National Cancer Institute


Posted Date: Apr 27, 2014

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

Childhood Hodgkin Lymphoma Treatment

General Information

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 primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, 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/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 Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For Hodgkin lymphoma, the 5-year survival rate has increased over the same time from 81% to more than 94% for children and adolescents. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects 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 (primarily musculoskeletal growth inhibition) 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 produces less long-term morbidity for these patients. Contemporary treatment programs use a risk-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field 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.

Epidemiology

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 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 non-European Union 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:Childhood form—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.Young adult form—effects 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.Older adult form—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.

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 compared with adolescents and young adults.
  • The incidence of EBV tumor cell positivity for Hodgkin lymphoma in developed countries is 15% to 25% in adolescents and young adults. There is a high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma 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. Patients with a prior 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.

Among individuals with immunodeficiency, the risk of Hodgkin lymphoma is increased, although 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 presentation, in part, reflecting the tendency of these patients to have either mixed cellularity or lymphocyte-predominant histology.
  • Approximately 20% of patients will have bulky adenopathy (maximum mediastinal diameter one-third of the chest diameter or greater and/or a node or nodal aggregate larger than 10 cm).
  • Based on data from large cooperative group cohorts, 80% to 85% of children and adolescents with Hodgkin lymphoma have involvement of lymph nodes and/or the spleen only (stages I–III).
  • The remaining 15% 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.
  • Only three specific constitutional (B) symptoms 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.

Prognostic Factors

As the treatment of Hodgkin lymphoma has improved, factors that are associated with outcome have become 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 codependent. Further complicating the identification of prognostic factors is their use in determining the aggressiveness of therapy. For example, in a report from the German-Austrian Pediatric multicenter trial DAL-HD-90, bulky disease was not a prognostic factor for outcome on multivariate analysis. However, in this study, boost irradiation doses were given to patients who had postchemotherapy residual disease, which could have obfuscated the relevance of bulky disease at presentation. This underscores the complexity in determining prognostic factors.

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 11,500/mm3 or higher).
  • Anemia (hemoglobin lower than 11.0 g/dL).
  • Male gender.
  • 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 gender 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 gender; stage IIB, IIIB, or IV disease; white blood cell count of 11,500/mm3 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 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. Fluorodeoxyglucose-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 based on early PET response is to be determined.

Although prognostic factors will continue to change because of risk stratification and choice of therapy, parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy are likely to remain relevant to outcome.

Cellular Classification and Biologic Correlates

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 that cannot synthesize immunoglobulin. 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 classic Hodgkin lymphoma is the Reed-Sternberg cell, which has the following features:

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

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, while nodular lymphocyte-predominant Hodgkin lymphoma almost never expresses CD15.
  • 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 were identified, which correlated with 70% increased risk of developing nodular sclerosis Hodgkin lymphoma. Another haplotype was associated with a 60% decreased risk. It is hypothesized that these haplotypes result in atypical immune responses that lead 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 human immunodeficiency virus. 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

  • There are variable estimates for the relative frequency of nodular lymphocyte-predominant Hodgkin lymphoma in the pediatric population, ranging from 5% to 10%. The relative frequency is higher for 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.
  • Patients with nodular lymphocyte-predominant Hodgkin lymphoma generally present with localized, nonbulky disease that infrequently 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 OCT-2 and BOB.1 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.
  • 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), underscoring the importance of judicious use of chemotherapy and radiation therapy at initial presentation and after recurrent disease.

Diagnosis and Staging

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.

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.
  • 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.
  • 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 information from CT is complemented by PET functional imaging, which is sensitive in determining initial sites of involvement, particularly sites too small to be considered abnormal by CT criteria.

The recommended functional imaging procedure for initial staging is now PET. In PET scanning, uptake of the radioactive glucose analog, 18-fluoro-2-deoxyglucose (FDG) correlates with proliferative activity in tumors undergoing 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 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 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 report of 38 patients compared bone marrow involvement diagnosed by biopsy with bone marrow involvement assessed by PET scan positivity. The report showed that the sensitivity of PET was 87.5% and the negative predictive value of PET was 96% for bone marrow involvement.
  • Integration of data acquired from PET scans can lead to significant changes in staging. In the previously mentioned study, PET findings resulted in a change in staging in 50% of patients (with a nearly equal number of patients up- and down-staged), and subsequent adjustments in involved-field radiation therapy treatment volumes in 70% of patients (more likely an addition rather than exclusion).
  • 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 which is PET-negative should not be considered involved unless proven by biopsy.

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. 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.

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. Based on 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.
  • 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. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans, can be done with the patient on his or her side or prone.
  • If airway compromise precludes the performance of a diagnostic operative procedure, preoperative treatment with steroids or 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.
  • 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.

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. 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.

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 various pediatric research groups, and often even between different studies conducted by the same group, as summarized in Table 2.

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 its completion.

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 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.

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.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 70% to 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 definition of complete response varies by protocol/cooperative group. GPOH studies use very stringent criteria of at least 95% reduction in tumor volume or less than 2 mL residual volume on CT. Consideration of this difference in complete response criteria compared with that used in North American protocols is an important consideration for the omission of radiation therapy, which is stipulated in GPOH trials among favorable-risk patients achieving these strict complete-response criteria.
    • 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 70% to 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 definition of complete response varies by protocol/cooperative group. GPOH studies use very stringent criteria of at least 95% reduction in tumor volume or less than 2 mL residual volume on CT. Consideration of this difference in complete response criteria compared with that used in North American protocols is an important consideration for the omission of radiation therapy, which is stipulated in GPOH trials among favorable-risk patients achieving these strict complete-response criteria.
  • 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 should be 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.
    • Timing of PET scanning after completing therapy is an important issue. For patients treated with chemotherapy alone, PET scanning should be 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.
  • Use of anatomic and functional imaging to assess response.Response assessment using anatomic and functional imaging appears to be superior to that of anatomic imaging alone. A review of the revised International Workshop Criteria comparing Hodgkin lymphoma response evaluation by CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone. While the International Harmonization for assessment of FDG-PET response has been attempted in adults, it has yet to be evaluated in pediatric populations.A Children's Oncology Group study evaluated surveillance CT and detection of relapse in intermediate-stage and advanced-stage Hodgkin lymphoma. The majority of 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/recurrent disease is recommended before modification of therapeutic plans.
    • Response assessment using anatomic and functional imaging appears to be superior to that of anatomic imaging alone.
    • A review of the revised International Workshop Criteria comparing Hodgkin lymphoma response evaluation by CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone. While the International Harmonization for assessment of FDG-PET response has been attempted in adults, it has yet to be evaluated in pediatric populations.
    • A Children's Oncology Group study evaluated surveillance CT and detection of relapse in intermediate-stage and advanced-stage Hodgkin lymphoma. The majority of 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/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 imaging. Age, gender, and histological subtype may also be considered in treatment planning.

  • 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.
  • No single treatment approach is ideal for all pediatric and young adult patients because of the differences in age-related developmental status and gender-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.
  • Gender-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.

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 treatment approach is supported by the following findings from the literature:

  • 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 death from lymphoma.
  • 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. In one trial of 52 nodular lymphocyte-predominant Hodgkin lymphoma patients who were treated with chemotherapy alone, the 5-year EFS was 96%.[Level of evidence: 1iiDi] Surgical resection of localized disease produces a prolonged disease-free survival in a substantial proportion of patients obviating the need for immediate cytotoxic therapy. Recurrence after surgical resection has not been associated with significant upstaging or histological transformation to a more aggressive B-cell lymphoma.

A summary of treatment approaches for nodular lymphocyte-predominant Hodgkin lymphoma can be found in Table 8.

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.

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 utilizing 15 to 21 Gy, treatment of contralateral uninvolved sites is not necessary in all but perhaps the very young.

General trends in radiation treatment volume are summarized as follows:

  • Total nodal and regional RT fields have largely been replaced by IFRT (see Table 3).
  • Targeted therapy, which involves restricting RT to areas of initial bulky disease (generally defined as ≥5 cm at the time of disease presentation) or postchemotherapy residual disease (generally defined as ≥2.5 cm or residual positron emission tomography [PET] avidity), is under investigation (COG-AHOD0831).
  • Involved-nodal RT, 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 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 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 for RT, specifically the whole site where the lymphoma was located before chemotherapy was given. The exact size of this volume will depend on the individual case scenario.

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.

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

  • Doses of 15 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 in regions with suboptimal response to chemotherapy.

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 blocking.
  • 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 chemotherapy used and patient age. Possible indications for whole-heart irradiation (~10 Gy) are pericardial involvement, as suggested by a large pericardial effusion or frank pericardial invasion with tumor.
  • Whole-lung irradiation (~10 Gy), with partial transmission blocks, are a consideration in the setting of overt pulmonary nodules. For example, the GPOH HD-95 trial administered ipsilateral whole-lung RT to patients who had not achieved a complete response (CR) in the lungs to the first two cycles of chemotherapy. COG-9425 and COG-AHOD0031 used whole-lung RT in patients with pulmonary nodules at diagnosis, with the latter protocol randomly assigning some patients on the basis of response.
  • While CT-based 2-dimensional radiation therapy remains the standard technique for radiation delivery in pediatric Hodgkin lymphoma, 3-dimensional conformal radiation therapy (3-D CRT) or intensity-modulated radiation therapy (IMRT) may be considered in situations where the more conformal techniques would reduce dose to surrounding normal critical structures (e.g., when treating the thorax to spare dose to the heart, lungs, and developing breast tissue, or when treating the abdomen and pelvis to minimize dose to the highly radiosensitive reproductive organs).
  • 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.

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-IFRT 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 treatment efficacy and minimizing risks for late toxicity associated with both RT and chemotherapy.
  • The use of LD-IFRT 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/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 produces a superior EFS for children with intermediate/high-risk Hodgkin lymphoma who achieve a CR to multiagent chemotherapy, but it does not affect OS because of the success of second-line therapy. Adjuvant radiation therapy may be associated with excess late effects or mortality.
  • Radiation consolidation may facilitate local disease control in individuals with refractory/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.

Additionally, when considering the role of RT in the initial management of Hodgkin lymphoma, one must carefully consider the endpoint that is being evaluated. Unlike most other pediatric malignancies, Hodgkin lymphoma is often salvageable if initial treatment does not result in a CR or if relapse occurs. For example, studies comparing combination chemotherapy with or without RT in adults with advanced-stage Hodgkin lymphoma showed that EFS was higher for patients who received initial chemotherapy and RT; however, OS was no different for patients whose initial therapy was chemotherapy alone. Among adult Hodgkin lymphoma patients, study results conflict regarding whether adjuvant RT improves OS compared with chemotherapy alone, despite an improvement in EFS, because of the ability to effectively salvage patients who relapse after initial therapy. Thus, it is not clear whether EFS or OS should be the appropriate endpoint for a trial comparing chemotherapy with or without radiation.

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.

Chemotherapy

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 4.

Results from Selected Clinical 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 complete response 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.[Level of evidence: 1iiDi] 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 for 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 as-treated analysis) 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 as-treated analysis).

Another CCG Study (COG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP regimen followed by a gender-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[Level of evidence: 2Dii] For rapid early responding girls, an additional four courses of COPP/ABV (without IFRT) were given. Rapid early responding boys received two cycles of ABVD followed by IFRT. Slow early responders received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girl's therapy was intended to reduce the risk of breast cancer. Key findings from this trial include the following:

  • 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 achieve an early CR have a comparable 5-year EFS to those treated with four cycles of VAMP chemotherapy plus 25.5 Gy IFRT (89% vs. 88%).

In the last 30 years, German investigators have implemented a series of risk-adapted trials evaluating gender-based treatments featuring multiagent chemotherapy with 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 to risk- and gender-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.[Level of evidence: 2A]

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 gender is also considered in treatment planning.

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 more 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 8 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 low-dose IFRT. Because of the relative rarity of this subtype, most trials are limited by small cohort numbers and nonrandom allocation of treatment.

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 medical oncology practices typically involves at least six cycles of ABVD chemotherapy that would deliver a cumulative anthracycline dose of 300 mg/m2. 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. 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 or 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 Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of 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 Web site.

Treatment of Primary Refractory/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:[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 following treatment with more intensive conventional chemotherapy.

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

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.

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

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