Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 2013 and 2019, the 5-year overall survival rate was 98% for patients younger than 20 years with Hodgkin lymphoma.[2]
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, strategies using chemotherapy and lower-dose radiation were developed. Presently, treatment approaches for pediatric and adult patients are merging, focusing on improving outcomes while reducing late effects in both populations.
Approximately 90% to 95% of children and adolescents with Hodgkin lymphoma can be cured, prompting increased attention to therapy that lessens long-term morbidity. 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.
Hodgkin lymphoma accounts for 6.5% 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 (31.2 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 30-fold lower rates of Hodgkin lymphoma, respectively, than do adolescents.[2] In low-income countries, the incidence rate is similar in young adults but much higher in children.[3]
Hodgkin lymphoma has the following unique epidemiological features:
Individuals aged 14 years and younger have a higher prevalence of the non-classical nodular lymphocyte-predominant disease (NLPHL) 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.[4]
Early exposure to common infections in early childhood appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity.[5,6]
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 affected first-degree relatives.[13] Using linkage and a tiered variant prioritization algorithm, 44 Hodgkin lymphoma pathogenic risk variants were identified (33 coding variants and 11 noncoding variants). A recurrent coding variant was seen in KDR, and a 5’ untranslated region variant was seen in KLHDC8B—both of which have previously been identified. Two new noncoding variants were seen in PAX5 (intron 5) and GATA3 (intron 3). In addition, multiple unrelated families harbored novel loss of function variants in POLR1E and stop-gain variants in IRF7 and EEF2KMT. These findings validated previous studies and identified additional germline pathogenic variants associated with an increased risk of Hodgkin lymphoma.
| Variables | Childhood HL | AYA HL | Adult HL | Older Adult HL | |
|---|---|---|---|---|---|
| Age Range | ≤14 y | 15–34 y | ≥35 y | ≥55 y | |
| Prevalence of HL | 10%–12% | 50% | 35% | ||
| Sex (Male-to-Female Ratio) | 2–3:1 | 1:1–1.3:1 | 1.2:1–1:1.1 | ||
| 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. | |||||
| aAdapted from Punnett et al.[14] | |||||
EBV has been implicated in the etiology of some cases of Hodgkin lymphoma. Some patients with Hodgkin lymphoma have high EBV titers, suggesting that a previous EBV infection may precede the development of Hodgkin lymphoma. 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.[15] In children and adolescents with intermediate-risk Hodgkin lymphoma, EBV DNA in cell-free blood correlated with the presence of EBV in the tumor. EBV DNA found in cell-free blood 8 days after the initiation of therapy predicted an inferior event-free survival (EFS).[15]
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,[16-18,20] but plasma EBV DNA has been associated with an inferior outcome in adults.[21] However, children with intermediate-risk disease with higher levels of EBV DNA at diagnosis have better outcomes.[15] This also correlates with better outcomes for patients with mixed-cellularity disease treated with dose-dense chemotherapy (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide [ABVE-PC]). Patients with a previous history of serologically confirmed infectious mononucleosis have a fourfold increased risk of developing EBV-positive Hodgkin lymphoma. These patients are not at increased risk of developing EBV-negative Hodgkin lymphoma.[22]
Individuals with immunodeficiency have an increased risk of Hodgkin lymphoma,[23] although the risk of non-Hodgkin lymphoma is even higher.
Characteristics of Hodgkin lymphoma presenting in the context of immunodeficiency are as follows:
The following presenting features of Hodgkin lymphoma result from direct or indirect effects of nodal or extranodal involvement and/or constitutional symptoms related to cytokine release from HRS cells and cell signaling within the tumor microenvironment:[29]
Approximately 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.[30,31]
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 associated with an adverse outcome include the following:
Prognostic factors identified in select multi-institutional studies include the following:
The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important.[42-44] Response evaluation in previous generations of trials relied on computed tomography and gallium uptake; positron emission tomography (PET) scanning is now routinely used to assess early response in pediatric Hodgkin lymphoma.[45] Fluorine F 18-fludeoxyglucose PET avidity after two cycles of chemotherapy (PET2) for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[46-48] Reduction in PET avidity after one cycle of chemotherapy was associated with a favorable EFS outcome in children with limited-stage classical Hodgkin lymphoma.[38] Additional studies in children are ongoing to assess the role of early PET-based response in modifying therapy and predicting outcome.
Prognostic factors will continue to change because of risk stratification and choice of therapy, with parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy used to stratify therapeutic assignment.
Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (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.[1-3]
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.[4-6]
The hallmark of Hodgkin lymphoma is the HRS cell and its variants,[7] which have the following features:
Hodgkin lymphoma can be divided into the following two broad pathological classes:[11,12]
cHL is divided into four subtypes, which are defined according to the number of HRS cells, characteristics of the inflammatory milieu, and the presence or absence of fibrosis.[3]
Characteristics of the four histological subtypes of cHL 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 (TGF-beta) may be responsible for the fibrosis in this subtype.
A study of over 600 patients with NS 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 NS Hodgkin lymphoma.[14] Another haplotype was associated with a 60% decreased risk of developing Hodgkin lymphoma. These haplotypes are thought to be associated with atypical immune responses that predispose patients to 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 MC 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 NS classical Hodgkin lymphoma with lymphocyte depletion.[17]
The frequency of NLPHL 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.[13] This type of Hodgkin lymphoma is most common in males younger than 18 years.[18,19]
Characteristics of NLPHL include the following:
Classical Hodgkin lymphoma has a molecular profile that differs from that of non-Hodgkin lymphomas. The exception is primary mediastinal B-cell lymphoma, which shares many genomic and cytogenetic characteristics with Hodgkin lymphoma.[1,2] Characterization of genomic alterations for Hodgkin lymphoma is challenging because malignant Hodgkin and Reed-Sternberg (HRS) cells make up only a small percentage of the overall tumor mass. Because of this finding, special methods, such as microdissection of HRS cells or flow cytometry cell sorting, are required before applying molecular analysis methods.[2-5] Hodgkin lymphoma genomic alterations can also be assessed using special sequencing methods applied to circulating cell-free DNA (cfDNA) in peripheral blood of patients with Hodgkin lymphoma.[6,7]
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:
The lymphocyte-predominant (LP) cells of NLPHL 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.
Staging and evaluation of disease status is undertaken at diagnosis, early in the course of chemotherapy, and at the end of chemotherapy.
The diagnostic and staging evaluation is critical for the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following:
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:
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.[2,4] Metabolic tumor volume calculations may enhance the prognostic utility of PET scans.[5]
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.[4]
The criteria for bulky mediastinal and nonmediastinal disease are as follows:
These two definitions differ from the published consensus guidelines from the International Conference on Malignant Lymphomas Imaging Group (Lugano), which defines bulk as a mass 10 cm or larger seen unidimensionally on CT.[6]
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:
The recommended functional imaging procedure for initial staging is PET, using the radioactive glucose analogue 18F-FDG.[2,9,10] 18F-FDG PET identifies areas of increased metabolic activity, specifically anaerobic glycolysis. PET-CT, which integrates functional and anatomical tumor characteristics, is often used for staging and monitoring of pediatric patients with Hodgkin lymphoma. Residual or persistent 18F-FDG avidity has been correlated with poor prognosis and the need for additional therapy in posttreatment evaluation.[11-13]; [14][Level of evidence B4] Whole-body MRI, with diffusion-weighted imaging, compares favorably to PET-CT for staging of pediatric Hodgkin lymphoma.[15]
Newer factors to consider for using PET for prognostication include metabolic tumor volume, tumor dissemination on PET (Dmax), and total lesion surface.[5,16]
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.[9]
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.[5] The COG and EuroNet definitions of PET response of lymph nodes or nodal masses are described in Table 3.
| 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 uses 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 uses 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. | |
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:
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).[23] The Lugano classification system replaces the Ann Arbor classification system, which was adopted in 1971 at the Ann Arbor Conference,[24] with some modifications 18 years later from the Cotswolds meeting.[25] Staging is independent of the imaging modality used.
| Stage | Description |
|---|---|
| Note: Hodgkin lymphoma uses A or B designation with stage group. | |
| aAdapted 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.[23,26] | |
| bStage II bulky may be considered either early or advanced stage based on lymphoma histology and prognostic factors. | |
| cThe 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 bulkyb | 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; or noncontiguous extralymphatic organ involvement in conjunction with nodal stage II disease or any extralymphatic organ involvement in nodal stage III disease. Stage IV includes any 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 based on findings of the clinical evaluation. However, pathological confirmation of noncontiguous extralymphatic involvement is strongly suggested for assignment to stage IV.
After the diagnostic and staging evaluation data are acquired, patients are further classified into risk groups for 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.[27]
| 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. | |||||
| aAdapted from Mauz-Körholz et al.[27] | |||||
| bEuroNet-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 | ||
The COG has collaborated with adult cancer cooperative groups for the treatment of patients with Hodgkin lymphoma. In these trials, risk stratification is similar to that of adult patients (i.e., early stage [stage I/II] and advanced stage [stage III/IV]).
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.[4]
Risk classification may be further refined by assessing response after initial cycles of chemotherapy or at the completion of chemotherapy.
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.[28,29]; [14][Level of evidence B4]
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 tumor 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.[7,30,31]
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.[28,29,31,32]
The significance of new pulmonary lesions found on CT scan at the time of interim analysis was evaluated in a retrospective study of 1,300 patients enrolled in the EuroNet-PHL-C1 trial. New nodules were common (119 patients; 9.2%) and most (97%) were smaller than 10 mm. These nodules occurred regardless of initial lung involvement or whether a patient had a relapse. Of the 119 patients with new lung lesions, 17 (14%) subsequently had a relapse or progression. Of these patients, 11 patients had relapse staging imaging available for central review. In all 11 patients, the new lesions seen at interim analysis had all resolved on relapse staging. New lung lesions occurred in 102 patients (7.8%) without subsequent relapse. The authors concluded that most new nodules at interim staging are likely not malignant and require no further action.[33]
Several studies have evaluated the use of interim response to titrate additional therapy:
The EuroNet Hodgkin lymphoma trials use a similar early response assessment definition of PET positivity, which is a Deauville score of greater than 3 after two cycles of vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin) (OEPA).[34]
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:
Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:
For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Children and adolescents with Hodgkin lymphoma have achieved long-term survival rates after treatment with radiation therapy, multiagent chemotherapy, and combined-modality therapy. In select cases of localized nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), complete surgical resection may be curative and obviate the need for cytotoxic therapy.
Treatment options for children and adolescents with Hodgkin lymphoma include the following:
MOPP-related sequelae include a dose-related risk of infertility and subsequent myelodysplasia and leukemia.[2,9] The use of MOPP-derivative regimens substituting less leukemogenic and gonadotoxic alkylating agents (e.g., cyclophosphamide) for mechlorethamine or restricting cumulative alkylating agent dose exposure reduces this risk.[10] However, COPP-based regimens (substituting cyclophosphamide for mechlorethamine) are not commonly used in contemporary treatment protocols because of the restricted availability of procarbazine in many parts of the world.
ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin.[11-13] The cumulative dose of these agents has been proactively restricted in pediatric patients to reduce this risk.
In an effort to reduce chemotherapy-related toxicity, hybrid regimens alternating MOPP and ABVD or derivative therapy were developed. They use lower total cumulative doses of alkylators, doxorubicin, and bleomycin.[14,15]
With the use of a cardioprotectant and replacing bleomycin with other agents, ABVD-based regimens are being used more in pediatric patients.[16]
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.[18,19]
Contemporary treatment of 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 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.[26][Level of evidence B4] The risk of relapse was 25% in patients with an effusion, compared with less than 15% in patients without an effusion. Patients with effusions were more often older (15 years vs. 14 years) and had nodular-sclerosing histology.
Localized disease (stages I, II, and IIIA) with unfavorable features may be treated similarly to advanced-stage disease in some treatment protocols or treated with therapy of intermediate intensity.[25]
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 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 have and are also testing the efficacy of regimens integrating novel, potentially less-toxic agents such as brentuximab vedotin and immune modulating therapies such as checkpoint inhibitors.[30]
The use of combination chemotherapy and/or radiation therapy can produce excellent long-term progression-free survival (PFS) and OS in patients with NLPHL.[27,31,32] Late recurrences have been reported and are typically responsive to re-treatment. Because deaths observed among individuals with this histological subtype are frequently related to complications from cytotoxic therapy or transformation to non-Hodgkin lymphoma, risk-adapted treatment assignment is particularly important for limiting exposure to agents with established dose-related toxicities.[31,32]
Histological subtype may direct therapy in patients with stage I, completely resected NLPHL, whose initial treatment may be surgery alone.[27]
Evidence (surgery alone for localized NLPHL):
Advanced-stage NLPHL 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 NLPHL with unfavorable characteristics):
Retrospective case series report on responses with rituximab alone [37] or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [38] in adults with NLPHL. However, pediatric data have not been reported.
A summary of treatment approaches for NLPHL 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.[27,28,33,39] In patients with NLPHL, transformation to aggressive large B-cell lymphoma rarely occurs. When it does, it substantially increases the risk of mortality.[40] In adults with NLPHL, a variant immunoarchitectural pattern has been associated with a higher risk of progression to aggressive lymphoma and more advanced disease.[41] Among long-term survivors of NLPHL, death is more likely to result from treatment-related toxicity (both acute and long-term) than from lymphoma.[42,43]
In addition to variable responses by histology for NLPHL, 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). This EFS rate was significantly better than the 75.8% EFS rate for patients who had nodular-sclerosing histology (P = .008).[44]
As previously mentioned, most newly diagnosed children are treated with risk-adapted chemotherapy, either alone or in combination with consolidative radiation therapy. Radiation therapy volumes can vary and have 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.[45]
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.[46]
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 (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.[51] Ongoing studies seek to determine whether doses to other critical organs, such as the heart and lungs, can be reduced with proton therapy, without compromising survival outcomes.[52][Level of evidence C1] Long-term results are pending.
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.[45,50] For example, in the AHOD0031 trial, radiation therapy was given to involved sites at diagnosis,[20] but in the AHOD1331 trial, it was given to bulky mediastinal disease and to slow responding disease sites (based on interim PET scan).[53] There is emerging evidence for omitting radiation therapy entirely in patients who have a complete, PET-based response. Thus, in the S1826 trial, radiation therapy was given only to patients with residual, metabolically active posttherapy sites as defined on PET.[30]
The dose of radiation also varies and is often protocol specific.
General considerations regarding radiation dose include the following:
Technical considerations for the use of radiation therapy to treat Hodgkin lymphoma include the following:
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 was 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.[24]
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 patients with rapid responses who were randomly assigned to IFRT versus 84.3% (P = .11) for patients with rapid responses who were not assigned to IFRT. The OS rate was 98.8% in both groups.[20] In a subset analysis of patients with anemia and bulky limited-stage disease, the EFS rate was 89.3% for patients with rapid early responses or complete remissions who received IFRT, compared with 77.9% for patients who did not receive IFRT (P = .019).[57][Level of evidence B1]
Adjuvant radiation therapy may be associated with an increased risk of late effects or mortality.[58]
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.
Many chemotherapy combinations have been used to effectively treat pediatric patients with Hodgkin lymphoma. Many of the agents in original MOPP and ABVD regimens continue to be used. 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. Current treatment approaches for pediatric patients with Hodgkin lymphoma use procarbazine-free standard backbone regimens, such as ABVE-PC in North America [20,21] and OEPA-COPDAC in Europe.[22] Both of these regimens represent dose-dense therapies that use six drugs to maximize intensity without exceeding thresholds of toxicity. In North America, pediatric patients with Hodgkin lymphoma are treated with ABVD-based regimens. However, bleomycin has been replaced by other agents (i.e., brentuximab vedotin or nivolumab), and the cardioprotectant dexrazoxane has been used to reduce the risk of late effects.
Combination chemotherapy regimens used in trials are summarized in Table 6.
| Name | Drugs | Dosage | Route | Days |
|---|---|---|---|---|
| IV = intravenous; PO = oral. | ||||
| aABVE-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. | ||||
| COPDAC [22] | Cyclophosphamide | 600 mg/m2 | IV | 1, 8 |
| Vincristine (Oncovin) | 1.4 mg/m2 | IV | 1, 8 | |
| Prednisone | 40 mg/m2 | PO | 1–15 | |
| Dacarbazine | 250 mg/m2 | IV | 1–3 | |
| CAPDAC [63] | Brentuximab vedotin substituted for vincristine in COPDAC | 1.2 mg/kg | IV | 1, 8 |
| OEPA [22] | 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 [63] | Brentuximab vedotin substituted for vincristine in OEPA | 1.2 mg/kg | IV | 1, 8, 15 |
| ABVD [8] | 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 [30] | 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 | |
| ABVE-PCa [21] | 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) [53] | Brentuximab vedotin | 1.8 mg/kg | IV | 1 |
| Vincristine | 1.4 mg/m2 (maximum dose, 2.8 mg/m2) | IV | 8 | |
| BEACOPP [64] | 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 [65] | Cyclophosphamide | 500 mg/m2 | IV | 1 |
| Vinblastine | 6 mg/m2 | IV | 1, 8 | |
| Prednisolone | 40 mg/m2 | PO | 1–8 | |
| AV-PC [27,44] | 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 | |
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 whose disease 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.[54]
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:
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.
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 Rate (No. of Years of Follow-up) | Survival Rate (No. of Years of Follow-up) |
|---|---|---|---|---|---|
| CS = clinical stage; IFRT = involved-field radiation therapy; N/A = not applicable; No. = number. | |||||
| aFor more information about the chemotherapy regimens, see Table 6. | |||||
| bIncluded patients with nodular lymphocyte-predominant Hodgkin lymphoma. | |||||
| OEPA (2) [24] | IFRT (20–35) | I, IIA | 281 | 94% (5) | N/A |
| None | 113 | 97% (5) | |||
| ABVD [77] | IFRT (21–35) | I–IV | 209 | 85% (5) | 97% (5) |
| ABVE (2-4)b [66] | IFRT (25.5) | IA, IIA, IIIA1, without bulky disease | 51 | 91% (6) | 98% (6) |
| AV-PC [44] | None | IA, IIA, without bulky disease | 278 | 79.9% (4) | 99.6% (4) |
| Response-based IFRT (21) | |||||
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 Rate (No. of Years of Follow-up) | Survival Rate (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. | |||||
| aFor more information about the chemotherapy regimens, see Table 6. | |||||
| OEPA (2) + COPDAC (2) [22] | IFRT (20–35) | IE, IIB, IIEA, IIIA | 139 | 88.3% (5) | 98.5% (5) |
| ABVE-PC (3–5) [21] | IFRT (21) | IIA/IIIA, if bulky disease | 53 | 84% (5) | 95% (5) |
| ABVE-PC: RER/CR [20] | IFRT (21) | IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease | 380 | 87.9% (4) | 98.8% (4) |
| ABVE-PC: RER/CR [20] | None | IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease | 382 | 84.3% (4) | 98.8% (4) |
| ABVE-PC: SER: +DECA [20] | IFRT (21) | IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease | 153 | 79.3% (4) | 96.5% (4) |
| ABVE-PC: SER: -DECA [20] | IFRT (21) | 151 | 75.2% (4) | 94.3% (4) | |
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 Rate (No. of Years of Follow-up) | Survival Rate (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. | |||||
| aFor more information about the chemotherapy regimens, see Table 6. | |||||
| OEPA (2) + COPDAC (4) [22] | IFRT (20–35) | IIEB, IIIEA/B, IIIB, IVA/B | 239 | 86.9% (5) | 94.9% (5) |
| ABVE-PC (3-5) [21,78] | IFRT (21) | IIB, IIIB, IV | 163 | 85% (5) | 95% (5) |
| AEPA (2); CAPDAC (4) [63] | Individual residual nodal (25.5) | IIB, IIIB, IV | 77 | 97.4% (3) | 98.7% (3) |
| Bv-AVE-PC (5) [53] | ISRT | IIB + Bulk, IIIB, IV | 587 | 92.1% (3) | 99.3% (3) |
| N-AVD (6) [30] | None | III, IV | 489 total (120 aged 12–17 y) | PFS: 94% (1) | 99% (1) |
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
Table 10 summarizes the results of treatment approaches used for pediatric patients with NLPHL, 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 Rate (No. of Years of Follow-up) | Survival Rate (No. of Years of Follow-up) |
|---|---|---|---|---|
| IFRT = involved-field radiation therapy; N/A = not applicable; No. = number. | ||||
| aFor more information about the chemotherapy regimens, see Table 6. | ||||
| bSingle lymph node surgically resected. | ||||
| cAll involved lymph nodes surgically resected. | ||||
| CVP (3) [65] | None | 55 | 74% (5) | 100% (5) |
| Noneb [27] | Noneb | 52 | 77% (5) | 100% (5) |
| AV-PC [27] | None | 124 | 85.5% (5) | 100% (5) |
| IFRT (21) | 11 | |||
| Nonec [28] | None | 51 | 67% (2) | 100% (2) |
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.[79,80] For more information, see Hodgkin Lymphoma Treatment. In late-health outcome studies of pediatric cancer survivors, the risk of anthracycline cardiomyopathy has been shown to exponentially increase after exposure to cumulative anthracycline doses of 250 to 300 mg/m2.[81,82] Subsequent need for mediastinal radiation can further enhance the risk of several late cardiac events.[83] In an effort to optimize disease control and preserve both cardiac and gonadal function, pediatric regimens for low-risk disease most often feature a restricted number of cycles of ABVD derivative combinations. For those with intermediate-risk and high-risk disesase, alkylating agents and etoposide are integrated into anthracycline-containing regimens.
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.[84]
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 NCI website.
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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.[1]
Adverse prognostic factors after relapse include the following:[2][Level of evidence C1]
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.[6,7]
Treatment options for children and adolescents with refractory or recurrent Hodgkin lymphoma include the following:
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.
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):
The FDA approved nivolumab for 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.[29,32]
Evidence (pembrolizumab):
The FDA approved pembrolizumab for use in patients with refractory disease or relapse after three or more lines of therapy.
Trials are ongoing to determine the toxicity and efficacy of combining and/or comparing brentuximab vedotin and nivolumab with chemotherapy in pediatric patients with Hodgkin lymphoma.
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.[8,36-38]; [39,40][Level of evidence C1] This approach is also recommended for patients who have recurrent, extensive disease after the first year of completing therapy or for those with recurrent disease after initial therapy that included intensive (alkylating agents and anthracyclines) multiagent chemotherapy and radiation 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 (PET) scan before autologous HSCT.[2,42,43,45,51,52]
For more information about transplant, see Pediatric Autologous Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.
For patients who do not improve after autologous HSCT and patients with chemoresistant disease, allogeneic HSCT has been used with encouraging results.[15,41,53] Investigations of reduced-intensity allogeneic transplant that typically use fludarabine or low-dose total body irradiation to provide a nontoxic immunosuppression have demonstrated acceptable rates of TRM.[54-57]
For more information about transplant, see Pediatric Allogeneic Hematopoietic Stem Cell Transplant and Pediatric Hematopoietic Stem Cell Transplant and Cellular Therapy for Cancer.
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.[58] For patients who are not responsive to salvage therapy, ISRT may be considered before HSCT.[59,60] Consolidative ISRT is particularly appropriate in the following situations:[1]
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):
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.[23][Level of evidence B4]
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
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 bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine.[64] Treated patients had a median of seven previous lines of therapy, including brentuximab vedotin, checkpoint inhibitors, and autologous and allogeneic HSCTs. The overall response rate was 72% for the 32 patients with active disease who received fludarabine-based lymphodepletion. For all evaluable patients, the 1-year PFS rate was 36%, and the OS rate was 94%. The CD30 CAR T-cell therapy was well tolerated.
A number of clinical trials of anti-CD30 CAR T-cell therapy for patients with relapsed Hodgkin lymphoma are listed on ClinicalTrials.gov. The following is an example of a national and/or institutional clinical trial that is currently enrolling patients younger than 18 years:
Anti–PD-1 antibodies being studied in children with Hodgkin lymphoma include the following:
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
Childhood and adolescent survivors of Hodgkin lymphoma may be at risk of developing numerous late complications of treatment related to radiation, specific chemotherapeutic exposures, and surgical staging.[1,2] Adverse treatment effects may impact the following:
In the past 30 to 40 years, pediatric Hodgkin lymphoma therapy has changed dramatically to 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.[3]
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 this topic, 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 |
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.
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 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.
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.[21]
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).[22] Risk factors for the development of thyroid nodules in Hodgkin lymphoma survivors reported by CCSS include time since diagnosis of more than 10 years (RR, 4.8; 95% confidence interval [CI], 3.0–7.8), female sex (RR, 4.0; 95% CI, 2.5–6.7), and radiation dose to thyroid higher than 25 Gy (RR, 2.9; 95% CI, 1.4–6.9).[22] The absolute risk of thyroid cancer is relatively low, with approximately 1% of the CCSS Hodgkin cohort developing thyroid cancer, with a median follow-up of approximately 15 years.[22]
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.[24]
For more information, see the Thyroid Gland section in Late Effects of Treatment for Childhood Cancer summary.
Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk of long-term cardiac toxicity. The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. The pathogenesis of injury differs, however, with radiation primarily affecting the fine vasculature of the heart and anthracyclines directly damaging myocytes.[25-27]
Survivors of childhood Hodgkin lymphoma older than 50 years 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. Also, survivors have one severe, life-threatening, or fatal cardiovascular condition, on average.[28]
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.[29]
Applying a model to predict late cardiac toxic effects of therapy, patients with intermediate- and high-risk Hodgkin lymphoma who were treated in four consecutive COG trials between 2002 and 2020 were assessed for risk of grade 3 to grade 5 cardiac disease at 30 years after completion of therapy. Over this time period, the percentage of patients who received mediastinal radiation therapy decreased from 50% to less than 1%, which led to lower cardiac radiation exposure. Anthracycline doses increased from 200 mg/m2 to 300 mg/m2. However, use of the cardioprotectant dexrazoxane increased from 0% to 80%. The results demonstrated the predicted risk of grade 3 to grade 5 cardiac disease at 30 years will decrease from 10% to 6%, which would be highly statistically significant. The 6% incidence of cardiac disease is similar to the predicted 5% incidence for the general population, which questions the necessity of current long-term cardiac monitoring guidelines.[30]
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.
For more information, see the Late Effects of the Cardiovascular System section in Late Effects of Treatment for Childhood Cancer.
Series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published.[46-53]; [54][Level of evidence C1] Many of the patients included in these series received high-dose radiation therapy and high-dose alkylating agent chemotherapy regimens, which are no longer used.
Subsequent hematological malignancy is related to the use of alkylating agents, anthracyclines, and etoposide and exhibit a brief latency period (<10 years from the primary cancer).[57] This excess risk is largely related to cases of myelodysplasia and subsequent AML.
A single-study experience suggests that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity.[43]
Clinical trials using dexrazoxane in childhood leukemia have not observed an excess risk of subsequent neoplasms.[43,58,59]
Chemotherapy-related myelodysplasia and AML are less prevalent after contemporary therapy because of the restriction of cumulative alkylating agent doses.[60,61]
Among 1,711 intermediate-risk Hodgkin lymphoma survivors treated with response-adapted therapy in the COG AHOD0031 (NCT00025259) trial (median follow-up, 7.3 years), the 10-year cumulative incidence of subsequent malignancy was 1.3%, and the cumulative incidence of secondary myelodysplastic syndrome or AML was 0.2%. Of the three cases of secondary AML, the median time to onset was 2 years (range, 1.8–2.7 years).[62]
Solid neoplasms most often involve the skin, breast, thyroid, gastrointestinal tract, lung, and head and neck, with risk increasing with radiation dose.[51,53,63]; [54][Level of evidence C1] The risk of a solid subsequent neoplasm escalates with the passage of time after diagnosis of Hodgkin lymphoma, with a latency of 20 years or more. For more information about subsequent thyroid neoplasms, see the Thyroid Abnormalities section.
Breast cancer is the most common therapy-related, solid, subsequent neoplasm after treatment of 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):
Hereditary syndromes, other than high-risk breast cancer syndromes, and pathogenic variants may modify the effect of radiation exposure on breast cancer risk after childhood cancer.[79,80]
A study of women survivors who received chest radiation for Hodgkin lymphoma showed that one of the most important factors in obtaining breast cancer screenings per guidelines was recommendation from their treating physician.[81] Standard guidelines for routine breast screening are available. The COG guidelines recommend annual screening with magnetic resonance imaging and mammography for women beginning 8 years after treatment or at age 25 years, whichever is later.[81]
For more information, see the Subsequent Neoplasms section in Late Effects of Treatment for Childhood Cancer.
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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.
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/child-hodgkin-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389170]
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