanos, Karin Dieckmann, Regine Kluge, and Dieter Körholz, Pediatric Hodgkin Lymphoma, Journal of Clinical Oncology, volume 33, issue 27, pages 2975–2985. Reprinted with permission. © (2015) American Society of Clinical Oncology. All rights reserved.
Although all major research groups classify patients according to clinical criteria, such as stage and presence of B symptoms, extranodal involvement, or bulky disease, comparison of outcomes across trials is further complicated because of differences in how these individual criteria are defined.
Further refinement of risk classification may be performed through assessment of response after initial cycles of chemotherapy or at the completion of chemotherapy.
Interim response assessment
The interim response to initial therapy, which may be assessed on the basis of volume reduction of disease, functional imaging status, or both, is an important prognostic variable in both early- and advanced-stage pediatric Hodgkin lymphoma.[24,25,26,27]; [Level of evidence: 2Diii]
Definitions for interim response are variable and protocol specific but can range from 2-dimensional reductions in size of greater than 50% to the achievement of a complete response with 2-dimensional reductions in size of greater than 75% or 80% or a volume reduction of greater than 95% by anatomical imaging or resolution of 18F-FDG PET avidity.[5,28,29]
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.[26,27,29,30]
Results of selected trials using interim response to titrate therapy
Several studies have evaluated the use of interim response to titrate additional therapy:
End of chemotherapy response assessment
Restaging is carried out upon the completion of all planned initial chemotherapy and may be used to determine the need for consolidative radiation therapy. Key concepts to consider include the following:
Historical Overview of Treatment for Hodgkin Lymphoma
Long-term survival has been achieved in children and adolescents with Hodgkin lymphoma using radiation, multiagent chemotherapy, and combined-modality therapy. In selected cases of localized lymphocyte-predominant Hodgkin lymphoma, complete surgical resection may be curative and obviate the need for cytotoxic therapy.
Treatment options for children and adolescents with Hodgkin lymphoma include the following:
MOPP-related sequelae include a dose-related risk of infertility and subsequent myelodysplasia and leukemia.[2,8] The use of MOPP-derivative regimens substituting less leukemogenic and gonadotoxic alkylating agents (e.g., cyclophosphamide) for mechlorethamine or restricting cumulative alkylating agent dose exposure reduces this risk.
ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin.[10,11,12] The cumulative dose of these agents is proactively restricted in pediatric patients to reduce this risk.
Etoposide-related sequelae include an increased risk of subsequent myelodysplasia and leukemia that appears to be rare when etoposide is used in restricted doses in pediatric Hodgkin lymphoma regimens.
Contemporary Approaches to Treatment of Hodgkin Lymphoma
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 anatomical imaging. Age, sex, and histological subtype may also be considered in treatment planning.
Treatment options for childhood Hodgkin lymphoma include the following:
Risk designation depends on favorable and unfavorable clinical features, as follows:
Pleural effusions have been shown to be an adverse prognostic finding in patients treated for low-stage Hodgkin lymphoma.[Level of evidence: 2A] The risk of relapse was 25% in patients with an effusion, as opposed to less than 15% in patients without an effusion. Patients with effusions were more often older (15 years vs. 14 years) and had nodular-sclerosing histology.
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.
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, alkylating agents, and radiation therapy. Contemporary trials for patients with intermediate/unfavorable disease presentations are testing whether chemotherapy and radiation therapy can be limited in patients who achieve a rapid early response to dose-intensive chemotherapy regimens; trials are also testing the efficacy of regimens integrating novel, potentially less-toxic agents such as brentuximab vedotin.
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.
Evidence (surgery alone for localized nodular lymphocyte-predominant Hodgkin lymphoma):
Advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma is very rare, and there is no consensus regarding the optimal treatment, although outcomes for patients are excellent.
Evidence (chemotherapy for nodular lymphocyte-predominant Hodgkin lymphoma with unfavorable characteristics):
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.[24,25,27,31] Among long-term survivors of nodular lymphocyte-predominant Hodgkin lymphoma, death is more likely to result from treatment-related toxicity (both acute and long-term) than from lymphoma.[32,33]
Mixed-cellularity Hodgkin lymphoma
In addition to variable responses by histology for lymphocyte-predominant Hodgkin lymphoma, differences by mixed-cellularity histology have also been observed. COG investigators reported a 4-year EFS rate of 95.2% for children with stage I or stage II mixed-cellularity histology treated with minimal AV-PC therapy (and only rarely requiring radiation therapy), which was significantly better than the 75.8% EFS rate for patients who had nodular-sclerosing histology (P = .008).
As previously discussed, most newly diagnosed children will be treated with risk-adapted chemotherapy alone or in combination with consolidative radiation therapy. Radiation therapy 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. Radiation therapy field reductions are made to account for tumor regression with chemotherapy.
With advancements in systemic therapy, radiation therapy field definitions have evolved and become increasingly restricted. Radiation therapy is no longer needed to sterilize all disease. Advances in radiologic imaging allow more precise radiation target definition. With the use of effective chemotherapy and contemporary treatments using lower radiation doses (<21 Gy) and reduced volumes (involved-site radiation therapy [ISRT]), contralateral uninvolved sites are not irradiated.
General trends in radiation treatment volume are summarized as follows:
Breast-sparing radiation therapy plans using proton therapy are under evaluation to determine whether there is a statistically significant reduction in dose. Ongoing studies seek to determine whether doses to other critical organs, such as the heart and lungs, can be reduced with proton therapy. Long-term results are awaited.
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. Radiation therapy 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 radiation therapy may compromise organ function and limit the intensity of second-line therapy if relapse occurs. In patients with intermediate or advanced disease, who often have multifocal/extranodal disease, the current standard of therapy includes postchemotherapy ISRT that limits radiation exposure to large portions of the body.[14,40]
The dose of radiation is also variously defined and often protocol-specific.
General considerations regarding radiation dose include the following:
Technical considerations for the use of radiation therapy to treat Hodgkin lymphoma include the following:
Role of LD-ISRT in childhood and adolescent Hodgkin lymphoma
Because all children and adolescents with Hodgkin lymphoma receive chemotherapy, a question commanding significant attention is whether patients who achieve a rapid early response or a CR to chemotherapy require radiation therapy. 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.
The treatment approach for pediatric Hodgkin lymphoma should focus on maximizing disease control and minimizing risks of late toxicity associated with both radiation therapy and chemotherapy. Key points to consider in regard to the role of radiation in pediatric Hodgkin lymphoma include the following:
Compared with chemotherapy alone, adjuvant radiation has, in most studies, produced a superior EFS for children with intermediate-risk 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 (AHOD0031 [NCT00025259]) did not show a benefit for IFRT in patients who achieved a rapid CR to chemotherapy (defined as >60% reduction in 2-dimensional tumor burden after two cycles and metabolic remission and >80% reduction after four cycles). Four-year EFS was 87.9% for rapid responders who were randomly assigned to IFRT versus 84.3% (P = .11) for rapid responders who were not assigned to IFRT. OS was 98.8% in both groups. In a subset analysis from this study of patients with anemia and bulky limited-stage disease, the EFS was 89.3% for rapid early responder or complete remission patients who received IFRT, compared with 77.9% for patients who did not receive IFRT (P = .019).[Level of evidence: 1iiDi]
Adjuvant radiation therapy may be associated with an increased risk of late effects or mortality.
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 trials are summarized in Table 5.
North American cooperative and consortium trial results
A series of North American trials have evaluated response-based and risk-adapted therapy.
Evidence (response-based and risk-adapted therapy):
However, infectious complications during therapy and the long-term risks of infertility and subsequent neoplasms undermine this approach as an optimal treatment, particularly in light of new and safe strategies.
Key 4-year OS and EFS outcomes from this trial include the following:
An analysis of patterns of failure among patients who relapsed while enrolled in the AHOD0031 (NCT00025259) 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 trial results
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:
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 on the basis of 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 treatment approaches used for patients with low-risk Hodgkin lymphoma.
Classical Hodgkin lymphoma intermediate-risk disease
Table 7 summarizes the results of treatment approaches used for patients with intermediate-risk Hodgkin lymphoma.
Classical Hodgkin lymphoma high-risk disease
Table 8 summarizes the results of treatment approaches used for patients with high-risk Hodgkin lymphoma.
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The 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.[24,61,62] 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.[61,62]
Table 9 summarizes the results of 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 for single-node disease (n = 52), chemotherapy alone after CR to three cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy (n = 115), or chemotherapy with LD-IFRT (21 Gy) after incomplete response to AV-PC chemotherapy (n = 11), the 5-year EFS was 85.5%, and the OS was 100%. Five-year EFS was 77% for patients observed after total resection and 88.8% for patients treated with AV-PC chemotherapy.[Level of evidence: 1iiDi] Retrospective case series report on responses with rituximab alone  or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)  in adults with nodular lymphocyte-predominant Hodgkin lymphoma; however, pediatric data has not been reported.
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, and the optimal approach is debatable.
In patients with intermediate-risk or high-risk disease, the standard of care in adult oncology practices typically involves at least six cycles of ABVD chemotherapy that would deliver a cumulative anthracycline dose of 300 mg/m2.[65,66] (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) In late-health outcomes studies of pediatric cancer survivors, the risk of anthracycline cardiomyopathy has been shown to exponentially increase after exposure to cumulative anthracycline doses of 250 mg/m2 to 300 mg/m2.[67,68] Subsequent need for mediastinal radiation can further enhance the risk of a variety of late cardiac events.[67,68,69] 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-risk and high-risk disease.
No prospective studies of efficacy or toxicity in adolescent or young adults treated with pediatric versus adult regimens have been reported; however, some secondary analyses have been conducted.
The optimal approach for adolescents and young adults with Hodgkin lymphoma is complicated by critical but understudied variables. Factors such as tumor biology, disease control, supportive care needs, and long-term toxicities in adolescents and young adults with Hodgkin lymphoma remain understudied.
Participation in a clinical trial should be considered for adolescent and young adult patients with Hodgkin lymphoma. Information about ongoing clinical trials is available from the NCI website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
The excellent response to frontline therapy among children and adolescents with Hodgkin lymphoma limits opportunities to evaluate second-line (salvage) therapy. Because of the small number of patients that fail primary therapy, no uniform second-line treatment strategy exists for this patient population.
Adverse prognostic factors after relapse include the following:[Level of evidence: 3iiA]
Children with localized favorable (relapse ≥12 months after completing therapy) disease recurrences whose original therapy involved reduced cycles of risk-adapted therapy or with chemotherapy alone and/or low-dose involved-field radiation therapy (LD-IRFT) consolidation have a high likelihood of achieving long-term survival after treatment with more intensive conventional chemotherapy.[5,6]
Treatment options for children and adolescents with refractory or recurrent Hodgkin lymphoma include the following:
Chemotherapy and Targeted Therapy
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 pediatric Hodgkin lymphoma include the following:
There are ongoing trials to determine the toxicity and efficacy of combining brentuximab vedotin with chemotherapy.
Checkpoint Inhibitor Therapy
Treatments that block the interaction between programmed death-1 (PD-1) and its ligands have shown high levels of activity in adults with Hodgkin lymphoma.
Pembrolizumab is FDA approved for use in cases of refractory disease or relapse after three or more lines of therapy.
There are ongoing trials to determine the toxicity and efficacy of combining and/or comparing brentuximab vedotin and nivolumab with chemotherapy in pediatric patients with Hodgkin lymphoma.
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.[7,30,31,32,33,34,35,36,37]; [Level of evidence: 3iiA]; [Level of evidence: 3iiiA] 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.
Adverse prognostic features for outcome after autologous HCT include extranodal disease at relapse, bulky mediastinal mass at time of transplant, advanced stage at relapse, primary refractory disease, poor response to chemotherapy, and a positive positron emission tomography scan before autologous HCT.[1,41,42,43,48,49]
(Refer to the Autologous HCT section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
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.[13,40,50,51,52] 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.[53,54,55,56,57]
(Refer to the Allogeneic HCT section in the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.)
Involved-site Radiation Therapy (ISRT)
ISRT to sites of recurrent disease may enhance local control if these sites have not been previously irradiated. ISRT is generally administered after high-dose chemotherapy and stem cell rescue. For patients who are not responsive to salvage therapy, ISRT may be an appropriate consideration before HCT.[59,60]
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.
Evidence (response to treatment of primary refractory Hodgkin lymphoma):
Second Relapse After Initial Treatment With Autologous HCT
In a phase II study, patients (median age, 26.5 years) who had relapsed or refractory disease after autologous HCT received brentuximab vedotin, with an objective response rate of 73% and a complete remission rate of 34%. Patients who achieved a complete remission (n = 34) had a 3-year PFS rate of 58% and a 3-year OS rate of 73%, with only 6 of 34 patients proceeding to allogeneic SCT while in remission.[Level of evidence: 2A]
Treatment Options Under Clinical Evaluation
Anti-CD30 chimeric antigen receptor (CAR) T-cell therapy clinical trials
Preliminary data on CAR T cells targeting CD30 have been published. In a phase I/II trial of 41 adults with multiply relapsed or refractory Hodgkin lymphoma, CD30 CAR T cells were administered after lymphoreduction with either bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine. Treated patients had a median of seven previous lines of therapy, including brentuximab, checkpoint inhibitors, and autologous and allogeneic HCTs. The overall response rate was 72% for the 32 patients with active disease who received fludarabine-based lymphodepletion. For all evaluable patients, the 1-year PFS rate was 36%, and the OS rate was 94%. The CD30 CAR T-cell therapy was well tolerated.
A number of clinical trials of anti-CD30 CAR T-cell therapy for patients with relapsed Hodgkin lymphoma are listed on ClinicalTrials.gov. The following are examples of national and/or institutional clinical trials that are currently enrolling patients younger than 18 years:
Other clinical trials
The following are examples of other national and/or institutional clinical trials that are currently being conducted:
Anti–PD-1 antibodies being studied in children with Hodgkin lymphoma include the following:
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and their 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.
Childhood and adolescent survivors of Hodgkin lymphoma may be at risk of developing numerous late complications of treatment related to radiation, specific chemotherapeutic exposures, and surgical staging.[1,2] Adverse treatment effects may impact the following:
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 of specific treatment complications, the era of treatment should be considered.
In this regard, Childhood Cancer Survivor Study (CCSS) investigators determined the incidence of serious health conditions among 2,996 five-year survivors of pediatric Hodgkin lymphoma (mean age, 35.8 years), compared outcomes by treatment era and strategies, and estimated risks associated with contemporary therapy.
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
Important concepts related to male gonadal toxicity include the following:
(Refer to the Testis section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
Female Gonadal Toxicity
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.
Important concepts related to female gonadal toxicity include the following:
(Refer to the Ovary section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
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.
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.
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 in the PDQ summary on Late Effects of Treatment for Childhood Cancer summary for more information.)
Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk of 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.[25,26,27]
Survivors of childhood Hodgkin lymphoma older than 50 years will experience more than two times the number of chronic cardiovascular health conditions and nearly five times the number of more severe (grades 3–5) cardiovascular conditions compared with community controls and, on average, have one severe, life-threatening, or fatal cardiovascular condition.
Cardiac mortality is higher for survivors of adolescent Hodgkin lymphoma than for survivors of young adult Hodgkin lymphoma. This was demonstrated in the Teenage and Young Adult Cancer Survivor Study cohort, with standardized mortality ratios (SMR) of 10.4 (95% CI, 8.1–13.3) for those diagnosed at age 15 and 19 years, compared with an SMR of 2.8 (95% CI, 2.3–3.4) for those diagnosed at age 35 to 39 years.
Radiation-associated cardiovascular toxicity
The risks to the heart are related to the amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, and latency period.
Anthracycline-related cardiac toxicity
(Refer to the Late Effects of the Cardiovascular System section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
A number of series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published.[46,47,48,49,50,51,52,53,54,55]; [Level of evidence: 3iii] 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 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 subsequent 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.[43,60,61]
Chemotherapy-related myelodysplasia and AML are less prevalent following contemporary therapy because of the restriction of cumulative alkylating agent doses.[62,63]
Among 1,711 intermediate-risk Hodgkin lymphoma survivors treated with response-adapted therapy in the COG AHOD0031 (NCT00025259) trial (median follow-up, 7.3 years), the 10-year cumulative incidence of subsequent malignancy was 1.3%, and the cumulative incidence of secondary myelodysplastic syndrome or AML was 0.2%. Of the three cases of secondary AML, the median time to onset was 2 years (range, 1.8–2.7 years).
Solid neoplasms most often involve the skin, breast, thyroid, gastrointestinal tract, lung, and head and neck, with risk increasing with radiation dose.[53,55,65]; [Level of evidence: 3iii] The risk of a solid subsequent neoplasm escalates with the passage of time after diagnosis of Hodgkin lymphoma, with a latency of 20 years or more. (Refer to the Thyroid Abnormalities section of this summary for more information about subsequent thyroid neoplasms.)
Breast cancer is the most common therapy-related solid subsequent neoplasm after Hodgkin lymphoma:
(Refer to the Subsequent Neoplasms section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for more information.)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Treatment of Newly Diagnosed Children and Adolescents With Hodgkin Lymphoma
Revised Table 5 to add the CAPDAC and AEPA regimens (cited Metzger et al. as reference 46).
Added text about an open-label, single-arm, multicenter trial that evaluated brentuximab vedotin and risk-adapted residual node radiation therapy in patients with stage IIB, IIIB, or IV classical Hodgkin lymphoma (cited Metzger et al. as reference 46 and level of evidence 2A).
Revised Table 8 to add the results of a study that used the AEPA and CAPDAC chemotherapy regimens and residual nodal radiation therapy to treat patients with high-risk Hodgkin lymphoma.
Treatment of Primary Refractory or Recurrent Hodgkin Lymphoma in Children and Adolescents
Added Anti-CD30 chimeric antigen receptor (CAR) T-cell therapy clinical trials as a new subsection.
Late Effects From Childhood/Adolescent Hodgkin Lymphoma Therapy
Added text about the results of a Childhood Cancer Survivor Study (CCSS) study that determined the incidence of serious health conditions among 2,996 five-year survivors of pediatric Hodgkin lymphoma, compared outcomes by treatment era and strategies, and estimated risks associated with contemporary therapy (cited Oeffinger et al. as reference 3).
Added text to state that among 1,711 intermediate-risk Hodgkin lymphoma survivors treated with response-adapted therapy in the COG AHOD0031 trial, the 10-year cumulative incidence of subsequent malignancy was 1.3%, and the cumulative incidence of secondary myelodysplastic syndrome or acute myeloid leukemia (AML) was 0.2%. Of the three cases of secondary AML, the median time to onset was 2 years (cited Giulino-Roth et al. as reference 64).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Hodgkin Lymphoma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/child-hodgkin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389170]
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Last Revised: 2021-08-04
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