Learn about the medical, dental, pharmacy, behavioral, and voluntary benefits your employer may offer.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[
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 initial treatment approaches for children were modeled after those used for adults, substantial morbidities resulted from unacceptably high radiation doses. As a result, 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 to determine chemotherapy intensity include cancer stage, presence or absence of B symptoms (fever, weight loss, and night sweats), bulky disease, extranodal involvement, and/or erythrocyte sedimentation rate.
Epidemiology
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 (33.3 cases per 1 million per year). Children aged 10 to 14 years, 5 to 9 years, and 0 to 4 years have approximately threefold, tenfold, and 20-fold lower rates of Hodgkin lymphoma, respectively, than do adolescents.[
Hodgkin lymphoma has the following unique epidemiological features:
Individuals aged 14 years and younger have a higher prevalence of nodular lymphocyte-predominant disease and Epstein-Barr virus (EBV)–associated mixed-cellularity disease. EBV-associated 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.[
Nodular-sclerosing Hodgkin lymphoma is the most common subtype, followed by mixed cellularity.
A comprehensive whole genome sequencing effort was conducted in 234 individuals with and without Hodgkin lymphoma, selected from 36 pedigrees that had two or more first-degree affected relatives.[
Variables | Childhood HL | AYA HL | Adult HL | Older Adult HL | |
---|---|---|---|---|---|
Age Range | ≤14 y | 15–35 y | ≥35 y | ≥55 y | |
Prevalence of HL | 10%–12% | 50% | 35% | ||
Gender (Male-to-Female Ratio) | 2–3 to 1 | 1 to 1–1.3 to 1 | 1.2 to 1–1 to 1.1 | ||
Histology: | |||||
Nodular sclerosing | 40%–45% | 65%–80% | 35%–40% | ||
Mixed cellularity | 30%–45% | 10%–25% | 35%–50% | ||
NLPHL | 8%–20% | 2%–8% | 7%–10% | ||
EBV Associated | 27%–54% | 20%–25% | 34%–40% | 50%–56% | |
Advanced Stage | 30%–35% | 40% | 55% | ||
B Symptoms | 25% | 30%–40% | 50% | ||
Relative Survival: Rates at 5 Years | 94% (age <20 y) | 90% (age <50 y) | 65% (age >50 y) | ||
AYA = adolescent and young adult; EBV = Epstein-Barr virus; NLPHL = nodular lymphocyte-predominant Hodgkin lymphoma. | |||||
a Adapted from Punnett et al.[ |
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 cases. EBV genetic material can be detected in Hodgkin and Reed-Sternberg (HRS) cells from some patients with Hodgkin lymphoma, most commonly in those with mixed-cellularity disease.[
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,[
Immunodeficiency and Hodgkin lymphoma
Individuals with immunodeficiency have an increased risk of Hodgkin lymphoma,[
Characteristics of Hodgkin lymphoma presenting in the context of immunodeficiency are as follows:
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 HRS cells and cell signaling within the tumor microenvironment:[
A total of 15% to 20% of patients have noncontiguous extranodal involvement (stage IV). The most common sites of extranodal involvement are the lungs, liver, bones, and bone marrow.[
Prognostic Factors
As the treatment of Hodgkin lymphoma improved, factors associated with outcome became more difficult to identify. However, several factors continue to influence the success and choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and biological aggressiveness are frequently collinear.
Pretreatment factors
Pretreatment factors associated with an adverse outcome include the following:
Prognostic factors identified in select multi-institutional studies include the following:
A single-institution study showed that Black patients had a higher relapse rate than did White patients, but OS was similar.[
Response to initial chemotherapy
The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important.[
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.
References:
Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Hodgkin and Reed-Sternberg [HRS] cells) or large mononuclear cell variants (lymphocytic and histiocytic cells). These cells are 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 histological subtype. It has been conclusively shown that HRS cells and/or lymphocytic and histiocytic cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from germinal center B cells.[
The histological features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines, chemokines, and products of the tumor necrosis factor receptors family secreted by the HRS cells and cell signaling within the tumor microenvironment.[
The hallmark of Hodgkin lymphoma is the HRS cell and its variants,[
Hodgkin lymphoma can be divided into the following two broad pathological classes:[
Classical Hodgkin Lymphoma
Classical Hodgkin lymphoma is divided into four subtypes. These subtypes are defined according to the number of HRS 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 an HRS cell variant called the lacunar cell. Transforming growth factor-beta may be responsible for the fibrosis in this subtype.
A study of over 600 patients with nodular-sclerosing Hodgkin lymphoma from three 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.[
HRS 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 numerous large, bizarre malignant cells, many HRS 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.[
Characteristics of nodular lymphocyte-predominant Hodgkin lymphoma include the following:
References:
Genomics of Classical Hodgkin Lymphoma
Classical Hodgkin lymphoma has a gene expression and variant profile that differs from that of other lymphomas. The exception is primary mediastinal B-cell lymphoma, which shares many genomic and cytogenetic characteristics with Hodgkin lymphoma.[
The genomic alterations observed in Hodgkin lymphoma fall into several categories, including immune evasion alterations, JAK-STAT pathway alterations, alterations leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activation, and others:
Genomics of Nodular Lymphocyte-Predominant Hodgkin Lymphoma
The lymphocyte-predominant (LP) cells of nodular lymphocyte-predominant Hodgkin lymphoma have distinctive genomic characteristics compared with the HRS cells of Hodgkin lymphoma. As with Hodgkin lymphoma, genomic characterization is complicated by the low percentage of malignant cells within a tumor mass.
References:
Staging and evaluation of disease status is undertaken at diagnosis, early in the course of chemotherapy, and at the end of chemotherapy.
Diagnostic and Staging Evaluation
The diagnostic and staging evaluation is critical for the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following:
Systemic symptoms
The following three constitutional symptoms (B symptoms) correlate with prognosis and are used in assignment of stage:
Additional Hodgkin-associated constitutional symptoms that lack prognostic significance include the following:
Physical examination
Laboratory studies
Anatomical imaging
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 for defining lymphomatous involvement by CT or MRI include the following:
Functional imaging
The recommended functional imaging procedure for initial staging is PET, using the radioactive glucose analogue, 18F-FDG.[
General concepts to consider for 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. Calculation of metabolic tumor volume is an evolving approach that may enhance the prognostic utility of PET scans.[
Deauville Score (Visual Score) | Criteria |
---|---|
1 | No uptake. |
2 | Uptake ≤ mediastinal blood pool. |
3 | Uptake > mediastinal blood pool and ≤ normal liver. |
4 | Moderately increased uptake > normal liver. |
5 | Markedly increased uptake > normal liver. |
Timing of 18F-FDG PET | 18F-FDG PET Avidity |
---|---|
18F-FDG = fluorine F 18-fludeoxyglucose; PET = positron emission tomography. | |
Baseline PET (PET 0) response visual threshold utilizes mediastinal blood pool as the reference activity: | 18F-FDG PET positive is defined as visual score 3, 4, 5. |
18F-FDG PET negative is defined as visual score 1, 2. | |
Interim postcycle 2 PET (PET 2) response visual threshold uses normal liver as the reference activity: | 18F-FDG PET positive is defined as visual score 4, 5. |
18F-FDG PET negative is defined as visual score 1, 2, 3. | |
End of chemotherapy PET (PET 4 or 5) response visual threshold also utilizes mediastinal blood pool as the reference activity: | 18F-FDG PET positive is defined as visual score 3, 4, 5. |
18F-FDG PET negative is defined as visual score 1, 2. |
Establishing the Diagnosis of Hodgkin Lymphoma
After a careful physiological 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 include the following:
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.[
Lugano Staging Classification for Hodgkin Lymphoma
Stage is determined by anatomical evidence of disease using CT or MRI scanning in conjunction with functional imaging. The American Joint Committee on Cancer (AJCC) has adopted the Lugano classification to evaluate and stage lymphoma (see Table 4).[
Stage | Description |
---|---|
Note: Hodgkin lymphoma uses A or B designation with stage group. | |
a Adapted from AJCC: Pediatric Hodgkin and non-Hodgkin lymphomas. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 959–65.[ |
|
b Stage II bulky may be considered either early or advanced stage based on lymphoma histology and prognostic factors. | |
c The definition of disease bulk varies according to lymphoma histology. In the Lugano classification, bulk in Hodgkin lymphoma is defined as a mass greater than one third of the thoracic diameter on CT of the chest or a mass >10 cm. | |
Limited stage | |
I | Involvement of a single lymphatic site (i.e., nodal region, Waldeyer's ring, thymus, or spleen). |
IE | Single extralymphatic site in the absence of nodal involvement (rare in Hodgkin lymphoma). |
II | Involvement of two or more lymph node regions on the same side of the diaphragm. |
IIE | Contiguous extralymphatic extension from a nodal site with or without involvement of other lymph node regions on the same side of the diaphragm. |
II bulky b | Stage II with disease bulk. c |
Advanced stage | |
III | Involvement of lymph node regions on both sides of the diaphragm; or nodes above the diaphragm with spleen involvement. |
IV | Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; ornoncontiguous extralymphatic organ involvement in conjunction with nodal stage II disease orany extralymphatic organ involvement in nodal stage III disease. Stage IV includesany involvement of the bone marrow, liver, or lungs (other than by direct extension in stage IIE disease). |
Designations applicable to any stage | |
A | No symptoms. |
B | Fever (temperature >38.0ºC), drenching night sweats, unexplained loss of >10% of body weight within the preceding 6 months. |
E | Involvement of a single extranodal site that is contiguous or proximal to the known nodal site. |
S | Splenic involvement. |
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 pathological 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, pathological 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 treatment planning. The classification of patients into low-, intermediate-, or high-risk categories varies considerably among the pediatric research groups, and often even between different studies conducted by the same group, as summarized in Table 5.[
Study Group | Risk Group (Protocol) | Stage I | Stage II | Stage III | Stage IV |
---|---|---|---|---|---|
COG = Children's Oncology Group; EuroNet-PHL = European Network for Pediatric Hodgkin Lymphoma; TG = treatment group; TL = treatment level. | |||||
a Adapted from Mauz-Körholz et al.[ |
|||||
b EuroNet-PHL-C1 was amended in 2012: Low-risk (TG1) patients with an erythrocyte sedimentation rate of ≥30 mm/hour and/or bulk of ≥200 mL were treated in TG2 (intermediate risk). | |||||
COG | Low (AHOD0431) | IA | IIA | ||
Intermediate (AHOD0031) | IA with extranodal or bulky disease; IB | IIA with extranodal or bulky disease; IIB | IIIA | IVA | |
High (AHOD0831) | IIIB | IVB | |||
EuroNet-PHL-C1b | Low (TG1) | IA; IB | IIA | ||
Intermediate (TG2) | IA or IB with extranodal disease or risk factors | IIA with extranodal disease or risk factors; IIB | IIIA | ||
High (TG3) | IIB with extranodal disease | IIIA with extranodal disease; IIIB | IVA; IVB | ||
EuroNet-PHL-C2 | Low (TL1) | IA; IB | IIA | ||
Intermediate (TL2) | IA or IB with extranodal disease or risk factors | IIA with extranodal disease or risk factors; IIB | IIIA | ||
High (TL3) | IIB with extranodal disease | IIIA with extranodal disease; IIIB | IVA; IVB | ||
Pediatric Hodgkin Consortium | Low (HOD99/HOD08) | IA | IIA with fewer than 3 nodal sites | ||
Intermediate (HOD05) | IA with extranodal disease or mediastinal bulk; IB | IIA with extranodal disease or mediastinal bulk | IIIA | ||
High (HOD99/HLHR13) | IIB | IIIB | IVA; IVB |
Although all major research groups classify patients according to clinical criteria, such as stage and presence of B symptoms, extranodal involvement, or bulky disease, comparison of outcomes across trials is further complicated because of differences in how these individual criteria are defined.[
Response Assessment
Further refinement of risk classification may be performed through assessment of response after initial cycles of chemotherapy or at the completion of chemotherapy.
Interim response assessment
The interim response to initial therapy, which may be assessed on the basis of volume reduction of disease, functional imaging status, or both, is an important prognostic variable in both early- and advanced-stage pediatric Hodgkin lymphoma.[
Definitions for interim response are variable and protocol specific but can range from 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.[
The rapidity of response to early therapy has been used in risk stratification to titrate therapy in an effort to augment therapy in higher-risk patients or to reduce therapy in rapidly responding patients, which might, in turn, reduce the risk of late effects while maintaining efficacy.[
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 after all initial chemotherapy is completed. It may be used to determine the need for consolidative radiation therapy. Key concepts to consider include the following:
References:
Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[
For specific information about supportive care for children and adolescents with cancer, see the summaries on
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[
References:
History 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 select cases of localized nodular 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.[
ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin.[
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 Treatment of Hodgkin Lymphoma
Contemporary treatment for pediatric patients with 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
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.[
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 differences in age-related developmental status and sex-related sensitivity to chemotherapy toxicity.
Ongoing trials for patients with favorable disease 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 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.
Histology-based therapy
Nodular lymphocyte-predominant Hodgkin lymphoma
The use of combination chemotherapy and/or radiation therapy can achieve excellent long-term progression-free survival (PFS) and OS in patients with 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. There is no consensus regarding the optimal treatment for this disease, although outcomes for patients are excellent when they are treated according to standard regimens for intermediate-risk or high-risk Hodgkin lymphoma.
Evidence (chemotherapy for nodular lymphocyte-predominant Hodgkin lymphoma with unfavorable characteristics):
Retrospective case series report on responses with rituximab alone [
A summary of treatment approaches for nodular lymphocyte-predominant Hodgkin lymphoma can be found in Table 10. Both children and adults have a favorable outcome, particularly when the disease is localized (stage I), as it is for most patients.[
Mixed-cellularity Hodgkin lymphoma
In addition to variable responses by histology for nodular 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).[
Radiation Therapy
As previously mentioned, 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 they generally encompass lymph node sites initially involved at the time of diagnosis, without extensive inclusion of uninvolved regions, or positron emission tomography (PET)-avid sites at either interim or end-of-therapy assessment. Radiation therapy field reductions are made to account for tumor regression with chemotherapy.[
One study investigated the effects of central review of the interim fluorine F 18-fludeoxyglucose (18F-FDG) PET–computed tomography (CT) scan response (iPET) assessment on treatment allocation in the risk-based, response-adapted, COG AHOD1331 (NCT02166463) study for pediatric patients with high-risk Hodgkin lymphoma. The study evaluated the results of 573 patients after two cycles of chemotherapy. There was good agreement between central and institutional iPET analysis, with a concordance rate of 89.7% (514 of 573). Of 126 patients who were considered iPET positive by institutional review, 30% were found to be iPET negative by central review. Thus, these patients could avoid being treated with radiation therapy. Conversely, of 447 patients who were considered iPET negative by institutional review, 4.7% were considered positive by central review, which led to these patients receiving radiation therapy.[
Radiation volume
With advancements in systemic therapy, radiation therapy field definitions have become increasingly restricted. Radiation therapy is no longer needed to sterilize all disease. Advances in radiological imaging allow for a more precise radiation target definition. With 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.[
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.[
Radiation dose
The dose of radiation is also variously defined and often protocol-specific.
General considerations regarding radiation dose include the following:
Technical considerations
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, an important question 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 regarding the role of radiation 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). The 4-year EFS rate 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. The OS rate was 98.8% in both groups.[
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.
Chemotherapy
Many of the agents in original MOPP and ABVD regimens continue to be used in contemporary pediatric treatment regimens. Etoposide has been incorporated into some pediatric treatment regimens as an effective alternative to alkylating agents, in an effort to reduce gonadal toxicity and enhance antineoplastic activity. More recent pediatric trials have used procarbazine-free standard backbone regimens, such as ABVE-PC in North America [
Combination chemotherapy regimens used in trials are summarized in Table 6.
Name | Drugs | Dosage | Route | Days |
---|---|---|---|---|
IV = intravenous; PO = oral. | ||||
a ABVE-PC modifications during the P9425 study included reducing bleomycin to 5 units/m2 on day 0 and administering prednisone on days 0 to 7 (instead of days 0–9). In subsequent studies, doxorubicin dose was reduced to 25 mg/m2 in all trials, and for high-risk Hodgkin lymphoma, use of cyclophosphamide was increased to 600 mg/m2 on days 1 and 2. | ||||
COPP [ |
Cyclophosphamide | 600 mg/m2 | IV | 1, 8 |
Vincristine (Oncovin) | 1.4 mg/m2 | IV | 1, 8 | |
Procarbazine | 100 mg/m2 | PO | 1–15 | |
Prednisone | 40 mg/m2 | PO | 1–15 | |
COPDAC[ |
Dacarbazine substituted for procarbazine in COPP | 250 mg/m2 | IV | 1–3 |
CAPDAC[ |
Brentuximab vedotin substituted for vincristine in COPDAC | 1.2 mg/kg | IV | 1, 8 |
OPPA[ |
Vincristine (Oncovin) | 1.5 mg/m2 | IV | 1, 8, 15 |
Procarbazine | 100 mg/m2 | PO | 1–15 | |
Prednisone | 60 mg/m2 | PO | 1–15 | |
Doxorubicin (Adriamycin) | 40 mg/m2 | IV | 1, 15 | |
OEPA[ |
Vincristine (Oncovin) | 1.5 mg/m2 | IV | 1, 8, 15 |
Etoposide | 125 mg/m2 | IV | 3–6 | |
Prednisone | 60 mg/m2 | PO | 1–15 | |
Doxorubicin (Adriamycin) | 40 mg/m2 | IV | 1, 15 | |
AEPA[ |
Brentuximab vedotin substituted for vincristine in OEPA | 1.2 mg/kg | IV | 1, 8, 15 |
ABVD[ |
Doxorubicin (Adriamycin) | 25 mg/m2 | IV | 1, 15 |
Bleomycin | 10 units/m2 | IV | 1, 15 | |
Vinblastine | 6 mg/m2 | IV | 1, 15 | |
Dacarbazine | 375 mg/m2 | IV | 1, 15 | |
N-AVD[ |
Doxorubicin (Adriamycin) | 25 mg/m2 | IV | 1, 15 |
Vinblastine | 6 mg/m2 | IV | 1, 15 | |
Dacarbazine | 375 mg/m2 | IV | 1, 15 | |
Nivolumab | Age 12–17 y: 3 mg/kg (240 mg maximum); age 18 y or older: 240 mg | IV | 1, 15 | |
COPP/ABV[ |
Cyclophosphamide | 600 mg/m2 | IV | 0 |
Vincristine (Oncovin) | 1.4 mg/m2 | IV | 0 | |
Procarbazine | 100 mg/m2 | PO | 0–6 | |
Prednisone | 40 mg/m2 | PO | 0–13 | |
Doxorubicin (Adriamycin) | 35 mg/m2 | IV | 7 | |
Bleomycin | 10 units/m2 | IV | 7 | |
Vinblastine | 6 mg/m2 | IV | 7 | |
VAMP[ |
Vinblastine | 6 mg/m2 | IV | 1, 15 |
Doxorubicin (Adriamycin) | 25 mg/m2 | IV | 1, 15 | |
Methotrexate | 20 mg/m2 | IV | 1, 15 | |
Prednisone | 40 mg/m2 | PO | 1–14 | |
DBVE[ |
Doxorubicin | 25 mg/m2 | IV | 1, 15 |
Bleomycin | 10 units/m2 | IV | 1, 15 | |
Vincristine (Oncovin) | 1.5 mg/m2 | IV | 1, 15 | |
Etoposide | 100 mg/m2 | IV | 1–5 | |
ABVE-PC a[ |
Doxorubicin (Adriamycin) | 30 mg/m2 | IV | 0, 1 |
Bleomycin | 10 units/m2 | IV | 0, 7 | |
Vincristine (Oncovin) | 1.4 mg/m2(maximum dose, 2.8 mg/m2) | IV | 0, 7 | |
Etoposide | 75 mg/m2 | IV | 0–4 | |
Prednisone | 40 mg/m2 | PO | 0–9 | |
Cyclophosphamide | 800 mg/m2 | IV | 0 | |
Bv-AVE-PC(bleomycin omitted and brentuximab vedotin added to the ABVE-PC regimen)[ |
Brentuximab vedotin | 1.8mg/kg | IV | 1 |
Vincristine | 1.4 mg/m2(maximum dose, 2.8 mg/m2) | IV | 8 | |
BEACOPP[ |
Bleomycin | 10 units/m2 | IV | 7 |
Etoposide | 200 mg/m2 | IV | 0–2 | |
Doxorubicin (Adriamycin) | 35 mg/m2 | IV | 0 | |
Cyclophosphamide | 1,200 mg/m2 | IV | 1, 8 | |
Vincristine (Oncovin) | 2 mg/m2 | IV | 7 | |
Prednisone | 40 mg/m2 | PO | 0–13 | |
Procarbazine | 100 mg/m2 | PO | 0–6 | |
CVP[ |
Cyclophosphamide | 500 mg/m2 | IV | 1 |
Vinblastine | 6 mg/m2 | IV | 1, 8 | |
Prednisolone | 40 mg/m2 | PO | 1–8 | |
AV-PC[ |
Doxorubicin (Adriamycin) | 25 mg/m2 | IV | 1, 2 |
Vincristine | 1.4 mg/m2(maximum dose, 2.8 mg/m2) | IV | 1, 8 | |
Prednisone | 20 mg/m2 | PO | 1–7 | |
Cyclophosphamide | 600 mg/m2 | IV | 1, 2 |
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 newer and safer 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 occurred more often within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[
European multicenter trial results
In the last 30 years, European investigators have conducted 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
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 7 summarizes the results of treatment approaches used for pediatric patients with low-risk Hodgkin lymphoma.
Chemotherapy (No. of Cycles)a | Radiation (Gy) | Stage | No. of Patients | Event-Free Survival (No. of Years of Follow-up) | Survival (No. of Years of Follow-up) |
---|---|---|---|---|---|
CS = clinical stage; IFRT = involved-field radiation therapy; N/A = not applicable; No. = number. | |||||
a For more information about the chemotherapy regimens, see Table 6. | |||||
b Included patients with nodular lymphocyte-predominant Hodgkin lymphoma. | |||||
c Without bulky mediastinal (defined as one-third or more of intrathoracic ratio measured on an upright posteroanterior chest radiograph) or peripheral lymphadenopathy (defined as 6 cm or more) or B symptoms. | |||||
d Without adverse features, defined as one or more of the following: hilar adenopathy, involvement of more than four nodal regions; mediastinal tumor with diameter equal to or larger than one-third of the chest diameter, and node or nodal aggregate with a diameter larger than 10 cm. | |||||
e Results fromas-treated analysis. | |||||
VAMP (4)b[ |
IFRT (15–25.5) | CS I/IIc | 110 | 89% (10) | 96% (10) |
VAMP (4)b[ |
IFRT (25.5) | CS I/IIc | 41 | 88% (5) | 100% (5) |
None | 47 | 89% (5) | |||
COPP/ABV (4)[ |
IFRT (21) | CS IA/B, IIAd | 94 | 100% (10)e | 97% (10)e |
None | 113 | 89% (10)e | 96% (10)e | ||
OEPA/OPPA (2)[ |
IFRT (20–35) | I, IIA | 281 | 94% (5) | N/A |
None | 113 | 97% (5) | |||
ABVD[ |
IFRT (21–35) | I–IV | 209 | 85% (5) | 97% (5) |
ABVE (2-4)b[ |
IFRT (25.5) | IA, IIA, IIIA1, without bulky disease | 51 | 91% (6) | 98% (6) |
AV-PC[ |
None | IA, IIA, without bulky disease | 278 | 79.9% (4) | 99.6% (4) |
Response-based IFRT (21) |
Classical Hodgkin lymphoma, intermediate-risk disease
Table 8 summarizes the results of treatment approaches used for pediatric patients with intermediate-risk Hodgkin lymphoma.
Chemotherapy (No. of Cycles)a | Radiation (Gy) | Stage | No. of Patients | Event-Free Survival (No. of Years of Follow-up) | Survival (No. of Years of Follow-up) |
---|---|---|---|---|---|
CR = complete response; CS = clinical stage; E = extralymphatic; IFRT = involved-field radiation therapy; N/A = not applicable; RER = rapid early response; SER = slow early response. | |||||
a For more information about the chemotherapy regimens, see Table 6. | |||||
b With adverse disease features, defined as one or more of the following: hilar adenopathy, involvement of more than four nodal regions; mediastinal tumor with diameter equal to or larger than one-third of the chest diameter, and node or nodal aggregate with a diameter larger than 10 cm. | |||||
c Results fromas-treated analysis. | |||||
COPP/ABV (6)[ |
IFRT (21) | CS I/IIb, CS IIB, CS III | 103 | 84% (10)c | 100% (3) |
None | 122 | 78% (10)c | |||
OEPA/OPPA (2) + COPP (2)[ |
IFRT (20–35) | IIE A, IIB, IIIA | 212 | 92% (5) | N/A |
OEPA/OPPA (2) + COPDAC (2)[ |
IFRT (20–35) | IE, IIB, IIE A, IIIA | 139 | 88.3% (5) | 98.5% (5) |
ABVE-PC (3–5)[ |
IFRT (21) | IIA/IIIA, if bulky disease | 53 | 84% (5) | 95% (5) |
ABVE-PC: RER/CR[ |
IFRT (21) | IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease | 380 | 87.9% (4) | 98.8% (4) |
ABVE-PC: RER/CR[ |
None | IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease | 382 | 84.3% (4) | 98.8% (4) |
ABVE-PC: SER: +DECA[ |
IFRT (21) | IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease | 153 | 79.3% (4) | 96.5% (4) |
ABVE-PC: SER: -DECA[ |
IFRT (21) | 151 | 75.2% (4) | 94.3% (4) |
Classical Hodgkin lymphoma, high-risk disease
Table 9 summarizes the results of treatment approaches used for pediatric patients with high-risk Hodgkin lymphoma.
Chemotherapy (No. of Cycles)a | Radiation (Gy) | Stage | No. of Patients | Event-Free Survival (No. of Years of Follow-up) | Survival (No. of Years of Follow-up) |
---|---|---|---|---|---|
E = extralymphatic; IFRT = involved-field radiation therapy; ISRT = involved-site radiation therapy; N/A = not applicable; No. = number; PFS = progression-free survival; RER = rapid early response; SER = slow early response. | |||||
a For more information about the chemotherapy regimens, see Table 6. | |||||
b Results include all treatment strata. | |||||
OEPA/OPPA (2) + COPP (4)[ |
IFRT (20–35) | IIE B, IIIE A/B, IIIB, IVA/B | 265 | 91% (5) | N/A |
OEPA/OPPA (2) + COPDAC (4)[ |
IFRT (20–35) | IIE B, IIIE A/B, IIIB, IVA/B | 239 | 86.9% (5) | 94.9% (5) |
ABVE-PC (3-5)[ |
IFRT (21) | IIB, IIIB, IV | 163 | 85% (5) | 95% (5) |
BEACOPP (4); COPP/ABV (4) (RER; girls)[ |
None | IIB, IIIB, IV | 38 | 94% (5)b | 97% (5)b |
BEACOPP (4); ABVD (2) (RER; boys)[ |
IFRT (21) | IIB, IIIB, IV | 34 | ||
BEACOPP (8) (SER)[ |
IFRT (21) | IIB, IIIB, IV | 25 | ||
AEPA (2); CAPDAC (4)[ |
Individual residual nodal (25.5) | IIB, IIIB, IV | 77 | 97.4% (3) | 98.7% (3) |
Bv-AVE-PC (5)[ |
ISRT | IIB + Bulk, IIIB, IV | 587 | 92.1% (3) | 99.3% (3) |
N-AVD (6)[ |
None | III, IV | 489 total (120 aged 12–17 y) | PFS: 94% (1) | 99% (1) |
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the
Nodular lymphocyte-predominant Hodgkin lymphoma
Table 10 summarizes the results of treatment approaches used for pediatric patients with 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.
Chemotherapy (No. of Cycles)a | Radiation (Gy) | No. of Patients | Event-Free Survival (No. of Years of Follow-up) | Survival (No. of Years of Follow-up) |
---|---|---|---|---|
IFRT = involved-field radiation therapy; N/A = not applicable; No. = number. | ||||
a For more information about the chemotherapy regimens, see Table 6. | ||||
b Allocation to radiation therapy or no radiation therapy was based on response to therapy. These results were for the group of patients with mixed-cellularity histology and nodular lymphocyte-predominant Hodgkin lymphoma. | ||||
c Allocation was based on clinical response. | ||||
d Single lymph node surgically resected. | ||||
e All involved lymph nodes surgically resected. | ||||
COPP/ABV (4)b[ |
None | 52 | 96% (10) | N/A |
IFRT (21) | 35 | 96% (10) | ||
CVP (3)[ |
None | 55 | 74% (5) | 100% (5) |
DBVE (2–4)c[ |
None | 26 | 94% (8) | 100% (8) |
IFRT (25.5) | ||||
VAMP (4)c[ |
None | 26 | 89.4% (5) | N/A |
IFRT (25) | 6 | 85.7% (5) | N/A | |
VAMP (4)[ |
IFRT (15–25.5) | 33 | 100% (10) | 100% (10) |
Noned[ |
Noned | 52 | 77% (5) | 100% (5) |
AV-PC[ |
None | 124 | 85.5% (5) | 100% (5) |
IFRT (21) | 11 | |||
Nonee[ |
None | 51 | 67% (2) | 100% (2) |
Treatment of Adolescents and Young Adults With Hodgkin Lymphoma
The treatment approach for adolescents and young adults with Hodgkin lymphoma may vary based on community referral patterns and age restrictions at pediatric cancer centers. 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 delivers a cumulative anthracycline dose of 300 mg/m2.[
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 require further research.
Adolescent and young adult patients with Hodgkin lymphoma should consider participating in a clinical trial. Information about ongoing clinical trials is available from the
Current Clinical Trials
Use our
References:
Because children and adolescents with Hodgkin lymphoma have excellent responses to frontline therapy, second-line (salvage) therapy has only been evaluated in a limited capacity. Because primary therapy fails in relatively few patients, no uniform second-line treatment strategy exists for this population.[
Adverse prognostic factors after relapse include the following:[
Children with localized favorable relapses (≥12 months after completing therapy) whose original therapy involved reduced cycles of risk-adapted chemotherapy alone or chemotherapy with low-dose small-volume radiation therapy (consolidation therapy) have a high likelihood of achieving long-term survival after treatment with more intensive conventional chemotherapy.[
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. The choice of specific agents, dose intensity, and number of cycles is 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.
Evidence (nivolumab):
Nivolumab is FDA approved in adult patients with classical Hodgkin lymphoma who have relapsed or progressed after autologous HSCT and brentuximab vedotin or three or more lines of systemic therapy that included autologous HSCT.[
Evidence (pembrolizumab):
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 Stem Cell Transplant (HSCT)
Myeloablative chemotherapy with autologous HSCT is the recommended approach for patients who develop refractory disease during therapy or relapsed disease within 1 year after completing therapy.[
Adverse prognostic features for outcome after autologous HSCT 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 HSCT.[
For more information about transplant, see Pediatric Autologous Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.
Chemotherapy Followed by Allogeneic HSCT
For patients who do not improve after autologous HSCT and patients with chemoresistant disease, allogeneic HSCT has been used with encouraging results.[
For more information about transplant, see Pediatric Allogeneic Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.
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.[
Response Rates for Primary Refractory Hodgkin Lymphoma
Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with autologous HSCT and radiation. However, some studies have reported that intensification of therapy followed by HSCT consolidation can achieve long-term survival.
Evidence (response to treatment of primary refractory Hodgkin lymphoma):
Second Relapse After Initial Treatment With Autologous HSCT
In a phase II study, patients (median age, 26.5 years) who had relapsed or refractory disease after autologous HSCT 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%. Only 6 of 34 patients proceeded to allogeneic HSCT while in remission.[
Treatment Options Under Clinical Evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the
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.[
A number of clinical trials of anti-CD30 CAR T-cell therapy for patients with relapsed Hodgkin lymphoma are listed on
Other clinical trials
The following is an example 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:
Current Clinical Trials
Use our
References:
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.[
In the past 30 to 40 years, pediatric Hodgkin lymphoma therapy has changed dramatically to 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 11 summarizes late health effects observed in Hodgkin lymphoma survivors, followed by a limited discussion of common late effects. For a full discussion of the late effects of cancer treatment in children and adolescents, see Late Effects of Treatment for Childhood Cancer.
Health Effects | Predisposing Therapy | Clinical Manifestations |
---|---|---|
Reproductive | Alkylating agent chemotherapy | Hypogonadism |
Gonadal irradiation | Infertility | |
Thyroid | Radiation impacting thyroid gland | Hypothyroidism |
Hyperthyroidism | ||
Thyroid nodules | ||
Cardiovascular | Radiation impacting cardiovascular structures | Subclinical left ventricular dysfunction |
Cardiomyopathy | ||
Pericarditis | ||
Heart valve dysfunction | ||
Conduction disorder | ||
Coronary, carotid, subclavian vascular disease | ||
Myocardial infarction | ||
Stroke | ||
Anthracycline chemotherapy | Subclinical left ventricular dysfunction | |
Cardiomyopathy | ||
Congestive heart failure | ||
Subsequent neoplasms or disease | Alkylating agent chemotherapy | Myelodysplasia/acute myeloid leukemia |
Epipodophyllotoxins | Myelodysplasia/acute myeloid leukemia | |
Radiation | Solid benign and malignant neoplasms | |
Anthracycline chemotherapy | Breast cancer | |
Oral or dental | Any chemotherapy in a patient who has not developed permanent dentition | Dental maldevelopment (tooth or root agenesis, microdontia, root thinning and shortening, enamel dysplasia) |
Radiation impacting oral cavity and salivary glands | Salivary gland dysfunction | |
Xerostomia | ||
Accelerated dental decay | ||
Periodontal disease | ||
Pulmonary | Radiation impacting the lungs | Subclinical pulmonary dysfunction |
Bleomycin | Pulmonary fibrosis | |
Musculoskeletal | Radiation of musculoskeletal tissues in any patient who is not skeletally mature | Growth impairment |
Glucocorticosteroids | Bone mineral density deficit | |
Multiple sclerosis | ||
Immune | Splenectomy | Overwhelming post-splenectomy sepsis |
Male Gonadal Toxicity
Important concepts related to male gonadal toxicity include the following:
For more information, see the Testis section in Late Effects of Treatment for Childhood Cancer.
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:
For more information, see the Ovary section in Late Effects of Treatment for Childhood Cancer.
Thyroid Abnormalities
Abnormalities of the thyroid gland, including hypothyroidism, hyperthyroidism, and thyroid neoplasms, 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 emerged more than 20 years after the cancer diagnosis.[
The relative risk (RR) of thyroid cancer is higher among Hodgkin lymphoma survivors (approximately 18-fold for the CCSS Hodgkin lymphoma cohort compared with the general population).[
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.[
For more information, see the Thyroid Gland section in Late Effects of Treatment for Childhood Cancer summary.
Cardiac Toxicity
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.[
Survivors of childhood Hodgkin lymphoma older than 50 years will experience more than two times the number of chronic cardiovascular conditions and nearly five times the number of more severe (grades 3–5) cardiovascular conditions compared with community controls. Survivors will also, 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 finding 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
For more information, see the Late Effects of the Cardiovascular System section in Late Effects of Treatment for Childhood Cancer.
Subsequent Neoplasms
Series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published.[
Subsequent hematological malignancy (most commonly AML and myelodysplasia) is related to the use of alkylating agents, anthracyclines, and etoposide and exhibit a brief latency period (<10 years from the primary cancer).[
A single-study experience suggests that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity.[
Clinical trials using dexrazoxane in childhood leukemia have not observed an excess risk of subsequent neoplasms.[
Chemotherapy-related myelodysplasia and AML are less prevalent after contemporary therapy because of the restriction of cumulative alkylating agent doses.[
Among 1,711 intermediate-risk Hodgkin lymphoma survivors treated with response-adapted therapy in the Children's Oncology Group (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.[
Breast cancer is the most common therapy-related, solid, subsequent neoplasm after Hodgkin lymphoma:
Breast cancer risk after radiation therapy:
Breast cancer risk after chemotherapy (includes survivors of Hodgkin lymphoma and other childhood, adolescent, and young adult malignancies):
For more information, see the Subsequent Neoplasms section in Late Effects of Treatment for Childhood Cancer.
References:
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
Added text to state that the U.S. Food and Drug Administration approved brentuximab vedotin in combination with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide for pediatric patients aged 2 years and older with previously untreated high-risk classical Hodgkin lymphoma.
Treatment of Primary Refractory or Recurrent Hodgkin Lymphoma in Children and Adolescents
Added text to state that brentuximab vedotin as consolidation therapy (after hematopoietic stem cell transplant [HSCT]) was evaluated in 67 pediatric patients with relapsed or refractory Hodgkin lymphoma. The median follow-up was 37 months, and the 3-year progression-free survival rate was 85%. About 69% of these patients received brentuximab vedotin at any point during the pre-HSCT salvage treatment, for either upfront therapy or reinduction therapy (cited Forlenza et al. as reference 48).
This summary is written and maintained by the
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 in the care of their 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
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
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at:
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in
Disclaimer
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the
Contact Us
More information about contacting us or receiving help with the Cancer.gov website can be found on our
Last Revised: 2024-08-29
This information does not replace the advice of a doctor. Ignite Healthwise, LLC, disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the
Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Ignite Healthwise, LLC.
Individual and family medical and dental insurance plans are insured by Cigna Health and Life Insurance Company (CHLIC), Cigna HealthCare of Arizona, Inc., Cigna HealthCare of Illinois, Inc., Cigna HealthCare of Georgia, Inc., Cigna HealthCare of North Carolina, Inc., Cigna HealthCare of South Carolina, Inc., and Cigna HealthCare of Texas, Inc. Group health insurance and health benefit plans are insured or administered by CHLIC, Connecticut General Life Insurance Company (CGLIC), or their affiliates (see
All insurance policies and group benefit plans contain exclusions and limitations. For availability, costs and complete details of coverage, contact a licensed agent or Cigna sales representative. This website is not intended for residents of New Mexico.