Childhood Hodgkin Lymphoma Treatment – Health Professional Version

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For Hodgkin lymphoma, the 5-year survival rate has increased over the same time from 81% to more than 95% for children and adolescents.[1] Childhood and adolescent cancer survivors require close monitoring because late effects of cancer therapy may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Overview of Childhood Hodgkin Lymphoma

Childhood Hodgkin lymphoma is one of the few pediatric malignancies that shares aspects of its biology and natural history with an adult cancer. When treatment approaches for children were modeled after those used for adults, substantial morbidities resulted from the unacceptably high radiation doses. Thus, new strategies utilizing chemotherapy and lower-dose radiation were developed. Approximately 90% to 95% of children with Hodgkin lymphoma can be cured, prompting increased attention to devising therapy that lessens long-term morbidity for these patients. Contemporary treatment programs use a risk-based and response-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field or involved-site radiation therapy. Prognostic factors used in determining chemotherapy intensity include stage, presence or absence of B symptoms (fever, weight loss, and night sweats), and/or bulky disease.

Epidemiology

Hodgkin lymphoma comprises 6% of childhood cancers. In the United States, the incidence of Hodgkin lymphoma is age related and is highest among adolescents aged 15 to 19 years (29 cases per 1 million per year), with children ages 10 to 14 years, 5 to 9 years, and 0 to 4 years having approximately threefold, eightfold, and 30-fold lower rates, respectively.[2] In developing countries, there is a similar rate in young adults but a much higher incidence in childhood.[3]

Hodgkin lymphoma has the following unique epidemiological features:

• Hodgkin lymphoma has a bimodal age distribution that differs geographically and ethnically in industrialized countries; the early peak occurs in the middle-to-late 20s and the second peak after age 50 years. In developing countries, the early peak occurs before adolescence.[4]
• The male-to-female ratio varies markedly by age. Children younger than 5 years show a strong male predominance (M:F = 5.3) and children aged 15 to 19 years show a slight female predominance (M:F = 0.8).[5,6]
• There are three distinct forms of Hodgkin lymphoma:
  • Childhood form—occurs in individuals aged 14 years and younger. The childhood form of Hodgkin lymphoma increases in prevalence in association with larger family size and lower socioeconomic status.[4] Early exposure to common infections in early childhood appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity.[7,8]
  • Young adult form—affects individuals aged 15 to 34 years. The young adult form is associated with a higher socioeconomic status in industrialized countries, increased sibship size, and earlier birth order.[9] The lower risk of Hodgkin lymphoma observed in young adults with multiple older, but not younger, siblings, is consistent with the hypothesis that early exposure to viral infection (which the siblings bring home from school, for example) may play a role in the pathogenesis of the disease.[7]
  • Older adult form—most commonly presents in individuals aged 55 to 74 years.
• A family history of Hodgkin lymphoma in siblings or parents has been associated with an increased risk of this disease.[10,11] In a population-based study that evaluated risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex, the cumulative risk of Hodgkin lymphoma was 0.6%, representing a 3.3-fold increased risk compared with the general population risk.[12] The risk in siblings was significantly higher than the risk in parents and/or offspring. The risk in sisters was higher than the risk in brothers or siblings of opposite sex. The lifetime risk of Hodgkin lymphoma was higher when first-degree relatives were diagnosed before age 30 years.

Epstein-Barr virus and Hodgkin lymphoma

Epstein-Barr virus (EBV) has been implicated in the causation of Hodgkin lymphoma. A large proportion of patients with Hodgkin lymphoma have high EBV titers, suggesting that an enhanced activation of EBV may precede the development of Hodgkin lymphoma in some patients. EBV genetic material can be detected in Reed-Sternberg cells from some patients with Hodgkin lymphoma.

The incidence of EBV-associated Hodgkin lymphoma also shows the following distinct epidemiological features:

• EBV positivity is most commonly observed in tumors with mixed-cellularity histology and is almost never seen in patients with lymphocyte-predominant histology.[13,14]
• EBV positivity is more common in children younger than 10 years than in adolescents and young adults.[13,14]
• The incidence of EBV tumor cell positivity for Hodgkin lymphoma in developed countries ranges from 15% to 25% in adolescents and young adults.[13–15] A high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma is seen in developing countries, and these cases are generally EBV-positive (approximately 80%).[16]

EBV serologic status is not a prognostic factor for failure-free survival in pediatric and young adult Hodgkin lymphoma patients,[13–15,17,18] but plasma EBV DNA has been associated with an inferior outcome in adults.[19] Patients with a previous history of serologically confirmed infectious mononucleosis have a fourfold increased risk of developing EBV-positive Hodgkin lymphoma; these patients are not at increased risk for EBV-negative Hodgkin lymphoma.[20]

Immunodeficiency and Hodgkin lymphoma

Among individuals with immunodeficiency, the risk of Hodgkin lymphoma is increased, although it is not as high as the risk of non-Hodgkin lymphoma.

Characteristics of Hodgkin lymphoma presenting in the context of immunodeficiency are as follows:

• Hodgkin lymphoma usually occurs at a younger age and with histologies other than nodular sclerosing in patients with primary immunodeficiencies.[21]
• The risk of Hodgkin lymphoma increases as much as 50-fold over the general population in patients with autoimmune lymphoproliferative syndrome.[22]
• Although it is not an AIDS-defining malignancy, the incidence of Hodgkin lymphoma appears to be increased in HIV-infected individuals, including children.[23,24]

Clinical Presentation

The following presenting features of Hodgkin lymphoma result from direct or indirect effects of nodal or extranodal involvement and/or constitutional symptoms related to cytokine release from Reed-Sternberg cells.

• Approximately 80% of patients present with painless adenopathy, most commonly involving the supraclavicular or cervical area.
• Mediastinal disease is present in about 75% of adolescents and young adults and may be asymptomatic. In contrast, only about 35% of young children with Hodgkin lymphoma have mediastinal involvement, in part, reflecting the tendency of these patients to have either mixed cellularity or lymphocyte-predominant histology.
• Fifteen percent to 20% of patients will have noncontiguous extranodal involvement (stage IV). The most common sites of extranodal involvement are the lung, liver, bones, and bone marrow.[25,26]
• Nonspecific constitutional symptoms including fatigue, anorexia, weight loss, pruritus, night sweats, and fever occur in approximately 25% of patients.[25,26]
• Three specific constitutional (B) symptoms that have been correlated with prognosis—unexplained fever (temperature above 38.0°C orally), unexplained weight loss (10% of body weight within the 6 months preceding diagnosis), and drenching night sweats—are commonly used to assign risk in clinical trials.[27]

Prognostic Factors

As the treatment of Hodgkin lymphoma improved, factors associated with outcome became more difficult to identify. Several factors, however, continue to influence the success and choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and biologic aggressiveness are frequently collinear.

Pretreatment factors associated with an adverse outcome in one or more studies include the following:

• Advanced stage of disease.[28]
• Presence of B symptoms.[25,26]
• Presence of bulky disease.[25]
• Extranodal extension.
• Elevated erythrocyte sedimentation rate.
• Leukocytosis (white blood cell count of 11,500/mm3 or higher).[28]
• Anemia (hemoglobin lower than 11.0 g/dL).
• Male sex.[26,28]
• Response to initial treatment with chemotherapy.[29,30]

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

• In the Society for Paediatric Oncology and Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]) GPOH-95 study, B symptoms, histology, and male sex were adverse prognostic factors for event-free survival on multivariate analysis.[26]
• In 320 children with clinically staged Hodgkin lymphoma treated in the Stanford-St. Jude-Dana Farber Cancer Institute consortium, male sex; stage IIB, IIIB, or IV disease; white blood cell count of 11,500/mm3 or higher; and hemoglobin lower than 11.0 g/dL were significant prognostic factors for inferior disease-free survival and overall survival (OS). Prognosis was also associated with the number of adverse factors.[28]
• In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome.[25]
• One single-institutional study showed that African American patients had a higher relapse rate than did white patients, but OS was similar.[31]

The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important and is being used in the research setting to determine subsequent therapy.[29,30,32] Positron emission tomography (PET) scanning is being evaluated as a method to assess early response in pediatric Hodgkin lymphoma.[33] Fluorine F 18-fludeoxyglucose PET avidity after two cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[34–36] Further studies in children are required to assess the role of early response based on PET. The value of PET avidity to predict outcome and whether improved outcome can be achieved by altering the therapeutic strategy on the basis of early PET response is to be determined.

Prognostic factors will continue to change because of risk stratification and choice of therapy, with parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy used to stratify therapeutic assignment.

References

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
2. Ries LAG, Harkins D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2003. Bethesda, Md: National Cancer Institute, 2006. Also available online. Last accessed August 30, 2017.
3. Macfarlane GJ, Evstifeeva T, Boyle P, et al.: International patterns in the occurrence of Hodgkin’s disease in children and young adult males. Int J Cancer 61 (2): 165-9, 1995. [PUBMED Abstract]
4. Grufferman S, Delzell E: Epidemiology of Hodgkin’s disease. Epidemiol Rev 6: 76-106, 1984. [PUBMED Abstract]
5. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review 1973-1995. Bethesda, Md: National Cancer Institute, 1998. Also available online. Last accessed August 30, 2017.
6. Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 35-50. Also available online. Last accessed August 02, 2017.
7. Chang ET, Montgomery SM, Richiardi L, et al.: Number of siblings and risk of Hodgkin’s lymphoma. Cancer Epidemiol Biomarkers Prev 13 (7): 1236-43, 2004. [PUBMED Abstract]
8. Rudant J, Orsi L, Monnereau A, et al.: Childhood Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and factors related to the immune system: the Escale Study (SFCE). Int J Cancer 129 (9): 2236-47, 2011. [PUBMED Abstract]
9. Westergaard T, Melbye M, Pedersen JB, et al.: Birth order, sibship size and risk of Hodgkin’s disease in children and young adults: a population-based study of 31 million person-years. Int J Cancer 72 (6): 977-81, 1997. [PUBMED Abstract]
10. Crump C, Sundquist K, Sieh W, et al.: Perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood. Am J Epidemiol 176 (12): 1147-58, 2012. [PUBMED Abstract]
11. Linabery AM, Erhardt EB, Richardson MR, et al.: Family history of cancer and risk of pediatric and adolescent Hodgkin lymphoma: A Children’s Oncology Group study. Int J Cancer 137 (9): 2163-74, 2015. [PUBMED Abstract]
12. Kharazmi E, Fallah M, Pukkala E, et al.: Risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex: a joint study from five Nordic countries. Blood 126 (17): 1990-5, 2015. [PUBMED Abstract]
13. Claviez A, Tiemann M, Lüders H, et al.: Impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin’s lymphoma. J Clin Oncol 23 (18): 4048-56, 2005. [PUBMED Abstract]
14. Lee JH, Kim Y, Choi JW, et al.: Prevalence and prognostic significance of Epstein-Barr virus infection in classical Hodgkin’s lymphoma: a meta-analysis. Arch Med Res 45 (5): 417-31, 2014. [PUBMED Abstract]
15. Jarrett RF, Stark GL, White J, et al.: Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based study. Blood 106 (7): 2444-51, 2005. [PUBMED Abstract]
16. Chabay PA, Barros MH, Hassan R, et al.: Pediatric Hodgkin lymphoma in 2 South American series: a distinctive epidemiologic pattern and lack of association of Epstein-Barr virus with clinical outcome. J Pediatr Hematol Oncol 30 (4): 285-91, 2008. [PUBMED Abstract]
17. Armstrong AA, Alexander FE, Cartwright R, et al.: Epstein-Barr virus and Hodgkin’s disease: further evidence for the three disease hypothesis. Leukemia 12 (8): 1272-6, 1998. [PUBMED Abstract]
18. Herling M, Rassidakis GZ, Vassilakopoulos TP, et al.: Impact of LMP-1 expression on clinical outcome in age-defined subgroups of patients with classical Hodgkin lymphoma. Blood 107 (3): 1240; author reply 1241, 2006. [PUBMED Abstract]
19. Kanakry JA, Li H, Gellert LL, et al.: Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood 121 (18): 3547-53, 2013. [PUBMED Abstract]
20. Hjalgrim H, Askling J, Rostgaard K, et al.: Characteristics of Hodgkin’s lymphoma after infectious mononucleosis. N Engl J Med 349 (14): 1324-32, 2003. [PUBMED Abstract]
21. Robison LL, Stoker V, Frizzera G, et al.: Hodgkin’s disease in pediatric patients with naturally occurring immunodeficiency. Am J Pediatr Hematol Oncol 9 (2): 189-92, 1987. [PUBMED Abstract]
22. Straus SE, Jaffe ES, Puck JM, et al.: The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis. Blood 98 (1): 194-200, 2001. [PUBMED Abstract]
23. Biggar RJ, Jaffe ES, Goedert JJ, et al.: Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108 (12): 3786-91, 2006. [PUBMED Abstract]
24. Biggar RJ, Frisch M, Goedert JJ: Risk of cancer in children with AIDS. AIDS-Cancer Match Registry Study Group. JAMA 284 (2): 205-9, 2000. [PUBMED Abstract]
25. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002. [PUBMED Abstract]
26. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin’s disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001. [PUBMED Abstract]
27. Gobbi PG, Cavalli C, Gendarini A, et al.: Reevaluation of prognostic significance of symptoms in Hodgkin’s disease. Cancer 56 (12): 2874-80, 1985. [PUBMED Abstract]
28. Smith RS, Chen Q, Hudson MM, et al.: Prognostic factors for children with Hodgkin’s disease treated with combined-modality therapy. J Clin Oncol 21 (10): 2026-33, 2003. [PUBMED Abstract]
29. Landman-Parker J, Pacquement H, Leblanc T, et al.: Localized childhood Hodgkin’s disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90. J Clin Oncol 18 (7): 1500-7, 2000. [PUBMED Abstract]
30. Friedman DL, Chen L, Wolden S, et al.: Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children’s Oncology Group Study AHOD0031. J Clin Oncol 32 (32): 3651-8, 2014. [PUBMED Abstract]
31. Metzger ML, Castellino SM, Hudson MM, et al.: Effect of race on the outcome of pediatric patients with Hodgkin’s lymphoma. J Clin Oncol 26 (8): 1282-8, 2008. [PUBMED Abstract]
32. Weiner MA, Leventhal B, Brecher ML, et al.: Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin’s disease in pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 15 (8): 2769-79, 1997. [PUBMED Abstract]
33. Ilivitzki A, Radan L, Ben-Arush M, et al.: Early interim FDG PET/CT prediction of treatment response and prognosis in pediatric Hodgkin disease-added value of low-dose CT. Pediatr Radiol 43 (1): 86-92, 2013. [PUBMED Abstract]
34. Hutchings M, Loft A, Hansen M, et al.: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107 (1): 52-9, 2006. [PUBMED Abstract]
35. Gallamini A, Hutchings M, Rigacci L, et al.: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin’s lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25 (24): 3746-52, 2007. [PUBMED Abstract]
36. Dann EJ, Bar-Shalom R, Tamir A, et al.: Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 109 (3): 905-9, 2007. [PUBMED Abstract]

Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Reed-Sternberg cells) or large mononuclear cell variants (lymphocytic and histiocytic cells) in a background of inflammatory cells consisting of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts. The inflammatory cells are present in different proportions depending on the histologic subtype. It has been conclusively shown that Reed-Sternberg cells and/or lymphocytic and histiocytic cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from germinal center B cells.[1,2] The histologic features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines, chemokines, and products of the tumor necrosis factor receptors (TNF-R) family secreted by the Reed-Sternberg cells.[3]

The hallmark of Hodgkin lymphoma is the Reed-Sternberg cell and its variants,[4] which have the following features:

Hodgkin lymphoma can be divided into the following two broad pathologic classes:[9,10]

Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma is divided into the following four subtypes:

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

These subtypes are defined according to the number of Reed-Sternberg cells, characteristics of the inflammatory milieu, and the presence or absence of fibrosis.

Characteristics of the histological subtypes of classical Hodgkin lymphoma include the following:

• Lymphocyte-rich classical Hodgkin lymphoma may have a nodular appearance, but immunophenotypic analysis allows distinction between this form of Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma.[11] Lymphocyte-rich classical Hodgkin lymphoma cells express CD15 and CD30.
• Nodular sclerosis Hodgkin lymphoma histology accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents but only 55% of cases in younger children in the United States.[12] This subtype is distinguished by the presence of collagenous bands that divide the lymph node into nodules, which often contain an Reed-Sternberg cell variant called the lacunar cell. Some pathologists subdivide nodular sclerosis into two subgroups (NS-1 and NS-2) on the basis of the number of Reed-Sternberg cells present. Transforming growth factor-beta may be responsible for the fibrosis in the nodular sclerosis Hodgkin lymphoma subtype.

  A study of over 600 patients with nodular sclerosis Hodgkin lymphoma from three different university hospitals in the United States showed that two haplotypes in the HLA class II region correlated with a 70% increased risk of developing nodular sclerosis Hodgkin lymphoma.[13] Another haplotype was associated with a 60% decreased risk of developing Hodgkin lymphoma. It is hypothesized that these haplotypes are associated with atypical immune responses that predispose to Hodgkin lymphoma.

• Mixed-cellularity Hodgkin lymphoma is more common in young children than in adolescents and adults, with mixed-cellularity Hodgkin lymphoma accounting for approximately 20% of cases in children younger than 10 years, but only approximately 9% of older children and adolescents aged 10 to 19 years in the United States.[12] Reed-Sternberg cells are frequent in a background of abundant normal reactive cells (lymphocytes, plasma cells, eosinophils, and histiocytes). Interleukin-5 may be responsible for the eosinophilia in mixed-cellularity Hodgkin lymphoma. This subtype can be confused with non-Hodgkin lymphoma.
• Lymphocyte-depleted Hodgkin lymphoma is rare in children. It is common in adult patients with HIV. This subtype is characterized by the presence of numerous large, bizarre malignant cells, many Reed-Sternberg cells, and few lymphocytes. Diffuse fibrosis and necrosis are common. Many cases previously diagnosed as lymphocyte-depleted Hodgkin lymphoma are now recognized as diffuse large B-cell lymphoma, anaplastic large cell lymphoma, or nodular sclerosis classical Hodgkin lymphoma with lymphocyte depletion.[14]

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

The frequency of nodular lymphocyte-predominant Hodgkin lymphoma in the pediatric population ranges from 5% to 10% in different studies, with a higher frequency in children younger than 10 years compared with children aged 10 to 19 years.[12] Nodular lymphocyte-predominant Hodgkin lymphoma is most common in males younger than 18 years.[15,16] A comprehensive review of nodular lymphocyte-predominant Hodgkin lymphoma addressing biology, evaluation, and treatment has been published.[17]

Characteristics of nodular lymphocyte-predominant Hodgkin lymphoma include the following:

• Pediatric patients are more likely to have low-stage disease and no B symptoms or extranodal involvement than are adult patients.[16] Patients with nodular lymphocyte-predominant Hodgkin lymphoma generally present with localized, nonbulky, peripheral lymphadenopathy that rarely involves the mediastinum.[15] Almost all patients are asymptomatic.
• Nodular lymphocyte-predominant Hodgkin lymphoma is characterized by molecular and immunophenotypic evidence of B-lineage differentiation with the following distinctive features:
  • Nodular lymphocyte-predominant Hodgkin lymphoma is characterized by large cells with multilobed nuclei, referred to as popcorn cells. These cells express B-cell antigens, such as CD19, CD20, CD22, and CD79A, and are negative for CD15 and may or may not express CD30.[17]
  • The OCT-2 and BOB.1 oncogenes are both expressed in nodular lymphocyte-predominant Hodgkin lymphoma; they are not expressed in the cells of patients with classical Hodgkin lymphoma.[18]
  • Reliable discrimination from non-Hodgkin lymphoma is problematic in diffuse subtypes with lymphocytic and histiocytic cells set against a diffuse background of reactive T-cells.[19]
  • Nodular lymphocyte-predominant Hodgkin lymphoma can be difficult to distinguish from progressive transformation of germinal centers and/or T-cell–rich B-cell lymphoma.[20]
  • Histologic and immunophenotypic variants (including CD30 and immunoglobulin D expression) may impact event-free survival; this remains an active area of investigation.[21]
• Pediatric patients (aged <20 years) have better outcomes than do adult patients, even when controlled for other prognostic factors.[16] Chemotherapy and/or radiation therapy produce excellent long-term progression-free survival and overall survival in patients with nodular lymphocyte-predominant Hodgkin lymphoma; however, late recurrences have been reported up to 10 years after initial therapy.[22,23]; [24][Level of evidence: 2A]
• Deaths observed among individuals with nodular lymphocyte-predominant Hodgkin lymphoma are more frequently related to treatment complications and/or the development of subsequent neoplasms (including non-Hodgkin lymphoma) than in refractory disease, underscoring the importance of judicious use of chemotherapy and radiation therapy at initial presentation and after recurrent disease.[22,23]

References

1. Bräuninger A, Schmitz R, Bechtel D, et al.: Molecular biology of Hodgkin’s and Reed/Sternberg cells in Hodgkin’s lymphoma. Int J Cancer 118 (8): 1853-61, 2006. [PUBMED Abstract]
2. Mathas S: The pathogenesis of classical Hodgkin’s lymphoma: a model for B-cell plasticity. Hematol Oncol Clin North Am 21 (5): 787-804, 2007. [PUBMED Abstract]
3. Re D, Küppers R, Diehl V: Molecular pathogenesis of Hodgkin’s lymphoma. J Clin Oncol 23 (26): 6379-86, 2005. [PUBMED Abstract]
4. Küppers R, Schwering I, Bräuninger A, et al.: Biology of Hodgkin’s lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002. [PUBMED Abstract]
5. Portlock CS, Donnelly GB, Qin J, et al.: Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin’s disease. Br J Haematol 125 (6): 701-8, 2004. [PUBMED Abstract]
6. von Wasielewski R, Mengel M, Fischer R, et al.: Classical Hodgkin’s disease. Clinical impact of the immunophenotype. Am J Pathol 151 (4): 1123-30, 1997. [PUBMED Abstract]
7. Tzankov A, Zimpfer A, Pehrs AC, et al.: Expression of B-cell markers in classical Hodgkin lymphoma: a tissue microarray analysis of 330 cases. Mod Pathol 16 (11): 1141-7, 2003. [PUBMED Abstract]
8. Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002. [PUBMED Abstract]
9. Pileri SA, Ascani S, Leoncini L, et al.: Hodgkin’s lymphoma: the pathologist’s viewpoint. J Clin Pathol 55 (3): 162-76, 2002. [PUBMED Abstract]
10. Harris NL: Hodgkin’s lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999. [PUBMED Abstract]
11. Anagnostopoulos I, Hansmann ML, Franssila K, et al.: European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 96 (5): 1889-99, 2000. [PUBMED Abstract]
12. Bazzeh F, Rihani R, Howard S, et al.: Comparing adult and pediatric Hodgkin lymphoma in the Surveillance, Epidemiology and End Results Program, 1988-2005: an analysis of 21 734 cases. Leuk Lymphoma 51 (12): 2198-207, 2010. [PUBMED Abstract]
13. Cozen W, Li D, Best T, et al.: A genome-wide meta-analysis of nodular sclerosing Hodgkin lymphoma identifies risk loci at 6p21.32. Blood 119 (2): 469-75, 2012. [PUBMED Abstract]
14. Slack GW, Ferry JA, Hasserjian RP, et al.: Lymphocyte depleted Hodgkin lymphoma: an evaluation with immunophenotyping and genetic analysis. Leuk Lymphoma 50 (6): 937-43, 2009. [PUBMED Abstract]
15. Hall GW, Katzilakis N, Pinkerton CR, et al.: Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma – a Children’s Cancer and Leukaemia Group report. Br J Haematol 138 (6): 761-8, 2007. [PUBMED Abstract]
16. Gerber NK, Atoria CL, Elkin EB, et al.: Characteristics and outcomes of patients with nodular lymphocyte-predominant Hodgkin lymphoma versus those with classical Hodgkin lymphoma: a population-based analysis. Int J Radiat Oncol Biol Phys 92 (1): 76-83, 2015. [PUBMED Abstract]
17. Shankar A, Daw S: Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents–a comprehensive review of biology, clinical course and treatment options. Br J Haematol 159 (3): 288-98, 2012. [PUBMED Abstract]
18. Stein H, Marafioti T, Foss HD, et al.: Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97 (2): 496-501, 2001. [PUBMED Abstract]
19. Boudová L, Torlakovic E, Delabie J, et al.: Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma. Blood 102 (10): 3753-8, 2003. [PUBMED Abstract]
20. Kraus MD, Haley J: Lymphocyte predominance Hodgkin’s disease: the use of bcl-6 and CD57 in diagnosis and differential diagnosis. Am J Surg Pathol 24 (8): 1068-78, 2000. [PUBMED Abstract]
21. Untanu RV, Back J, Appel B, et al.: Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer 65 (1): , 2018. [PUBMED Abstract]
22. Chen RC, Chin MS, Ng AK, et al.: Early-stage, lymphocyte-predominant Hodgkin’s lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 28 (1): 136-41, 2010. [PUBMED Abstract]
23. Jackson C, Sirohi B, Cunningham D, et al.: Lymphocyte-predominant Hodgkin lymphoma–clinical features and treatment outcomes from a 30-year experience. Ann Oncol 21 (10): 2061-8, 2010. [PUBMED Abstract]
24. Appel BE, Chen L, Buxton AB, et al.: Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children’s Oncology Group. J Clin Oncol 34 (20): 2372-9, 2016. [PUBMED Abstract]

Staging and evaluation of disease status is undertaken at diagnosis and performed again early in the course of chemotherapy and at the end of chemotherapy.

Pretreatment Staging

The diagnostic and staging evaluation is a critical determinant in the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following:

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

Systemic symptoms

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

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

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

• Pruritus.
• Alcohol-induced nodal pain.

Physical examination

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

Laboratory studies

• Hematological and chemical blood parameters show nonspecific changes that may correlate with disease extent.
• Abnormalities of peripheral blood counts may include neutrophilic leukocytosis, lymphopenia, eosinophilia, and monocytosis.
• Acute-phase reactants such as the erythrocyte sedimentation rate and C-reactive protein, if abnormal at diagnosis, may be useful in follow-up evaluation.[1]

Anatomic imaging

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

Definition of bulky disease

Historically, the presence of bulky disease, especially mediastinal bulk, predicted an increased risk of local failure and resulted in the incorporation of bulk as an important factor in treatment assignment. The definition of bulk has varied across pediatric protocols and evolved over time with advances in diagnostic imaging technology. In North American protocols, the posteroanterior chest radiograph remains important because the criterion for bulky mediastinal lymphadenopathy is defined by the ratio of the diameter of the mediastinal lymph node mass to the maximal diameter of the rib cage on an upright chest radiograph; a ratio of 33% or higher is considered bulky. In contrast, the EuroNet-Pediatric Hodgkin Lymphoma Group defines mediastinal bulk by the volume of the largest contiguous lymph node mass being 200 mL or more on CT. These two definitions differ from the recently published consensus guidelines from the International Conference on Malignant Lymphomas Imaging Group (Lugano), where bulk is greater or equal to 10 cm unidimensionally on CT.[2]

The criteria for bulky peripheral (nonmediastinal) lymphadenopathy have also varied over the years per cooperative group study protocols (usually exceeding 4–6 cm), and this disease characteristic has not been consistently used for treatment stratification. In contemporary U.S. protocols, bulky peripheral lymphadenopathy is defined as greater than 6 cm, with aggregates measured transversely. In EuroNet protocols, it is defined as a volume of greater than 200 mL. In contrast to mediastinal bulk, this disease characteristic has not been consistently used for treatment stratification.

Criteria for lymphomatous involvement by CT

Defining strict CT size criteria for the establishment of lymphomatous nodal involvement is complicated by a number of factors, such as overlap between benign reactive hyperplasia and malignant lymphadenopathy and obliquity of node orientation to the scan plane. Additional difficulties more specific to children include greater variability of normal nodal size with body region and age and the frequent occurrence of reactive hyperplasia.

General concepts to consider in regard to defining lymphomatous involvement by CT include the following:

• Contiguous nodal clustering or matting is highly suggestive of lymphomatous involvement.
• Any focal mass lesion large enough to characterize in a visceral organ is considered lymphomatous involvement unless the imaging characteristics indicate an alternative etiology.
• Criteria for nodal involvement may vary by cooperative group or protocol.
  • Children’s Oncology Group (COG) and EuroNet protocols consider lymph nodes abnormal if the long axis is greater than 2.0 cm, regardless of the short axis and PET avidity. Lymph nodes with a long axis measuring between 1.0 cm and 2.0 cm are only considered abnormal if they are part of a conglomerate of nodes and are fluorine F 18-fludeoxyglucose (18F-FDG) PET positive.
  • In the Society for Paediatric Oncology and Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]) GPOH-HD-2002 study, nodal involvement was defined as node size greater than 2 cm in largest diameter. The node was not involved if it was less than 1 cm and was considered questionably involved if it was between 1 cm and 2 cm. The involvement decision was then based on all further clinical evidence available.[3]

Functional imaging

The recommended functional imaging procedure for initial staging is now PET, using the radioactive glucose analog, 18F-FDG.[4,5] 18F-FDG PET identifies areas of tumor with increased metabolic activity, specifically anaerobic glycolysis. PET-CT, which integrates functional and anatomic tumor characteristics, is often used for staging and monitoring of pediatric patients with Hodgkin lymphoma. Residual or persistent 18F-FDG avidity has been correlated with prognosis and the need for additional therapy in posttreatment evaluation.[6–9]

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

• Concordance between PET and CT data is generally high for nodal regions, but may be significantly lower for extranodal sites. In one study specifically analyzing pediatric Hodgkin lymphoma patients, assessment of initial staging comparing PET and CT data demonstrated concordance of approximately 86% overall. Concordance rates were significantly lower for the spleen, lung nodules, bone/bone marrow, and pleural and pericardial effusions.[10] A meta-analysis of nine clinical studies showed that PET-CT achieved high sensitivity (96.9%) and high specificity (99.7%) in detecting bone marrow involvement in newly diagnosed patients with Hodgkin lymphoma.[11]
• Integration of data acquired from PET scans can lead to changes in staging.[2,12]
• Staging criteria using PET and CT scan information is protocol dependent, but generally areas of PET positivity that do not correspond to an anatomic lesion by clinical examination or CT scan size criteria should be disregarded in staging.
• A suspected anatomic lesion that is PET-negative should not be considered involved unless proven by biopsy.

18F-FDG PET has limitations in the pediatric setting. Tracer avidity may be seen in a variety of nonmalignant conditions including thymic rebound commonly observed after completion of lymphoma therapy. 18F-FDG avidity in normal tissues, for example, brown fat of cervical musculature, may confound interpretation of the presence of nodal involvement by lymphoma.[4]

Establishing the Diagnosis of Hodgkin Lymphoma

After a careful physiologic and radiographic evaluation of the patient, the least invasive procedure should be used to establish the diagnosis of lymphoma. However, this should not be interpreted to mean that a needle biopsy is the optimal methodology. Small fragments of lymphoma tissue are often inadequate for diagnosis, resulting in the need for second procedures that delay the diagnosis.

Key issues to consider in choosing the diagnostic approach include the following:

• If possible, the diagnosis should be established by biopsy of one or more peripheral lymph nodes. Aspiration cytology alone is not recommended because of the lack of stromal tissue, the small number of cells present in the specimen, and the difficulty of classifying Hodgkin lymphoma into one of the subtypes.
• An image-guided biopsy may be used to obtain diagnostic tissue from intra-thoracic or intra-abdominal lymph nodes. On the basis of the involved sites of disease, alternative noninvasive procedures that may be considered include thoracoscopy, mediastinoscopy, and laparoscopy. Thoracotomy or laparotomy is rarely needed to access diagnostic tissue. The likelihood of obtaining sufficient tissue should be carefully considered when selecting a biopsy procedure.
• Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.[13] After careful planning with anesthesia, peripheral lymph node biopsy or image-guided core-needle biopsy of mediastinal lymph nodes may be feasible using light sedation and local anesthesia before proceeding to more invasive procedures.
• If airway compromise precludes the performance of a diagnostic operative procedure, preoperative treatment with steroids or low-dose, localized radiation therapy should be considered. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risks associated with general anesthesia or heavy sedation are alleviated. Treatment with steroids will make the PET-CT scan unreliable.
• Because bone marrow involvement is relatively rare in pediatric Hodgkin lymphoma patients, bilateral bone marrow biopsy should be performed only in patients with advanced disease (stage III or stage IV) and/or B symptoms.[14] In support of this, a meta-analysis of nine clinical studies including both pediatric and adult patients showed that PET-CT achieved high sensitivity (96.9%) and high specificity (99.7%) in detecting bone marrow involvement in newly diagnosed patients with Hodgkin lymphoma.[11] (Refer to the Stage Information for Adult HL section in the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) In a consensus statement based on these studies, this group no longer recommends bone marrow biopsy in the initial evaluation of adults with Hodgkin lymphoma, with PET-CT being used instead to identify bone marrow involvement.[2]

Ann Arbor Staging Classification for Hodgkin Lymphoma

Stage is determined by anatomic evidence of disease using CT scanning in conjunction with functional imaging. The staging classification used for Hodgkin lymphoma was adopted at the Ann Arbor Conference held in 1971 [15] and revised in 1989 (refer to Table 1).[16] Staging is independent of the imaging modality used.

Stage	Description
aReprinted with permission from AJCC: Hodgkin and non-Hodgkin lymphomas. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 607-11.[17]
I	Involvement of a single lymphatic site (i.e., nodal region, Waldeyer’s ring, thymus, or spleen) (I); or localized involvement of a single extralymphatic organ or site in the absence of any lymph node involvement (IE).
II	Involvement of two or more lymph node regions on the same side of the diaphragm (II); or localized involvement of a single extralymphatic organ or site in association with regional lymph node involvement with or without involvement of other lymph node regions on the same side of the diaphragm (IIE).
III	Involvement of lymph node regions on both sides of the diaphragm (III), which also may be accompanied by extralymphatic extension in association with adjacent lymph node involvement (IIIE) or by involvement of the spleen (IIIS) or both (IIIE,S).
IV	Diffuse or disseminated involvement of one or more extralymphatic organs, with or without associated lymph node involvement; or isolated extralymphatic organ involvement in the absence of adjacent regional lymph node involvement, but in conjunction with disease in distant site(s). Stage IV includes any involvement of the liver or bone marrow, lungs (other than by direct extension from another site), or cerebrospinal fluid.
Designations applicable to any stage
A	No symptoms.
B	Fever (temperature >38ºC), 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 pathologic proof of noncontiguous involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Current practice is to assign a clinical stage on the basis of findings of the clinical evaluation; however, pathologic confirmation of noncontiguous extralymphatic involvement is strongly suggested for assignment to stage IV.

Risk Stratification

After the diagnostic and staging evaluation data are acquired, patients are further classified into risk groups for the purposes of treatment planning. The classification of patients into low-, intermediate-, or high-risk categories varies considerably among the different pediatric research groups, and often even between different studies conducted by the same group, as summarized in Figure 1.[18]

Enlarge

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.[19,20]

Definitions for interim response are variable and protocol specific but can range from volume reductions of greater than 50% to the achievement of a complete response with a volume reduction of greater than 95% by anatomic imaging or resolution of 18F-FDG PET avidity.[3,21,22]

The rapidity of response to early therapy has been used in risk stratification to tailor therapy in an effort to augment therapy in higher-risk patients or to reduce the late effects while maintaining efficacy.[22–24]

Results of selected trials using interim response to titrate therapy

• The Pediatric Oncology Group used a response-based therapy approach consisting of dose-dense ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide-prednisone, cyclophosphamide) for intermediate-stage and advanced-stage patients, in combination with 21 Gy involved-field radiation therapy (IFRT).[22] The dose-dense approach permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response on CT imaging after three ABVE-PC cycles. Five-year event-free survival (EFS) was comparable for rapid early responders (86%; treated with three cycles of ABVE-PC) and slow early responders (83%; treated with five cycles of ABVE-PC). All patients received 21 Gy of regional radiation therapy.
• The Children’s Cancer Group (CCG) (CCG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) regimen followed by a sex-tailored consolidation for pediatric patients with stage IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[24] For rapid early responding girls, an additional four courses of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, vinblastine) (without IFRT) was given in an effort to reduce breast cancer risk. Rapid early responding boys received two cycles of ABVD followed by IFRT. Slow early responders received four additional courses of BEACOPP and IFRT. Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four BEACOPP cycles and 5-year EFS among the cohort was 94% (median follow-up, 6.3 years).
• The COG AHOD0031 (NCT00025259) trial also used interim response to titrate therapy. (Refer to the Results from selected clinical trials section of this summary for more information.)

End of chemotherapy response assessment

Restaging is carried out upon the completion of all planned initial chemotherapy and may be used to determine the need for consolidative radiation therapy. Key concepts to consider include the following:

• Defining complete response.
  • The International Working Group (IWG) defined complete response for adults with Hodgkin lymphoma in terms of complete metabolic response as assessed by 18F-FDG PET, even when a persistent mass is present.[25] These criteria were endorsed in the Lugano Classification, with the recommendation for using a 5-point scale in assessing response.[2,26] COG protocols have adopted this approach for defining complete response.
  • Previous studies have varied in the use of findings from clinical exam, anatomic imaging, and functional imaging to assess response. Although complete response can be defined as absence of disease by clinical examination and/or imaging studies, complete response in Hodgkin lymphoma trials is often defined by a greater than 80% reduction of disease and a change from initial positivity to negativity on functional imaging.[27] This definition is necessary in Hodgkin lymphoma because fibrotic residual disease is common, particularly in the mediastinum. In some studies, such patients are designated as having an unconfirmed complete response.
  • The Euronet Hodgkin lymphoma trials use a similar early response assessment definition of PET positivity, which is a Deauville score of greater than 3 after two cycles of OEPA (vincristine [Oncovin], etoposide, prednisone, doxorubicin [Adriamycin]). However, the definition for late response assessment after all chemotherapy is a Deauville score of greater than 1.[28]
  • The definition of complete response varies by protocol/cooperative group. GPOH studies use very stringent criteria that includes at least 95% reduction in tumor volume or less than 2 mL residual volume on CT, as patients achieving these metrics will have radiation therapy omitted.[3] This is in contrast to the COG AHOD1331 (NCT02166463) high-risk Hodgkin lymphoma initial therapeutics clinical trial, which uses 18F-FDG PET assessment graded by a 5-point visual scale or Deauville criteria after two chemotherapy cycles to define a rapid early-responding lesion for which radiation will be omitted. A mass of any size is permitted for a complete response designation if the PET is negative.
• Timing of PET scanning after completing therapy.
  • Timing of PET scanning after completing therapy is an important issue. For patients treated with chemotherapy alone, PET scanning is ideally performed a minimum of 3 weeks after the completion of therapy, while patients whose last treatment modality was radiation therapy should not undergo PET scanning until 8 to 12 weeks postradiation.[25]
  • A COG study evaluated surveillance CT and detection of relapse in intermediate-stage and advanced-stage Hodgkin lymphoma. Most relapses occurred within the first year after therapy or were detected based on symptoms, laboratory, or physical findings. The method of detection of late relapse, whether by imaging or clinical change, did not affect overall survival. Routine use of CT at the intervals used in this study did not improve outcome.[29] The concept of reduced frequency of imaging has been supported by other investigations.[30–32]
  • Caution should be used in making the diagnosis of relapsed or refractory disease based solely on anatomic and functional imaging because false-positive results are not uncommon.[33–35] Consequently, pathologic confirmation of refractory or recurrent disease is recommended before modification of therapeutic plans.

References

1. Haase R, Vilser C, Mauz-Körholz C, et al.: Evaluation of the prognostic meaning of C-reactive protein (CRP) in children and adolescents with classical Hodgkin’s lymphoma (HL). Klin Padiatr 224 (6): 377-81, 2012. [PUBMED Abstract]
2. Cheson BD, Fisher RI, Barrington SF, et al.: Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32 (27): 3059-68, 2014. [PUBMED Abstract]
3. Mauz-Körholz C, Hasenclever D, Dörffel W, et al.: Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin’s lymphoma: the GPOH-HD-2002 study. J Clin Oncol 28 (23): 3680-6, 2010. [PUBMED Abstract]
4. Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin’s lymphoma. Pediatr Radiol 34 (3): 190-8, 2004. [PUBMED Abstract]
5. Hernandez-Pampaloni M, Takalkar A, Yu JQ, et al.: F-18 FDG-PET imaging and correlation with CT in staging and follow-up of pediatric lymphomas. Pediatr Radiol 36 (6): 524-31, 2006. [PUBMED Abstract]
6. Naumann R, Vaic A, Beuthien-Baumann B, et al.: Prognostic value of positron emission tomography in the evaluation of post-treatment residual mass in patients with Hodgkin’s disease and non-Hodgkin’s lymphoma. Br J Haematol 115 (4): 793-800, 2001. [PUBMED Abstract]
7. Hutchings M, Loft A, Hansen M, et al.: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107 (1): 52-9, 2006. [PUBMED Abstract]
8. Lopci E, Burnelli R, Guerra L, et al.: Postchemotherapy PET evaluation correlates with patient outcome in paediatric Hodgkin’s disease. Eur J Nucl Med Mol Imaging 38 (9): 1620-7, 2011. [PUBMED Abstract]
9. Sucak GT, Özkurt ZN, Suyani E, et al.: Early post-transplantation positron emission tomography in patients with Hodgkin lymphoma is an independent prognostic factor with an impact on overall survival. Ann Hematol 90 (11): 1329-36, 2011. [PUBMED Abstract]
10. Robertson VL, Anderson CS, Keller FG, et al.: Role of FDG-PET in the definition of involved-field radiation therapy and management for pediatric Hodgkin’s lymphoma. Int J Radiat Oncol Biol Phys 80 (2): 324-32, 2011. [PUBMED Abstract]
11. Adams HJ, Kwee TC, de Keizer B, et al.: Systematic review and meta-analysis on the diagnostic performance of FDG-PET/CT in detecting bone marrow involvement in newly diagnosed Hodgkin lymphoma: is bone marrow biopsy still necessary? Ann Oncol 25 (5): 921-7, 2014. [PUBMED Abstract]
12. Cheng G, Servaes S, Zhuang H: Value of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scan versus diagnostic contrast computed tomography in initial staging of pediatric patients with lymphoma. Leuk Lymphoma 54 (4): 737-42, 2013. [PUBMED Abstract]
13. Anghelescu DL, Burgoyne LL, Liu T, et al.: Clinical and diagnostic imaging findings predict anesthetic complications in children presenting with malignant mediastinal masses. Paediatr Anaesth 17 (11): 1090-8, 2007. [PUBMED Abstract]
14. Simpson CD, Gao J, Fernandez CV, et al.: Routine bone marrow examination in the initial evaluation of paediatric Hodgkin lymphoma: the Canadian perspective. Br J Haematol 141 (6): 820-6, 2008. [PUBMED Abstract]
15. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971. [PUBMED Abstract]
16. Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7 (11): 1630-6, 1989. [PUBMED Abstract]
17. Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010.
18. Mauz-Körholz C, Metzger ML, Kelly KM, et al.: Pediatric Hodgkin Lymphoma. J Clin Oncol 33 (27): 2975-85, 2015. [PUBMED Abstract]
19. Kung FH, Schwartz CL, Ferree CR, et al.: POG 8625: a randomized trial comparing chemotherapy with chemoradiotherapy for children and adolescents with Stages I, IIA, IIIA1 Hodgkin Disease: a report from the Children’s Oncology Group. J Pediatr Hematol Oncol 28 (6): 362-8, 2006. [PUBMED Abstract]
20. Weiner MA, Leventhal B, Brecher ML, et al.: Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin’s disease in pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 15 (8): 2769-79, 1997. [PUBMED Abstract]
21. Keller FG, Nachman J, Constine L: A phase III study for the treatment of children and adolescents with newly diagnosed low risk Hodgkin lymphoma (HL). [Abstract] Blood 116 (21): A-767, 2010.
22. Schwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114 (10): 2051-9, 2009. [PUBMED Abstract]
23. Friedman DL, Chen L, Wolden S, et al.: Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children’s Oncology Group Study AHOD0031. J Clin Oncol 32 (32): 3651-8, 2014. [PUBMED Abstract]
24. Kelly KM, Sposto R, Hutchinson R, et al.: BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children’s Oncology Group. Blood 117 (9): 2596-603, 2011. [PUBMED Abstract]
25. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007. [PUBMED Abstract]
26. Barrington SF, Mikhaeel NG, Kostakoglu L, et al.: Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol 32 (27): 3048-58, 2014. [PUBMED Abstract]
27. Molnar Z, Simon Z, Borbenyi Z, et al.: Prognostic value of FDG-PET in Hodgkin lymphoma for posttreatment evaluation. Long term follow-up results. Neoplasma 57 (4): 349-54, 2010. [PUBMED Abstract]
28. Hasenclever D, Kurch L, Mauz-Körholz C, et al.: qPET – a quantitative extension of the Deauville scale to assess response in interim FDG-PET scans in lymphoma. Eur J Nucl Med Mol Imaging 41 (7): 1301-8, 2014. [PUBMED Abstract]
29. Voss SD, Chen L, Constine LS, et al.: Surveillance computed tomography imaging and detection of relapse in intermediate- and advanced-stage pediatric Hodgkin’s lymphoma: a report from the Children’s Oncology Group. J Clin Oncol 30 (21): 2635-40, 2012. [PUBMED Abstract]
30. Rathore N, Eissa HM, Margolin JF, et al.: Pediatric Hodgkin lymphoma: are we over-scanning our patients? Pediatr Hematol Oncol 29 (5): 415-23, 2012. [PUBMED Abstract]
31. Hartridge-Lambert SK, Schöder H, Lim RC, et al.: ABVD alone and a PET scan complete remission negates the need for radiologic surveillance in early-stage, nonbulky Hodgkin lymphoma. Cancer 119 (6): 1203-9, 2013. [PUBMED Abstract]
32. Friedmann AM, Wolfson JA, Hudson MM, et al.: Relapse after treatment of pediatric Hodgkin lymphoma: outcome and role of surveillance after end of therapy. Pediatr Blood Cancer 60 (9): 1458-63, 2013. [PUBMED Abstract]
33. Nasr A, Stulberg J, Weitzman S, et al.: Assessment of residual posttreatment masses in Hodgkin’s disease and the need for biopsy in children. J Pediatr Surg 41 (5): 972-4, 2006. [PUBMED Abstract]
34. Meany HJ, Gidvani VK, Minniti CP: Utility of PET scans to predict disease relapse in pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 48 (4): 399-402, 2007. [PUBMED Abstract]
35. Picardi M, De Renzo A, Pane F, et al.: Randomized comparison of consolidation radiation versus observation in bulky Hodgkin’s lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma 48 (9): 1721-7, 2007. [PUBMED Abstract]

Historical Overview of Treatment for Hodgkin Lymphoma

Long-term survival has been achieved in children and adolescents with Hodgkin lymphoma using radiation, multiagent chemotherapy, and combined-modality therapy. In selected cases of localized lymphocyte-predominant Hodgkin lymphoma, complete surgical resection may be curative and obviate the need for cytotoxic therapy.

Treatment options for children and adolescents with Hodgkin lymphoma include the following:

1. Radiation therapy as a single modality.
   • Recognition of the excess adverse effects of high-dose radiation therapy on musculoskeletal development in children motivated investigations of multiagent chemotherapy alone or with lower radiation doses (15–25.5 Gy) to reduced treatment volumes (involved-fields) and multiagent chemotherapy. It also led to the abandonment of the use of radiation as a single modality in skeletally immature children.[1–3]
   • Recognition of the excess risk of cardiovascular disease and secondary carcinogenesis in adult survivors who were treated for Hodgkin lymphoma during childhood led to the restriction of radiation therapy in contemporary trials.[4,5]
2. Multiagent chemotherapy as a single modality.
   • The establishment of the noncross-resistant combinations of MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, and prednisone) developed in the 1960s and ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) developed in the 1970s made long-term survival possible for patients with advanced and unfavorable (e.g., bulky, symptomatic) Hodgkin lymphoma.[6,7] MOPP-related sequelae include a dose-related risk of infertility and secondary myelodysplasia and leukemia.[2,8] The use of MOPP-derivative regimens substituting less leukemogenic and gonadotoxic alkylating agents (e.g., cyclophosphamide) for mechlorethamine or restricting cumulative alkylating agent dose exposure reduces this risk.[9] ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin.[10–12] The cumulative dose of these agents is 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 that utilized lower total cumulative doses of alkylators, doxorubicin, and bleomycin.[13,14]
   • Etoposide has been incorporated into treatment regimens as an effective alternative to alkylating agents in an effort to reduce gonadal toxicity and enhance antineoplastic activity.[15] Etoposide-related sequelae include an increased risk of secondary myelodysplasia and leukemia that appears to be rare when etoposide is used in restricted doses in pediatric Hodgkin lymphoma regimens.[16]
   • All of the agents in original MOPP and ABVD regimens continue to be used in contemporary pediatric treatment regimens. COPP (substituting cyclophosphamide for mechlorethamine) has almost uniformly replaced MOPP as the preferred alkylator regimen in most frontline trials. Contemporary trials have utilized a procarbazine-free COPP derivative, COPDAC.[17]
3. Radiation therapy and multiagent chemotherapy as a combined-modality therapy. Considerations for the use of multiagent chemotherapy alone versus combined-modality therapy include the following:
   • Treatment with noncross-resistant chemotherapy alone offers advantages for children managed in centers in developing countries lacking radiation facilities and trained personnel, as well as diagnostic imaging modalities needed for clinical staging. This treatment option also avoids the potential long-term growth inhibition, organ dysfunction, and solid tumor induction associated with radiation.
   • Chemotherapy-alone treatment protocols usually prescribe higher cumulative doses of alkylating agent and anthracycline chemotherapy, which may produce acute- and late-treatment morbidity from myelosuppression, cardiac toxic effects, gonadal injury, and secondary leukemia. However, more recent trials are designed to significantly reduce these risks, especially in those with chemotherapy-responsive disease.[18]
   • In general, the use of combined chemotherapy and low-dose involved-field radiation therapy (LD-IFRT) broadens the spectrum of potential toxicities, while reducing the severity of individual drug-related or radiation-related toxicities. The results of prospective and controlled randomized trials indicate that combined-modality therapy, compared with chemotherapy alone, produces a superior event-free survival (EFS). However, because of effective second-line therapy, overall survival (OS) has not differed among the groups studied.[19,20]

Treatment Approaches

Contemporary treatment for pediatric Hodgkin lymphoma uses a risk-adapted and response-based paradigm that assigns the length and intensity of therapy based on disease-related factors such as stage, number of involved nodal regions, tumor bulk, the presence of B symptoms, and early response to chemotherapy by functional and anatomic imaging. Age, sex, and histological subtype may also be considered in treatment planning.

Risk designation

• Favorable clinical features include localized nodal involvement in the absence of B symptoms and bulky disease. Risk factors considered in other studies include the number of involved nodal regions, the presence of hilar adenopathy, the size of peripheral lymphadenopathy, and extranodal extension.[21]
• Unfavorable clinical features include the presence of B symptoms, bulky mediastinal or peripheral lymphadenopathy, extranodal extension of disease, and advanced (stages IIIB–IV) disease.[21] Bulky mediastinal lymphadenopathy is designated when the ratio of the maximum measurement of mediastinal lymphadenopathy to intrathoracic cavity on an upright chest radiograph equals or exceeds 33%.
• Localized disease (stages I, II, and IIIA) with unfavorable features may be treated similarly to advanced-stage disease in some treatment protocols or treated with therapy of intermediate intensity.[21]
• Inconsistency in risk categorization across studies often makes comparison of study outcomes challenging.

Risk-adapted treatment paradigms

• No single treatment approach is ideal for all pediatric and young adult patients because of the differences in age-related developmental status and sex-related sensitivity to chemotherapy toxicity.
• The general treatment strategy that is used to treat children and adolescents with Hodgkin lymphoma is chemotherapy for all patients, with or without radiation. The number of cycles and intensity of chemotherapy may be determined by the rapidity and degree of response, as is the radiation dose and volume.
• Ongoing trials for patients with favorable disease presentations are evaluating the effectiveness of treatment with fewer cycles of combination chemotherapy alone that limit doses of anthracyclines and alkylating agents.
• Contemporary trials for patients with intermediate/unfavorable disease presentations are testing if chemotherapy and radiation therapy can be limited in patients who achieve a rapid early response to dose-intensive chemotherapy regimens.
• Sex-based regimens consider that male patients are more vulnerable to gonadal toxicity from alkylating agent chemotherapy and that female patients have a substantial risk of breast cancer after chest radiation. However, the cardiovascular risk to males after chest radiation suggests that limiting radiation exposure is also desirable in males.[22]

Histology-based therapy (stage I nodular lymphocyte-predominant Hodgkin lymphoma)

Histological subtype may direct therapy in patients with stage I completely resected, nodular lymphocyte-predominant Hodgkin lymphoma, whose initial treatment may be surgery alone.

This histology-based treatment approach is supported by the following findings from the literature:

• Although standard therapy for children with nodular lymphocyte-predominant Hodgkin lymphoma is chemotherapy plus LD-IFRT, there are reports in which patients have been treated with chemotherapy alone or with complete resection of isolated nodal disease without chemotherapy. Surgical resection of localized disease produces a prolonged disease-free survival in a substantial proportion of patients obviating the need for immediate cytotoxic therapy.[23–26]
• Results from a single-arm Children’s Oncology Group (COG) trial provide data to support the strategy of observation after surgical resection and treatment with limited chemotherapy for children with favorable stage IA or IIA Hodgkin lymphoma. Among 178 patients treated with surgical resection alone of single-node disease (n = 52), chemotherapy alone after complete response to three cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy (n = 115), or chemotherapy with LD-IFRT (21 Gy) after incomplete response to AV-PC chemotherapy (n = 11), the 5-year EFS was 85.5%, and the OS was 100%. Five-year EFS was 77% for patients observed after total resection and 88.8% for patients treated with AV-PC chemotherapy.[26][Level of evidence: 1iiDi]

Advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma is very rare, and there is no consensus regarding the optimal treatment, although outcomes for patients are excellent. In a retrospective review of 41 cases of advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma, many different chemotherapy regimens were used, some including rituximab. OS was 98%, with the only death being from secondary malignancy.[27][Level of evidence: 3iiiA]

A summary of treatment approaches for nodular lymphocyte-predominant Hodgkin lymphoma can be found in Table 9. Both children and adults treated for nodular lymphocyte-predominant Hodgkin lymphoma have a favorable outcome, particularly when the disease is localized (stage I), as it is for most patients.[23,24,26,28] Death among long-term survivors of nodular lymphocyte-predominant Hodgkin lymphoma is more likely to result from treatment-related toxicity (both acute and long-term) than from lymphoma.[29,30]

Radiation Therapy

As discussed in the previous sections, most newly diagnosed children will be treated with risk-adapted chemotherapy alone or in combination with consolidative radiation therapy (RT). RT volumes can have variable and protocol-specific definitions, but generally encompass lymph node regions initially involved at the time of diagnosis, without extensive inclusion of uninvolved regions. RT field reductions are made to account for tumor regression with chemotherapy.[31]

Volume considerations

With advancements in systemic therapy, RT field definitions have evolved and become increasingly restricted. RT is no longer needed to sterilize all disease. Advancements in radiologic imaging allow more precise radiation target definition. Historically, concerns about the symmetry of growth in young children with unilateral disease involvement often prompted treatment of the contralateral tissues. With contemporary treatments using lower radiation doses (15 to 21 Gy) and reduced volumes (involved-site RT [ISRT]), treatment of contralateral uninvolved sites is not necessary.

General trends in radiation treatment volume are summarized as follows:

• Regional RT fields (e.g., mantle, subtotal, or total nodal) are now historic and have been replaced by involved-nodal RT (INRT) or ISRT, or rarely, IFRT in select situations such as adolescents and young adults treated with radiation alone for nodular lymphocyte-predominant Hodgkin lymphoma (refer to Table 4).
• Involved-nodal RT (INRT), introduced by the European Organization for Research and Treatment of Cancer Lymphoma Group and the Groupe d’Etude des Lymphomes de l’Adulte, remains investigational, although initial clinical data are emerging.[32–34] This approach defines the treatment volume using the prechemotherapy positron emission tomography (PET)–computed tomography (CT) scan that is obtained with the patient positioned in a similar manner to the position that will be used at the time of RT. This volume is later contoured onto the postchemotherapy-planning CT scan. The final treatment volume only includes the initially involved nodes with a margin, typically 2 cm.
• Involved-site RT (ISRT) is an evolving approach to be used for patients when optimal prechemotherapy imaging (PET-CT in a position similar to what will be used at the time of RT) is not available to the radiation oncologist. Because the delineation of the area of involvement is less precise, a somewhat larger treatment volume is contoured than for INRT, specifically the whole nodal basin where the lymphoma was located before chemotherapy was given. The exact size of this volume will depend on the individual case scenario.[35]
• Modified involved-field RT (mIFRT) is the term used in the Euronet-PHL-C1 trial to describe treatment volumes that contain the involved lymph node(s) as seen before chemotherapy plus radiation planning margins of 1 cm to 2 cm, depending on the area of involvement. These volumes are comparable to ISRT fields, although the development preceded the widespread availability of CT-based planning. The subsequent Euronet-PHL-C2 trial employs INRT.
• Targeted therapy involves restricting RT to areas of initial bulky disease, slowly responding disease (based on PET avidity with a Deauville score of greater than 3 after initial cycles of chemotherapy, usually two cycles), or postchemotherapy residual disease (that has been variously defined but is currently based on residual PET avidity with a Deauville score of greater than 2).

Visual PET criteria are scored according to uptake involved by lymphoma from the Deauville 5-point scale, from 1 to 5, as described in Table 2. The Children’s Oncology Group and Euronet definitions of PET response of lymph nodes or nodal masses are described in Table 3.

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.

Involved Node(s)	Radiation Field
aAdapted from Terezakis et al.[36]
bUpper cervical region is not treated if supraclavicular involvement is an extension of the mediastinal disease.
cPrechemotherapy volume is treated except for lateral borders of the mediastinal field.
Cervical	Neck and/or supraclavicularb/infraclavicular
Supraclavicular	Supraclavicular/infraclavicular and lower neck
Axilla	Axilla ± supraclavicular/infraclavicular
Mediastinum	Mediastinum, hila, and infraclavicular/supraclavicularb,c
Hila	Hila, mediastinum
Spleen	Spleen ± para-aortic
Para-aortic	Para-aortic ± spleen
Iliac	Iliac, inguinal, femoral
Inguinal	External iliac, inguinal, femoral
Femoral	External iliac, inguinal, femoral

A breast-sparing radiation therapy plan using proton therapy is being evaluated to determine if there is a statistically significant reduction in dose.[37] Long-term results are awaited.

Considerations in ISRT or INRT Treatment Planning

Radiation therapy planning that uses CT scans obtained during the simulation procedure is a requirement for contemporary INRT or ISRT. Fusion of staging imaging (CT or PET-CT) with the planning CT dataset can facilitate delineation of the treatment volume. RT planning scans that encompass the full extent of organs at risk (e.g., lungs) are important so that normal tissue exposures can be calculated accurately.

Definitions that are important in planning radiation therapy include the following:

1. Prechemotherapy or presurgery gross tumor volume (GTV): Imaging abnormalities of nodal or non-nodal tissues at initially involved sites.
2. Postchemotherapy GTV: Imaging abnormalities at initially involved sites that remain abnormal after chemotherapy.
3. Postchemotherapy clinical target volume (CTV): Abnormal tissues originally involved with lymphoma, but taking into account the reduction in the axial (transverse) diameter that has occurred with chemotherapy. This delineation requires consideration of the expected routes of disease spread and the quality of pretreatment imaging.
4. Internal target volume (ITV): ITV encompasses the CTV, with an added margin to account for variation in shape and motion within the patient (e.g., breathing).
5. Planning target volume (PTV): This encompasses the ITV or CTV and accounts for variation in daily setup for radiation; generally 0.5 cm to 1 cm.
6. Boost radiation therapy: Some protocols, such as the EuroNet-PHL-C1 protocol, give additional radiation therapy (a boost) to sites with a poor response and/or bulky residual disease after initial chemotherapy. These volumes were determined after completion of all chemotherapy. This approach is sometimes used for patients with residual areas of PET avidity after chemotherapy.
7. Organ at risk (OAR) determination and dose constraints: Because of the importance of long-term tissue injury after radiation, the dose to normal tissues is kept as low as reasonably achievable while adequately treating the PTV. Some specific organ radiation dose tolerances exist to guide these decisions, and these organs are considered organs at risk.

The treatment volume for unfavorable or advanced disease is somewhat variable and often protocol-specific. Large-volume RT may compromise organ function and limit the intensity of second-line therapy if relapse occurs. In patients with intermediate or advanced disease, who often have multifocal/extranodal disease, the current standard of therapy includes postchemotherapy ISRT that limits radiation exposure to large portions of the body.[14,38]

Radiation dose

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

• Doses of 15 Gy to 25 Gy are typically used, with modifications based on patient age, the presence of bulky or residual (postchemotherapy) disease, and normal tissue concerns.
• Some protocols have prescribed a boost of 5 Gy to 10 Gy in regions with suboptimal response to chemotherapy.[38]

Technical considerations

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

• A linear accelerator with a beam energy of 6 mV is desirable because of its penetration, well-defined edge, and homogeneity throughout an irregular treatment field.
• Individualized immobilization devices are preferable for young children to ensure accuracy and reproducibility.
• Attempts should be made to exclude or position breast tissue under the lung/axillary shielding.
• When the decision is made to include some or all of a critical organ (such as liver, kidney, or heart) in the radiation field, then normal tissue constraints are critical depending on the chemotherapy used and patient age. An untested indication for whole-heart irradiation (~10 Gy) is frank pericardial involvement with tumor.
• Whole-lung irradiation (~10 Gy), with partial transmission blocks or intensity modulation, is a consideration in the setting of overt pulmonary nodules that have not achieved a CR.[18,38,39] For example, the GPOH HD-95, GPOH 2002, and EuroNet-PHL-C1 trials administered ipsilateral whole-lung RT to patients who had not achieved a CR in the lungs to the first two cycles of chemotherapy.[38] COG-9425 and COG-AHOD0031 used whole-lung RT in patients with pulmonary nodules at diagnosis, with the latter protocol randomly assigning some patients on the basis of response.
• Three-dimensional conformal radiation therapy (3-D CRT) or intensity-modulated radiation therapy (IMRT) are standard techniques in the treatment of lymphoma. Appropriate CT-based image guided treatment planning and delivery is standard, preferably with fusion of staging CT and PET imaging with RT planning CT datasets to delineate the target volumes.[35]
• Data are accumulating in regard to the efficacy of IMRT and the decrease in median dose to normal surrounding tissues. Some uncertainty exists about the potential for increased late effects from IMRT, particularly secondary malignancy, because with IMRT, a larger area of the body receives a low dose compared with conventional techniques (although the mean dose to a volume may be decreased).
• Proton therapy is currently being investigated and may further decrease the mean dose to the surrounding normal tissue compared with IMRT or 3-D CRT, without increasing the volume of normal tissue receiving lower-dose radiation.

Role of LD-ISRT in childhood and adolescent Hodgkin lymphoma

Because all children and adolescents with Hodgkin lymphoma receive chemotherapy, a question commanding significant attention is whether patients who achieve a rapid early response or a CR to chemotherapy require RT. Conversely, the judicious use of LD-ISRT may permit a reduction in the intensity or duration of chemotherapy below toxicity thresholds that would not be possible if single modality chemotherapy were used, thus decreasing overall acute and late toxicities.

Key points to consider in regard to the role of radiation in pediatric Hodgkin lymphoma include the following:

• The treatment approach for pediatric Hodgkin lymphoma should focus on maximizing disease control and minimizing risks for late toxicity associated with both RT and chemotherapy.
• The use of LD-IFRT or ISRT in pediatric Hodgkin lymphoma permits reduction in duration or intensity of chemotherapy and thus dose-related toxicity of anthracyclines, alkylating agents, and bleomycin that may preserve cardiopulmonary and gonadal function and reduce the risk of secondary leukemia.
• Radiation has been used as an adjunct to multiagent chemotherapy in clinical trials for intermediate- and high-risk pediatric Hodgkin lymphoma with the goal of reducing risk of relapse in initially involved sites and preventing toxicity associated with second-line therapy.
• Compared with chemotherapy alone, adjuvant radiation has, in most studies, produced a superior EFS for children with intermediate-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.[20] 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. Four-year EFS was 87.9% for rapid responders who were randomly assigned to IFRT versus 84.3% (P = .11) for rapid responders who were not assigned to IFRT. OS was 98.8% in both groups.[18] In a subset analysis from this study of patients with anemia and bulky limited-stage disease, the EFS was 89.3% for patients who received IFRT, compared with 77.9% for patients who did not receive IFRT (P = .019).[40][Level of evidence: 1iiDi] Adjuvant radiation therapy may be associated with an increased risk of late effects or mortality.[41]
• Radiation consolidation may facilitate local disease control in individuals with refractory or recurrent disease, especially in those who have limited or bulky sites of disease progression/recurrence, or persistent disease that does not completely respond to chemotherapy.[42]

Finally, an inherent assumption is made in a trial comparing chemotherapy alone versus chemotherapy and radiation that the effect of radiation on EFS will be uniform across all patient subgroups. However, it is not clear how histology, presence of bulky disease, presence of B symptoms, or other variables affect the efficacy of postchemotherapy radiation.

Chemotherapy

All of the agents in original MOPP and ABVD regimens continue to be used in contemporary pediatric treatment regimens. COPP (substituting cyclophosphamide for mechlorethamine) has almost uniformly replaced MOPP as the preferred alkylator regimen in most frontline trials. Etoposide has been incorporated into treatment regimens as an effective alternative to alkylating agents in an effort to reduce gonadal toxicity and enhance antineoplastic activity.

Combination chemotherapy regimens used in contemporary trials are summarized in Table 5.

Name	Drugs	Dosage	Route	Days
IV = intravenous; PO = oral.
COPP [17]	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 [17]	Dacarbazine substituted for procarbazine in COPP	250 mg/m2	IV	1–3
OPPA [17]	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 [17]	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
ABVD [7]	Doxorubicin (Adriamycin)	25 mg/m2	IV	1, 15
	Bleomycin	10 U/m2	IV	1, 15
	Vinblastine	6 mg/m2	IV	1, 15
	Dacarbazine	375 mg/m2	IV	1, 15
COPP/ABV [14]	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 U/m2	IV	7
	Vinblastine	6 mg/m2	IV	7
VAMP [43]	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 [44,45]	Doxorubicin	25 mg/m2	IV	1, 15
	Bleomycin	10 U/m2	IV	1, 15
	Vincristine (Oncovin)	1.5 mg/m2	IV	1, 15
	Etoposide	100 mg/m2	IV	1–5
ABVE-PC [39]	Doxorubicin (Adriamycin)	30 mg/m2	IV	0, 1
	Bleomycin	10 U/m2	IV	0, 7
	Vincristine (Oncovin)	1.4 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
BEACOPP [46]	Bleomycin	10 U/m2	IV	7
	Etoposide	200 mg/m2	IV	0–2
	Doxorubicin (Adriamycin)	35 mg/m2	IV	0
	Cyclophosphamide	1200 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 [47]	Cyclophosphamide	500 mg/m2	IV	1
	Vinblastine	6 mg/m2	IV	1, 8
	Prednisolone	40 mg/m2	PO	1–8

Results from selected clinical trials

North American cooperative and consortium trials

The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy utilizing ABVE (doxorubicin [Adriamycin], bleomycin, vincristine, and etoposide) [45] for favorable low-stage patients and dose-dense ABVE-PC (prednisone and cyclophosphamide) for unfavorable advanced-stage patients in combination with 21 Gy IFRT.[39]

Key findings from these trials include the following:

• Children and adolescents with low-risk Hodgkin lymphoma (stages I, IIA, IIIA1) treated with IFRT (25.5 Gy) after CR to two cycles of DBVE (doxorubicin, bleomycin, vincristine, and etoposide) had outcomes comparable to those treated with four cycles of DBVE and IFRT (25.5 Gy). This response-dependent approach permitted reduction in chemotherapy exposure in 45% of patients.[45]
• A dose-dense, early response–based treatment approach with ABVE-PC permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response after three ABVE-PC cycles.[39][Level of evidence: 1iiDi]
• Five-year EFS was comparable for rapid early responders (86%) and slow early responders (83%) treated with three and five cycles of ABVE-PC, respectively, followed by 21 Gy radiation. Patients who received dexrazoxane had more hematological and pulmonary toxicity.[39]
• Although etoposide is associated with an increased risk of therapy-related acute myeloid leukemia with 11q23 abnormalities, the risk is very low in those treated with ABVE or ABVE-PC without dexrazoxane.[16,48]

The Children’s Cancer Group (CCG) undertook a randomized controlled trial comparing survival outcomes in children treated with risk-adapted COPP/ABV hybrid chemotherapy alone with those treated with COPP/ABV hybrid chemotherapy plus LD-IFRT.[14] The study was closed early because of a significantly higher number of relapses among patients treated with chemotherapy alone. Long-term results include the following:[14,19]

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

Another CCG Study (COG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP regimen followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[46][Level of evidence: 2Dii] For rapid early responding girls, an additional four courses of COPP/ABV (without IFRT) were given. Rapid early responding boys received two cycles of ABVD followed by IFRT. Slow early responders received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girl’s therapy was intended to reduce the risk of breast cancer. Key findings from this trial include the following:[46]

• Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four cycles of BEACOPP.[46]
• The 5-year EFS was 94%, with a median follow-up time of 6.3 years.
• Results support that early intensification followed by less intense response-based therapy results in high EFS.

The Stanford, St. Jude Children’s Research Hospital, and Boston Consortium administered a series of risk-adapted trials over the last 20 years. Key findings include the following:

• Substitution of nonalkylating agent chemotherapy (e.g., methotrexate or etoposide) as an alternative to alkylating agent chemotherapy results in an inferior EFS among patients with unfavorable clinical presentations.[49,50]
• The combination of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) is an effective regimen (10-year EFS, 89%) for favorable-risk (low stage without B symptoms or bulky disease) children and adolescents with Hodgkin lymphoma when used in combination with response-based LD-IFRT (15–25.5 Gy).[43]
• Patients with favorable-risk Hodgkin lymphoma treated with four cycles of VAMP chemotherapy alone who achieved an early CR had a comparable 5-year EFS to those treated with four cycles of VAMP chemotherapy plus 25.5 Gy IFRT (89% vs. 88%).[51]

The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulk disease, and IA or IIA with bulk disease. All patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation.[18]

1. Rapid early responders (defined by CT imaging after two cycles) received two additional ABVE-PC cycles, followed by CR evaluation.
   • Rapid early responders with CR (based on CT imaging and additionally requiring negative PET or gallium scans) were randomly assigned to receive either IFRT or no additional therapy.
   • Rapid early responders with less than a CR were nonrandomly assigned to IFRT.
2. Slow early responders were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All slow early responders were assigned to receive IFRT.

Key 4-year OS and EFS outcomes from this trial include the following:

• Early response was an important prognostic factor. Overall EFS was 85.0% and significantly (P < .001) higher for rapid early responders (86.9%) than was for slow early responders (77.4%). OS was 97.8% and significantly (P < .001) higher for rapid early responders (98.5%) than was for slow early responders (95.3%).
• Approximately 45% of patients were rapid early responders and achieved CR by the end of chemotherapy. For this population, EFS did not differ significantly (P = .11) among those who were randomly assigned to IFRT (87.9%) versus no IFRT (84.3%). OS for those receiving IFRT was 98.8% (95% confidence interval [CI], 96.8%–99.5%) and OS for those receiving chemotherapy alone was 98.8% (95% CI, 96.9%–99.6%).
• Approximately 20% of patients were slow early responders. For this population, EFS did not differ significantly (P = .11) among those who were randomly assigned to DECA (79.3%) versus no DECA (75.2%).
• Study results confirm the prognostic significance of early chemotherapy response and support the safety of avoidance of IFRT based on rapid early response with CR by the end of chemotherapy.
• An analysis of patterns of failure among patients who relapsed on the AHOD0031 (NCT00025259) study demonstrated that first relapses more commonly occurred within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[52]

German multicenter trials

In the last 30 years, German investigators have implemented a series of risk-adapted trials evaluating sex-based treatments featuring multiagent chemotherapy with vincristine, prednisone, procarbazine, and doxorubicin (OPPA)/COPP and IFRT.

Key findings from these trials include the following:

• Substitution of cyclophosphamide for mechlorethamine in the MOPP combination results in a low risk of secondary myelodysplasia/leukemia.[9]
• Omission of procarbazine from the OPPA combination and substitution of methotrexate for procarbazine in the COPP combination (OPA/COMP) results in a substantially inferior EFS.[53]
• Substitution of etoposide for procarbazine in the OPPA combination (OEPA) in boys produces comparable EFS to that of girls treated with OPPA and is associated with hormonal parameters, suggesting lower risk of gonadal toxicity.[54]
• Omission of radiation for patients completely responding (defined as complete resolution or only minor residuals in all previously involved regions using clinical examination and anatomic imaging) to risk- and sex-based OEPA or OPPA/COPP chemotherapy results in a significantly lower EFS in intermediate- and high-risk patients compared with irradiated patients (79% vs. 91%), but no difference among nonirradiated and irradiated patients assigned to the favorable-risk group.[20]
• Substitution of dacarbazine for procarbazine (OEPA-COPDAC) in boys produces comparable results to standard OPPA-COPP in girls when used in combination with IFRT for intermediate- and high-risk patients.[17][Level of evidence: 2A]

Accepted Risk-Adapted Treatment Strategies for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma

Contemporary trials for pediatric Hodgkin lymphoma involve a risk-adapted, response-based treatment approach that titrates the length and intensity of chemotherapy and dose of radiation based on disease-related factors including stage, number of involved nodal regions, tumor bulk, the presence of B symptoms, and early response to chemotherapy as determined by functional imaging. In addition, vulnerability related to age and sex is also considered in treatment planning.

Classical Hodgkin lymphoma low-risk disease

Table 6 summarizes the results of contemporary treatment approaches used for low-risk Hodgkin lymphoma.

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.
aRefer to Table 5 for more information about the chemotherapy regimens.
bWithout 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.
cWithout 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.
dResults from as-treated analysis.
VAMP (4) [43]	IFRT (15–25.5)	CS I/IIb	110	89% (10)	96% (10)
VAMP (4) [51]	IFRT (25.5)	CS I/IIb	41	88% (5)	100% (5)
	None		47	89% (5)
COPP/ABV (4) [14,19]	IFRT (21)	CS IA/B, IIAc	94	100% (10)d	97% (10)d
	None		113	89% (10)d	96% (10)d
OEPA/OPPA (2) [20]	IFRT (20–35)	I, IIA	281	94% (5)	N/A
	None		113	97% (5)
ABVE (2-4) [45]	IFRT (25.5)	IA, IIA, IIIA1	51	91% (6)	98% (6)

Classical Hodgkin lymphoma intermediate-risk disease

Table 7 summarizes the results of contemporary treatment approaches used for 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.
aRefer to Table 5 for more information about the chemotherapy regimens.
bWith 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.
cResults from as-treated analysis.
COPP/ABV (6) [19]	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) [20]	IFRT (20–35)	IIEA, IIB, IIIA	212	92% (5)	N/A
OEPA/OPPA (2) + COPDAC (2) [17]	IFRT (20–35)	IE, IIB, IIEA, IIIA	139	88.3% (5)	98.5% (5)
ABVE-PC (3–5) [39]	IFRT (21)	IB, IIA, IIIA	53	84% (5)	95% (5)
ABVE-PC: RER/CR [18]	IFRT (21)	IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease	380	87.9% (4)	98.8% (4)
ABVE-PC: RER/CR [18]	None	IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease	382	84.3% (4)	98.8% (4)
ABVE-PC: SER: +DECA [18]	IFRT (21)	IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease	153	79.3% (4)	96.5% (4)
ABVE-PC: SER: -DECA [18]	IFRT (21)		151	75.2% (4)	94.3% (4)

Classical Hodgkin lymphoma high-risk disease

Table 8 summarizes the results of contemporary treatment approaches used for 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; N/A = not applicable; No. = number; RER = rapid early response; SER = slow early response.
aRefer to Table 5 for more information about the chemotherapy regimens.
bResults include all treatment strata.
OEPA/OPPA (2) + COPP (4) [20]	IFRT (20–35)	IIEB, IIIEA/B, IIIB, IVA/B	265	91% (5)	N/A
OEPA/OPPA (2) + COPDAC (4) [17]	IFRT (20–35)	IIEB, IIIEA/B, IIIB, IVA/B	239	86.9% (5)	94.9% (5)
ABVE-PC (3-5) [39]	IFRT (21)	IIB, IIIB, IV	163	85% (5)	95% (5)
BEACOPP (4); COPP/ABV (4) (RER; girls) [46]	None	IIB, IIIB, IV	38	94% (5)b	97% (5)b
BEACOPP (4); ABVD (2) (RER; boys) [46]	IFRT (21)	IIB, IIIB, IV	34
BEACOPP (8) (SER) [46]	IFRT (21)	IIB, IIIB, IV	25

Treatment options under clinical evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

• HLHR13 (NCT01920932) (Adcetris [Brentuximab Vedotin], Combination Chemotherapy, and Radiation Therapy in Treating Younger Patients With Stage IIB, IIIB, and IV Hodgkin Lymphoma): A clinical trial at St. Jude Children’s Research Hospital is evaluating the safety of brentuximab vedotin, etoposide, prednisone, and doxorubicin hydrochloride (two cycles of AEPA) and cyclophosphamide, brentuximab vedotin, prednisone, and dacarbazine (two cycles of CAPDac), and the efficacy (early CR) after the two cycles of AEPA chemotherapy in high-risk patients with Hodgkin lymphoma (stages IIB, IIIB, IVA, and IVB.) The study will compare EFS in high-risk Hodgkin lymphoma patients treated with AEPA/CAPDac with the historical control, unfavorable-risk 2 arm of the St. Jude HOD99 study.
• AHOD1331 (NCT02166463) (A Randomized Phase III Study of Brentuximab Vedotin [SGN-35] for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma in Children and Adolescents): AHOD1331 is a randomized phase III clinical trial comparing brentuximab vedotin and combination chemotherapy to combination chemotherapy alone in treating younger patients (aged 2 to 18 years) with newly diagnosed high-risk Hodgkin lymphoma. The chemotherapy used with brentuximab vedotin is AVE-PC (doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide). The chemotherapy-alone arm uses the same agents and additionally incorporates bleomycin (ABVE-PC). Those patients who remain fluorine F 18-fludeoxyglucose PET positive after two cycles receive response-based ISRT.

Nodular lymphocyte-predominant Hodgkin lymphoma

The use of combination chemotherapy and/or radiation therapy can achieve excellent long-term progression-free survival and OS in patients with nodular lymphocyte-predominant Hodgkin lymphoma.[26,55,56] Late recurrences have been reported and are typically responsive to re-treatment. Because deaths observed among individuals with this histological subtype are frequently related to complications from cytotoxic therapy, risk-adapted treatment assignment is particularly important for limiting exposure to agents with established dose-related toxicities.[55,56] Table 9 summarizes the results of contemporary treatment approaches used for nodular lymphocyte-predominant Hodgkin lymphoma, some of which feature surgery alone for completely resected disease and limited cycles of chemotherapy with or without LD-IFRT. Because of the relative rarity of this subtype, most trials are limited by small cohort numbers and nonrandom allocation of treatment. Results from a single-arm COG trial provide data to support the strategy of observation after surgical resection and treatment with limited chemotherapy for children with favorable stage IA or IIA Hodgkin lymphoma. Among 178 patients treated with surgical resection alone of single-node disease (n = 52), chemotherapy alone after complete response to three cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy (n = 115), or chemotherapy with LD-IFRT (21 Gy) after incomplete response to AV-PC chemotherapy (n = 11), the 5-year EFS was 85.5%, and the OS was 100%. Five-year EFS was 77% for patients observed after total resection and 88.8% for patients treated with AV-PC chemotherapy.[26][Level of evidence: 1iiDi]

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.
aRefer to Table 5 for more information about the chemotherapy regimens.
bAllocation to radiation therapy or no radiation therapy based on response to therapy.
cAllocation based on clinical response.
dAll involved lymph nodes surgically resected.
COPP/ABV (4)b [26]	None	52	96% (5)	100% (5)
	IFRT (21)	29	100% (5)
CVP (3) [47]	None	55	74% (5)	100% (5)
VAMP (4)c [51]	None	26	89.4% (5)	N/A
	IFRT (25)	6	85.7% (5)	N/A
VAMP (4) [43]	IFRT (15–25.5)	33	100% (10)	100% (10)
Noned [23]	None	51	67% (2)	100% (2)
DBVE (2–4)c [45]	None	26	94% (8)	100% (8)
	IFRT (25.5)

Treatment of Adolescents and Young Adults with Hodgkin Lymphoma

The treatment approach used for adolescents and young adults with Hodgkin lymphoma may vary based on community referral patterns and age restrictions at pediatric cancer centers. In patients with high-risk disease, the standard of care in adult oncology practices typically involves at least six cycles of ABVD chemotherapy that would deliver a cumulative anthracycline dose of 300 mg/m2.[57,58] (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) In late-health outcomes studies of pediatric cancer survivors, the risk of anthracycline cardiomyopathy has been shown to exponentially increase after exposure to cumulative anthracycline doses of 250 mg/m2 to 300 mg/m2.[59,60] Subsequent need for mediastinal radiation can further enhance the risk of a variety of late cardiac events.[59–61] In an effort to optimize disease control and preserve both cardiac and gonadal function, pediatric regimens for low-risk disease most often feature a restricted number of cycles of ABVD derivative combinations, whereas alkylating agents and etoposide are integrated into anthracycline-containing regimens for those with intermediate- and high-risk disease.

Participation in a clinical trial should be considered for adolescent and young adult patients with Hodgkin lymphoma. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

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.

References

1. Donaldson SS, Kaplan HS: Complications of treatment of Hodgkin’s disease in children. Cancer Treat Rep 66 (4): 977-89, 1982. [PUBMED Abstract]
2. Donaldson SS, Link MP: Combined modality treatment with low-dose radiation and MOPP chemotherapy for children with Hodgkin’s disease. J Clin Oncol 5 (5): 742-9, 1987. [PUBMED Abstract]
3. Jenkin D, Chan H, Freedman M, et al.: Hodgkin’s disease in children: treatment results with MOPP and low-dose, extended-field irradiation. Cancer Treat Rep 66 (4): 949-59, 1982. [PUBMED Abstract]
4. Bhatia S, Robison LL, Oberlin O, et al.: Breast cancer and other second neoplasms after childhood Hodgkin’s disease. N Engl J Med 334 (12): 745-51, 1996. [PUBMED Abstract]
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6. Devita VT Jr, Serpick AA, Carbone PP: Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 73 (6): 881-95, 1970. [PUBMED Abstract]
7. Bonadonna G, Santoro A: ABVD chemotherapy in the treatment of Hodgkin’s disease. Cancer Treat Rev 9 (1): 21-35, 1982. [PUBMED Abstract]
8. Ortin TT, Shostak CA, Donaldson SS: Gonadal status and reproductive function following treatment for Hodgkin’s disease in childhood: the Stanford experience. Int J Radiat Oncol Biol Phys 19 (4): 873-80, 1990. [PUBMED Abstract]
9. Schellong G, Riepenhausen M, Creutzig U, et al.: Low risk of secondary leukemias after chemotherapy without mechlorethamine in childhood Hodgkin’s disease. German-Austrian Pediatric Hodgkin’s Disease Group. J Clin Oncol 15 (6): 2247-53, 1997. [PUBMED Abstract]
10. Mefferd JM, Donaldson SS, Link MP: Pediatric Hodgkin’s disease: pulmonary, cardiac, and thyroid function following combined modality therapy. Int J Radiat Oncol Biol Phys 16 (3): 679-85, 1989. [PUBMED Abstract]
11. Fryer CJ, Hutchinson RJ, Krailo M, et al.: Efficacy and toxicity of 12 courses of ABVD chemotherapy followed by low-dose regional radiation in advanced Hodgkin’s disease in children: a report from the Children’s Cancer Study Group. J Clin Oncol 8 (12): 1971-80, 1990. [PUBMED Abstract]
12. Weiner MA, Leventhal BG, Marcus R, et al.: Intensive chemotherapy and low-dose radiotherapy for the treatment of advanced-stage Hodgkin’s disease in pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 9 (9): 1591-8, 1991. [PUBMED Abstract]
13. Chow LM, Nathan PC, Hodgson DC, et al.: Survival and late effects in children with Hodgkin’s lymphoma treated with MOPP/ABV and low-dose, extended-field irradiation. J Clin Oncol 24 (36): 5735-41, 2006. [PUBMED Abstract]
14. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002. [PUBMED Abstract]
15. Gerres L, Brämswig JH, Schlegel W, et al.: The effects of etoposide on testicular function in boys treated for Hodgkin’s disease. Cancer 83 (10): 2217-22, 1998. [PUBMED Abstract]
16. Smith MA, Rubinstein L, Anderson JR, et al.: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17 (2): 569-77, 1999. [PUBMED Abstract]
17. Mauz-Körholz C, Hasenclever D, Dörffel W, et al.: Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin’s lymphoma: the GPOH-HD-2002 study. J Clin Oncol 28 (23): 3680-6, 2010. [PUBMED Abstract]
18. Friedman DL, Chen L, Wolden S, et al.: Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk hodgkin lymphoma: a report from the Children’s Oncology Group Study AHOD0031. J Clin Oncol 32 (32): 3651-8, 2014. [PUBMED Abstract]
19. Wolden SL, Chen L, Kelly KM, et al.: Long-term results of CCG 5942: a randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin’s lymphoma–a report from the Children’s Oncology Group. J Clin Oncol 30 (26): 3174-80, 2012. [PUBMED Abstract]
20. Dörffel W, Lüders H, Rühl U, et al.: Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin’s disease in children and adolescents: analysis and outlook. Klin Padiatr 215 (3): 139-45, 2003 May-Jun. [PUBMED Abstract]
21. Kelly KM: Management of children with high-risk Hodgkin lymphoma. Br J Haematol 157 (1): 3-13, 2012. [PUBMED Abstract]
22. Castellino SM, Geiger AM, Mertens AC, et al.: Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 117 (6): 1806-16, 2011. [PUBMED Abstract]
23. Mauz-Körholz C, Gorde-Grosjean S, Hasenclever D, et al.: Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma. Cancer 110 (1): 179-85, 2007. [PUBMED Abstract]
24. Pellegrino B, Terrier-Lacombe MJ, Oberlin O, et al.: Lymphocyte-predominant Hodgkin’s lymphoma in children: therapeutic abstention after initial lymph node resection–a Study of the French Society of Pediatric Oncology. J Clin Oncol 21 (15): 2948-52, 2003. [PUBMED Abstract]
25. Shankar A, Daw S: Nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents–a comprehensive review of biology, clinical course and treatment options. Br J Haematol 159 (3): 288-98, 2012. [PUBMED Abstract]
26. Appel BE, Chen L, Buxton AB, et al.: Minimal Treatment of Low-Risk, Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children’s Oncology Group. J Clin Oncol 34 (20): 2372-9, 2016. [PUBMED Abstract]
27. Shankar AG, Roques G, Kirkwood AA, et al.: Advanced stage nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents: clinical characteristics and treatment outcome – a report from the SFCE & CCLG groups. Br J Haematol 177 (1): 106-115, 2017. [PUBMED Abstract]
28. Nogová L, Reineke T, Brillant C, et al.: Lymphocyte-predominant and classical Hodgkin’s lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 26 (3): 434-9, 2008. [PUBMED Abstract]
29. Diehl V, Sextro M, Franklin J, et al.: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin’s disease and lymphocyte-rich classical Hodgkin’s disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin’s Disease. J Clin Oncol 17 (3): 776-83, 1999. [PUBMED Abstract]
30. Sandoval C, Venkateswaran L, Billups C, et al.: Lymphocyte-predominant Hodgkin disease in children. J Pediatr Hematol Oncol 24 (4): 269-73, 2002. [PUBMED Abstract]
31. Yahalom J, Mauch P: The involved field is back: issues in delineating the radiation field in Hodgkin’s disease. Ann Oncol 13 (Suppl 1): 79-83, 2002. [PUBMED Abstract]
32. Girinsky T, van der Maazen R, Specht L, et al.: Involved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines. Radiother Oncol 79 (3): 270-7, 2006. [PUBMED Abstract]
33. Campbell BA, Voss N, Pickles T, et al.: Involved-nodal radiation therapy as a component of combination therapy for limited-stage Hodgkin’s lymphoma: a question of field size. J Clin Oncol 26 (32): 5170-4, 2008. [PUBMED Abstract]
34. Maraldo MV, Aznar MC, Vogelius IR, et al.: Involved node radiation therapy: an effective alternative in early-stage hodgkin lymphoma. Int J Radiat Oncol Biol Phys 85 (4): 1057-65, 2013. [PUBMED Abstract]
35. Hodgson DC, Dieckmann K, Terezakis S, et al.: Implementation of contemporary radiation therapy planning concepts for pediatric Hodgkin lymphoma: Guidelines from the International Lymphoma Radiation Oncology Group. Pract Radiat Oncol 5 (2): 85-92, 2015 Mar-Apr. [PUBMED Abstract]
36. Terezakis SA, Hudson MM, Constine LS: Hodgkin lymphoma. In: Halperin EC, Constine LS, Tarbell NJ, et al.: Pediatric Radiation Oncology. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 137-165.
37. Andolino DL, Hoene T, Xiao L, et al.: Dosimetric comparison of involved-field three-dimensional conformal photon radiotherapy and breast-sparing proton therapy for the treatment of Hodgkin’s lymphoma in female pediatric patients. Int J Radiat Oncol Biol Phys 81 (4): e667-71, 2011. [PUBMED Abstract]
38. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin’s disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001. [PUBMED Abstract]
39. Schwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114 (10): 2051-9, 2009. [PUBMED Abstract]
40. Charpentier AM, Friedman DL, Wolden S, et al.: Predictive Factor Analysis of Response-Adapted Radiation Therapy for Chemotherapy-Sensitive Pediatric Hodgkin Lymphoma: Analysis of the Children’s Oncology Group AHOD 0031 Trial. Int J Radiat Oncol Biol Phys 96 (5): 943-950, 2016. [PUBMED Abstract]
41. Yeh JM, Diller L: Pediatric Hodgkin lymphoma: trade-offs between short- and long-term mortality risks. Blood 120 (11): 2195-202, 2012. [PUBMED Abstract]
42. Biswas T, Culakova E, Friedberg JW, et al.: Involved field radiation therapy following high dose chemotherapy and autologous stem cell transplant benefits local control and survival in refractory or recurrent Hodgkin lymphoma. Radiother Oncol 103 (3): 367-72, 2012. [PUBMED Abstract]
43. Donaldson SS, Link MP, Weinstein HJ, et al.: Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin’s disease. J Clin Oncol 25 (3): 332-7, 2007. [PUBMED Abstract]
44. Tebbi CK, Mendenhall N, London WB, et al.: Treatment of stage I, IIA, IIIA1 pediatric Hodgkin disease with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: a Pediatric Oncology Group (POG) study. Pediatr Blood Cancer 46 (2): 198-202, 2006. [PUBMED Abstract]
45. Tebbi CK, Mendenhall NP, London WB, et al.: Response-dependent and reduced treatment in lower risk Hodgkin lymphoma in children and adolescents, results of P9426: a report from the Children’s Oncology Group. Pediatr Blood Cancer 59 (7): 1259-65, 2012. [PUBMED Abstract]
46. Kelly KM, Sposto R, Hutchinson R, et al.: BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children’s Oncology Group. Blood 117 (9): 2596-603, 2011. [PUBMED Abstract]
47. Shankar A, Hall GW, Gorde-Grosjean S, et al.: Treatment outcome after low intensity chemotherapy [CVP] in children and adolescents with early stage nodular lymphocyte predominant Hodgkin’s lymphoma – an Anglo-French collaborative report. Eur J Cancer 48 (11): 1700-6, 2012. [PUBMED Abstract]
48. Tebbi CK, London WB, Friedman D, et al.: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin’s disease. J Clin Oncol 25 (5): 493-500, 2007. [PUBMED Abstract]
49. Friedmann AM, Hudson MM, Weinstein HJ, et al.: Treatment of unfavorable childhood Hodgkin’s disease with VEPA and low-dose, involved-field radiation. J Clin Oncol 20 (14): 3088-94, 2002. [PUBMED Abstract]
50. Hudson MM, Krasin M, Link MP, et al.: Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin’s disease. J Clin Oncol 22 (22): 4541-50, 2004. [PUBMED Abstract]
51. Metzger ML, Weinstein HJ, Hudson MM, et al.: Association between radiotherapy vs no radiotherapy based on early response to VAMP chemotherapy and survival among children with favorable-risk Hodgkin lymphoma. JAMA 307 (24): 2609-16, 2012. [PUBMED Abstract]
52. Dharmarajan KV, Friedman DL, Schwartz CL, et al.: Patterns of relapse from a phase 3 Study of response-based therapy for intermediate-risk Hodgkin lymphoma (AHOD0031): a report from the Children’s Oncology Group. Int J Radiat Oncol Biol Phys 92 (1): 60-6, 2015. [PUBMED Abstract]
53. Schellong G: The balance between cure and late effects in childhood Hodgkin’s lymphoma: the experience of the German-Austrian Study-Group since 1978. German-Austrian Pediatric Hodgkin’s Disease Study Group. Ann Oncol 7 (Suppl 4): 67-72, 1996. [PUBMED Abstract]
54. Schellong G, Pötter R, Brämswig J, et al.: High cure rates and reduced long-term toxicity in pediatric Hodgkin’s disease: the German-Austrian multicenter trial DAL-HD-90. The German-Austrian Pediatric Hodgkin’s Disease Study Group. J Clin Oncol 17 (12): 3736-44, 1999. [PUBMED Abstract]
55. Chen RC, Chin MS, Ng AK, et al.: Early-stage, lymphocyte-predominant Hodgkin’s lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol 28 (1): 136-41, 2010. [PUBMED Abstract]
56. Jackson C, Sirohi B, Cunningham D, et al.: Lymphocyte-predominant Hodgkin lymphoma–clinical features and treatment outcomes from a 30-year experience. Ann Oncol 21 (10): 2061-8, 2010. [PUBMED Abstract]
57. Viviani S, Zinzani PL, Rambaldi A, et al.: ABVD versus BEACOPP for Hodgkin’s lymphoma when high-dose salvage is planned. N Engl J Med 365 (3): 203-12, 2011. [PUBMED Abstract]
58. Chisesi T, Bellei M, Luminari S, et al.: Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin’s lymphoma: a study from the Intergruppo Italiano Linfomi. J Clin Oncol 29 (32): 4227-33, 2011. [PUBMED Abstract]
59. van der Pal HJ, van Dalen EC, van Delden E, et al.: High risk of symptomatic cardiac events in childhood cancer survivors. J Clin Oncol 30 (13): 1429-37, 2012. [PUBMED Abstract]
60. Blanco JG, Sun CL, Landier W, et al.: Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes–a report from the Children’s Oncology Group. J Clin Oncol 30 (13): 1415-21, 2012. [PUBMED Abstract]
61. Mulrooney DA, Yeazel MW, Kawashima T, et al.: Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ 339: b4606, 2009. [PUBMED Abstract]

The excellent response to frontline therapy among children and adolescents with Hodgkin lymphoma limits opportunities to evaluate second-line (salvage) therapy. Because of the small number of patients that fail primary therapy, no uniform second-line treatment strategy exists for this patient population. Adverse prognostic factors after relapse include the following:[1][Level of evidence: 3iiA]

Children with localized favorable (relapse ≥12 months after completing therapy) disease recurrences whose original therapy involved reduced cycles of risk-adapted therapy or with chemotherapy alone and/or low-dose involved-field radiation therapy (LD-IRFT) consolidation have a high likelihood of achieving long-term survival after treatment with more intensive conventional chemotherapy.[5,6]

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

Patients treated with HCT may experience relapse as late as 5 years after the procedure; they should be monitored for relapse and late treatment sequelae.

Response Rates for Primary Refractory Hodgkin Lymphoma

Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with autologous HCT and radiation. However, intensification of therapy followed by HCT consolidation has been reported to achieve long-term survival in some studies.

• In one large series of patients, 5-year OS after primary refractory Hodgkin lymphoma was attained with aggressive second-line therapy (high-dose chemoradiation therapy) and autologous HCT in 49%.[46]
• In a Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) study, patients with primary refractory Hodgkin lymphoma (progressive disease on therapy or relapse within 3 months from the end of therapy) had 10-year event-free survival (EFS) and OS rates of 41% and 51%, respectively.[3]
• A study of 53 adolescent patients of the same types as those who participated in the GPOH study had similar results for EFS and OS.[47] Chemosensitivity to standard-dose second-line chemotherapy predicted a better survival (66% OS), and those who remained refractory did poorly (17% OS).[48]
• Another group has reported the PFS post-HCT for chemosensitive patients as 80% compared with 0% for those with chemoresistant disease.[28]

Second Relapse After Initial Treatment With Autologous HCT

In a phase II study, patients (median age, 26.5 years) who had relapsed or refractory disease after autologous HCT received brentuximab vedotin, with an objective response rate of 73% and a complete remission rate of 34%. Patients who achieved a complete remission (n = 34) had a 3-year PFS rate of 58% and a 3-year OS rate of 73%, with only 6 of 34 patients proceeding to allogeneic SCT while in remission.[18][Level of evidence: 2A]

Treatment Options Under Clinical Evaluation

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

1. 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. The anti–PD-1 antibody nivolumab induced objective responses in 20 of 23 patients (87%) with relapsed Hodgkin lymphoma.[49] Nivolumab is approved by the U.S. FDA for the treatment of adults and children with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin. Another anti–PD-1 antibody, pembrolizumab, produced an objective response rate of 65% in 31 heavily pretreated Hodgkin lymphoma patients who relapsed after receiving brentuximab vedotin.[50] Anti–PD-1 antibodies being studied in children with Hodgkin lymphoma include nivolumab (ADVL1412 [NCT02304458]) and pembrolizumab (NCT02332668). The anti–PD-L1 antibody atezolizumab is also being studied in children with Hodgkin lymphoma (NCT02541604).
2. APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 3,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.

   Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the ClinicalTrials.gov website for APEC1621 (NCT03155620).

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Metzger ML, Hudson MM, Krasin MJ, et al.: Initial response to salvage therapy determines prognosis in relapsed pediatric Hodgkin lymphoma patients. Cancer 116 (18): 4376-84, 2010. [PUBMED Abstract]
2. Moskowitz CH, Nimer SD, Zelenetz AD, et al.: A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood 97 (3): 616-23, 2001. [PUBMED Abstract]
3. Schellong G, Dörffel W, Claviez A, et al.: Salvage therapy of progressive and recurrent Hodgkin’s disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group. J Clin Oncol 23 (25): 6181-9, 2005. [PUBMED Abstract]
4. Gorde-Grosjean S, Oberlin O, Leblanc T, et al.: Outcome of children and adolescents with recurrent/refractory classical Hodgkin lymphoma, a study from the Société Française de Lutte contre le Cancer des Enfants et des Adolescents (SFCE). Br J Haematol 158 (5): 649-56, 2012. [PUBMED Abstract]
5. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin’s disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002. [PUBMED Abstract]
6. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin’s disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001. [PUBMED Abstract]
7. Cairo MS, Shen V, Krailo MD, et al.: Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children’s cancer group report. J Pediatr Hematol Oncol 23 (1): 30-8, 2001. [PUBMED Abstract]
8. Horton TM, Drachtman RA, Chen L, et al.: A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children’s Oncology Group study. Br J Haematol 170 (1): 118-22, 2015. [PUBMED Abstract]
9. Trippett TM, Schwartz CL, Guillerman RP, et al.: Ifosfamide and vinorelbine is an effective reinduction regimen in children with refractory/relapsed Hodgkin lymphoma, AHOD00P1: a children’s oncology group report. Pediatr Blood Cancer 62 (1): 60-4, 2015. [PUBMED Abstract]
10. Cole PD, Schwartz CL, Drachtman RA, et al.: Phase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin’s disease: a children’s oncology group report. J Clin Oncol 27 (9): 1456-61, 2009. [PUBMED Abstract]
11. Shankar A, Hayward J, Kirkwood A, et al.: Treatment outcome in children and adolescents with relapsed Hodgkin lymphoma–results of the UK HD3 relapse treatment strategy. Br J Haematol 165 (4): 534-44, 2014. [PUBMED Abstract]
12. Wimmer RS, Chauvenet AR, London WB, et al.: APE chemotherapy for children with relapsed Hodgkin disease: a Pediatric Oncology Group trial. Pediatr Blood Cancer 46 (3): 320-4, 2006. [PUBMED Abstract]
13. Sandlund JT, Pui CH, Mahmoud H, et al.: Efficacy of high-dose methotrexate, ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or refractory childhood malignant lymphoma. Ann Oncol 22 (2): 468-71, 2011. [PUBMED Abstract]
14. Schulz H, Rehwald U, Morschhauser F, et al.: Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG). Blood 111 (1): 109-11, 2008. [PUBMED Abstract]
15. Younes A, Bartlett NL, Leonard JP, et al.: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363 (19): 1812-21, 2010. [PUBMED Abstract]
16. Sea: ADCETRIS (Brentuximab Vedotin): Prescribing Information. Bothell, Wa: Seattle Genetics, 2012. Available online. Last accessed August 30, 2017.
17. Younes A, Gopal AK, Smith SE, et al.: Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol 30 (18): 2183-9, 2012. [PUBMED Abstract]
18. Gopal AK, Chen R, Smith SE, et al.: Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood 125 (8): 1236-43, 2015. [PUBMED Abstract]
19. Chen R, Gopal AK, Smith SE, et al.: Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma. Blood 128 (12): 1562-6, 2016. [PUBMED Abstract]
20. Rancea M, Monsef I, von Tresckow B, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. Cochrane Database Syst Rev 6: CD009411, 2013. [PUBMED Abstract]
21. Aparicio J, Segura A, Garcerá S, et al.: ESHAP is an active regimen for relapsing Hodgkin’s disease. Ann Oncol 10 (5): 593-5, 1999. [PUBMED Abstract]
22. Kobrinsky NL, Sposto R, Shah NR, et al.: Outcomes of treatment of children and adolescents with recurrent non-Hodgkin’s lymphoma and Hodgkin’s disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children’s Cancer Group Study CCG-5912. J Clin Oncol 19 (9): 2390-6, 2001. [PUBMED Abstract]
23. Bonfante V, Viviani S, Santoro A, et al.: Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin’s disease. Br J Haematol 103 (2): 533-5, 1998. [PUBMED Abstract]
24. Zinzani PL, Bendandi M, Stefoni V, et al.: Value of gemcitabine treatment in heavily pretreated Hodgkin’s disease patients. Haematologica 85 (9): 926-9, 2000. [PUBMED Abstract]
25. Santoro A, Bredenfeld H, Devizzi L, et al.: Gemcitabine in the treatment of refractory Hodgkin’s disease: results of a multicenter phase II study. J Clin Oncol 18 (13): 2615-9, 2000. [PUBMED Abstract]
26. Baker KS, Gordon BG, Gross TG, et al.: Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin’s disease in children and adolescents. J Clin Oncol 17 (3): 825-31, 1999. [PUBMED Abstract]
27. Akhtar S, Rauf SM, Elhassan TA, et al.: Outcome analysis of high-dose chemotherapy and autologous stem cell transplantation in adolescent and young adults with relapsed or refractory Hodgkin lymphoma. Ann Hematol 95 (9): 1521-35, 2016. [PUBMED Abstract]
28. Shafer JA, Heslop HE, Brenner MK, et al.: Outcome of hematopoietic stem cell transplant as salvage therapy for Hodgkin’s lymphoma in adolescents and young adults at a single institution. Leuk Lymphoma 51 (4): 664-70, 2010. [PUBMED Abstract]
29. Claviez A, Sureda A, Schmitz N: Haematopoietic SCT for children and adolescents with relapsed and refractory Hodgkin’s lymphoma. Bone Marrow Transplant 42 (Suppl 2): S16-24, 2008. [PUBMED Abstract]
30. Peniket AJ, Ruiz de Elvira MC, Taghipour G, et al.: An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant 31 (8): 667-78, 2003. [PUBMED Abstract]
31. Lieskovsky YE, Donaldson SS, Torres MA, et al.: High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin’s disease: results and prognostic indices. J Clin Oncol 22 (22): 4532-40, 2004. [PUBMED Abstract]
32. Akhtar S, Abdelsalam M, El Weshi A, et al.: High-dose chemotherapy and autologous stem cell transplantation for Hodgkin’s lymphoma in the kingdom of Saudi Arabia: King Faisal specialist hospital and research center experience. Bone Marrow Transplant 42 (Suppl 1): S37-S40, 2008. [PUBMED Abstract]
33. Harris RE, Termuhlen AM, Smith LM, et al.: Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children’s Oncology Group study A5962. Biol Blood Marrow Transplant 17 (2): 249-58, 2011. [PUBMED Abstract]
34. Moskowitz CH, Nademanee A, Masszi T, et al.: Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 385 (9980): 1853-62, 2015. [PUBMED Abstract]
35. Wadehra N, Farag S, Bolwell B, et al.: Long-term outcome of Hodgkin disease patients following high-dose busulfan, etoposide, cyclophosphamide, and autologous stem cell transplantation. Biol Blood Marrow Transplant 12 (12): 1343-9, 2006. [PUBMED Abstract]
36. Jabbour E, Hosing C, Ayers G, et al.: Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer 109 (12): 2481-9, 2007. [PUBMED Abstract]
37. Cooney JP, Stiff PJ, Toor AA, et al.: BEAM allogeneic transplantation for patients with Hodgkin’s disease who relapse after autologous transplantation is safe and effective. Biol Blood Marrow Transplant 9 (3): 177-82, 2003. [PUBMED Abstract]
38. Claviez A, Klingebiel T, Beyer J, et al.: Allogeneic peripheral blood stem cell transplantation following fludarabine-based conditioning in six children with advanced Hodgkin’s disease. Ann Hematol 83 (4): 237-41, 2004. [PUBMED Abstract]
39. Sureda A, Schmitz N: Role of allogeneic stem cell transplantation in relapsed or refractory Hodgkin’s disease. Ann Oncol 13 (Suppl 1): 128-32, 2002. [PUBMED Abstract]
40. Carella AM, Cavaliere M, Lerma E, et al.: Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma. J Clin Oncol 18 (23): 3918-24, 2000. [PUBMED Abstract]
41. Robinson SP, Goldstone AH, Mackinnon S, et al.: Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 100 (13): 4310-6, 2002. [PUBMED Abstract]
42. Devetten MP, Hari PN, Carreras J, et al.: Unrelated donor reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Biol Blood Marrow Transplant 15 (1): 109-17, 2009. [PUBMED Abstract]
43. Robinson SP, Sureda A, Canals C, et al.: Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognostic factors predicting outcome. Haematologica 94 (2): 230-8, 2009. [PUBMED Abstract]
44. Rauf MS, Maghfoor I, Elhassan TA, et al.: High-dose chemotherapy and auto-SCT for relapsed and refractory Hodgkin’s lymphoma patients refractory to first-line salvage chemotherapy but responsive to second-line salvage chemotherapy. Med Oncol 32 (1): 388, 2015. [PUBMED Abstract]
45. Wadhwa P, Shina DC, Schenkein D, et al.: Should involved-field radiation therapy be used as an adjunct to lymphoma autotransplantation? Bone Marrow Transplant 29 (3): 183-9, 2002. [PUBMED Abstract]
46. Morabito F, Stelitano C, Luminari S, et al.: The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin’s lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL). Bone Marrow Transplant 37 (3): 283-8, 2006. [PUBMED Abstract]
47. Akhtar S, El Weshi A, Rahal M, et al.: High-dose chemotherapy and autologous stem cell transplant in adolescent patients with relapsed or refractory Hodgkin’s lymphoma. Bone Marrow Transplant 45 (3): 476-82, 2010. [PUBMED Abstract]
48. Moskowitz CH, Kewalramani T, Nimer SD, et al.: Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin’s disease. Br J Haematol 124 (5): 645-52, 2004. [PUBMED Abstract]
49. Ansell SM, Lesokhin AM, Borrello I, et al.: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372 (4): 311-9, 2015. [PUBMED Abstract]
50. Armand P, Shipp MA, Ribrag V, et al.: Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol 34 (31): 3733-3739, 2016. [PUBMED Abstract]

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing 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 health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:

(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

References

1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]

Children and adolescent survivors of Hodgkin lymphoma may be at risk for numerous late complications of treatment related to radiation, specific chemotherapeutic exposures, and surgical staging.[1] Adverse treatment effects may impact oral/dental health; musculoskeletal growth and development; endocrine, reproductive, cardiovascular and pulmonary function; and risk of secondary carcinogenesis. In the past 30 to 40 years, pediatric Hodgkin lymphoma therapy has changed dramatically to proactively limit exposure to radiation and chemotherapeutic agents, such as anthracyclines, alkylating agents, and bleomycin. When counseling individual patients about the risk for specific treatment complications, the era of treatment should be considered.

Table 10 summarizes late health effects observed in Hodgkin lymphoma survivors, followed by a limited discussion of the common late effects. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for a full discussion of the late effects of cancer treatment in children and adolescents.)

Health Effects	Predisposing Therapy	Clinical Manifestations
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
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
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
		MS
Reproductive	Alkylating agent chemotherapy	Hypogonadism
	Gonadal irradiation	Infertility
Immune	Splenectomy	Overwhelming post-splenectomy sepsis
Subsequent neoplasm or disease	Alkylating agent chemotherapy	Myelodysplasia/acute myeloid leukemia
	Epipodophyllotoxins	Myelodysplasia/acute myeloid leukemia
	Radiation	Solid benign and malignant neoplasms

Male Gonadal Toxicity

• Gonadal radiation and alkylating agent chemotherapy may produce testicular Leydig cell or germ cell dysfunction, with risk related to cumulative dose of both modalities.
• Hypoandrogenism associated with Leydig cell dysfunction may manifest as lack of sexual development; small, atrophic testicles; and sexual dysfunction. Hypoandrogenism also increases the risk of osteoporosis and metabolic disorders associated with chronic disease.[2,3]
• Infertility caused by azoospermia is the most common manifestation of gonadal toxicity. Some pubertal male patients will have impaired spermatogenesis before they begin therapy.[4,5]
• The prepubertal testicle is likely equally or slightly less sensitive to chemotherapy compared with the pubertal testicle. Pubertal status is not protective of chemotherapy-associated gonadal toxicity.[6,7]
• Testicular Leydig cells are relatively resistant to treatment toxicity compared with testicular germ cells. Survivors who are azoospermic after gonadal toxic therapy may maintain adequate testosterone production.[6–8]
• Chemotherapy regimens that include no alkylating agents such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), ABVE (doxorubicin [Adriamycin], bleomycin, vincristine, etoposide), OEPA (vincristine [Oncovin], etoposide, prednisone, doxorubicin [Adriamycin]), or VAMP (vincristine, doxorubicin [Adriamycin], methotrexate, prednisone) are not associated with male infertility.
• Chemotherapy regimens that include more than one alkylating agent, usually procarbazine in conjunction with cyclophosphamide (i.e., COPP [cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine]), chlorambucil, or nitrogen mustard (MOPP) confer a high risk of permanent azoospermia if treatment exceeds three cycles.[9,10]
• Investigations evaluating germ cell function in relation to single alkylating agent exposure suggest that the incidence of permanent azoospermia will be low if the cyclophosphamide dose is less than 7.5 g/m2.[7,11]

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

Female Gonadal Toxicity

• Because ovarian hormone production is linked to the maturation of primordial follicles, depletion of follicles by alkylating agent chemotherapy can potentially affect both fertility and ovarian hormone production.
• Because of their greater complement of primordial follicles, the ovaries of young and adolescent girls are less sensitive to the effects of alkylating agents than are the ovaries of older women. In general, girls maintain ovarian function at higher cumulative alkylating agent doses compared with the germ cell function maintained in boys.
• Most females treated with contemporary risk-adapted therapy will have menarche (if prepubertal at treatment) or regain normal menses (if pubertal at treatment) unless pelvic radiation therapy is given without oophoropexy. Current regimens used in pediatric oncology are tailored to minimize the risk of ovarian failure. Data presented below related to pediatric treatment before 1987 [12,13] or adult trials in Europe (European Organisation for Research and Treatment of Cancer H1–H9 trials) [14] are not likely reflective of the expected reproductive outcomes in the current era.
• Ovarian transposition to a lateral or medial region from the planned radiation volume may preserve ovarian function in young and adolescent girls who require pelvic radiation therapy for lymphoma.[15]
• The risk of acute ovarian failure and premature menopause is substantial if treatment includes combined-modality therapy with alkylating agent chemotherapy and abdominal or pelvic radiation or dose-intensive alkylating agents for myeloablative conditioning before hematopoietic cell transplantation.[12,13] The risk of ovarian failure after treatment with contemporary regimens using lower cumulative doses of cyclophosphamide without procarbazine is anticipated to be lower.
• In the Childhood Cancer Survivor Study (CCSS), investigators observed that Hodgkin lymphoma survivors were among the highest risk groups for acute ovarian failure and early menopause. In this cohort, the cumulative incidence of nonsurgical premature menopause among survivors treated with alkylating agents and abdominal or pelvic radiation approached 30%.[12,13] These patients were treated before 1986, usually with substantially higher doses of alkylating agents than are used in current regimens in the Children’s Oncology Group, Euronet, or other consortiums.
• A German study demonstrated that parenthood for female survivors of Hodgkin lymphoma was similar to that of the general population, although parenthood was lower for survivors who received pelvic radiation therapy.[16]

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

Thyroid Abnormalities

• Abnormalities of the thyroid gland, including hypothyroidism, hyperthyroidism, and thyroid neoplasms have been reported to occur at a higher rate among survivors of Hodgkin lymphoma than in the general population.
• Risk factors for hypothyroidism include increasing dose of radiation, female sex, and older age at diagnosis.[17–19] CCSS investigators reported a 20-year actuarial risk of 30% of developing hypothyroidism in Hodgkin survivors treated with 3,500 cGy to 4,499 cGy and 50% for subjects whose thyroid received 4,500 cGy or more.
• Hypothyroidism develops most often in the first 5 years after treatment, but new cases have been reported to emerge more than 20 years after the diagnosis.[18]
• Hyperthyroidism has been observed after treatment for Hodgkin lymphoma, with a clinical picture similar to that of Graves disease.[20] Higher radiation dose has been associated with greater risk of hyperthyroidism.[18]
• Thyroid neoplasms, both benign and malignant, have been reported with increased frequency after neck irradiation. The incidence of nodules varies substantially across studies (2%–65%) depending on the length of follow-up and detection methods used.[17–19]

  The relative risk (RR) of thyroid cancer is increased among Hodgkin lymphoma survivors (approximately 18-fold for the CCSS Hodgkin lymphoma cohort compared with the general population).[19] 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).[19] 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.[19]

  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.[21]

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

Cardiac Toxicity

Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk for long-term cardiac toxicity. The effects of thoracic radiation therapy are difficult to separate from those of anthracyclines because few children undergo thoracic radiation therapy without the use of anthracyclines. The pathogenesis of injury differs, however, with radiation primarily affecting the fine vasculature of the heart, and anthracyclines directly damaging myocytes.[22–24]

Radiation-associated cardiovascular toxicity

• Late effects of radiation to the heart may include the following:[25–28]
  • Delayed pericarditis.
  • Pancarditis including pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
  • Cardiomyopathy.
  • Coronary artery disease.[24,28]
  • Functional valve injury.[24,29]
  • Conduction defects.

  The risks to the heart are related to the amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, and latency period.

• Modern radiation techniques allow a reduction in the volume of cardiac tissue incidentally exposed to higher radiation doses. It is anticipated that this will reduce the risk of adverse cardiac events.
• Austrian-German investigators evaluated the development of cardiac disease (via patient self-report supplemented by physician report) in a cohort of 1,132 pediatric Hodgkin lymphoma survivors monitored for a median of 20 years. The 25-year cumulative incidence of heart disease increased with higher mediastinal radiation doses: 3% (unirradiated), 5% (20 Gy), 6% (25 Gy), 10% (30 Gy), and 21% (36 Gy). Valve defects were most common, followed by coronary artery disease, cardiomyopathy, rhythm disorders, and pericardial abnormalities.[29]
• In a study of adult survivors of Hodgkin lymphoma, vigorous exercise lowered the risk of cardiovascular events, independent of the treatment received.[30]

Anthracycline-related cardiac toxicity

• Late complications related to anthracycline injury may include subclinical left ventricular dysfunction, cardiomyopathy, and congestive heart failure.[24]
• Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, cumulative doses higher than 200 mg/m2 to 300 mg/m2, younger age at time of exposure, and increased time from exposure.[31]
• Prevention or amelioration of anthracycline-induced cardiomyopathy is important because the continued usage of anthracyclines is required in cancer therapy in more than one-half of children with newly diagnosed cancer.[32,33]
• Dexrazoxane (a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent) has been shown to prevent heart damage in adults and children treated with anthracyclines.[34] Studies suggest that dexrazoxane is safe and does not interfere with chemotherapeutic efficacy.
• Studies of cancer survivors treated with anthracyclines have not demonstrated the benefit of enalapril in preventing progressive cardiac toxicity.[35,36]

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

Subsequent Neoplasms

• A number of series evaluating the incidence of subsequent neoplasms in survivors of childhood and adolescent Hodgkin lymphoma have been published.[37–46] Many of the patients included in these series received high-dose radiation therapy and high-dose alkylating agent chemotherapy regimens, which are no longer used.
• Subsequent neoplasms comprise two distinct groups: chemotherapy-related myelodysplasia and acute myeloid leukemia (AML) and solid neoplasms that are predominately radiation related.[47,48]
• Secondary hematological malignancy (most commonly AML and myelodysplasia) is related to the use of alkylating agents, anthracycline, and etoposide and exhibit a brief latency period (<10 years from the primary cancer).[49] This excess risk is largely related to cases of myelodysplasia and secondary AML. A single-study experience suggests that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity.[50] Clinical trials using dexrazoxane in childhood leukemia have not observed an excess risk of subsequent neoplasms.[50–52]
• Chemotherapy-related myelodysplasia and AML are less prevalent following contemporary therapy because of the restriction of cumulative alkylating agent doses.[53,54]
• Solid neoplasms most often involve the skin, breast, thyroid, gastrointestinal tract, lung, and head and neck, with risk increasing with radiation dose.[44,46,55]
• The risk of a secondary solid tumor escalates with the passage of time after diagnosis of Hodgkin lymphoma, with a latency of 20 years or more.
• Breast cancer is the most common therapy-related solid subsequent neoplasm after Hodgkin lymphoma. The absolute excess risk ranges from 18.6 to 79 per 10,000 person-years, and the cumulative incidence ranges from 12% to 26%, 25 to 30 years after radiation exposure.[43,56–58]
• High risk of breast cancer has been found to increase as early as 8 years from radiation exposure, is rare before age 25 years, and continues to increase with time from exposure. Importantly, breast cancer in female childhood cancer survivors typically develops at least 25 years earlier than that of primary breast cancer in the general population and often years before the implementation of population-based screening.[43]
• The cumulative incidence of breast cancer by age 40 to 45 years ranges from 13% to 20%, compared with a 1% risk for women in the general population.[43,56,58,59] This risk is similar to what is observed for women with a BRCA gene mutation, where, by age 40 years, the cumulative incidence of breast cancer ranges from 10% to 19%.[60]
• The risk for breast cancer in female survivors of Hodgkin lymphoma is directly related to the dose of radiation therapy received over a range from 4 Gy to 40 Gy.[61] Female patients treated with both radiation therapy and alkylating agent chemotherapy have a lower RR for developing breast cancer than women receiving radiation therapy alone.[44,62] CCSS investigators also demonstrated that breast cancer risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries.[63] The protective effect of alkylating chemotherapy and ovarian radiation is believed to be mediated through induction of premature menopause, suggesting that hormone stimulation contributes to the development of radiation-induced breast cancer.[64]
• A study of women survivors who received chest radiation for Hodgkin lymphoma showed that one of the most important factors in obtaining breast cancer screening per guidelines was recommendation from their treating physician.[65] Standard guidelines for routine breast screening are available. The COG guidelinesExit Disclaimer recommend annual screening with magnetic resonance imaging and mammograms for women beginning 8 years after treatment or at age 25 years, whichever is later.[65]

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

References

1. Ng AK: Current survivorship recommendations for patients with Hodgkin lymphoma: focus on late effects. Blood 124 (23): 3373-9, 2014. [PUBMED Abstract]
2. Greenfield DM, Walters SJ, Coleman RE, et al.: Prevalence and consequences of androgen deficiency in young male cancer survivors in a controlled cross-sectional study. J Clin Endocrinol Metab 92 (9): 3476-82, 2007. [PUBMED Abstract]
3. Howell SJ, Radford JA, Adams JE, et al.: The impact of mild Leydig cell dysfunction following cytotoxic chemotherapy on bone mineral density (BMD) and body composition. Clin Endocrinol (Oxf) 52 (5): 609-16, 2000. [PUBMED Abstract]
4. Fitoussi, Eghbali H, Tchen N, et al.: Semen analysis and cryoconservation before treatment in Hodgkin’s disease. Ann Oncol 11 (6): 679-84, 2000. [PUBMED Abstract]
5. Viviani S, Ragni G, Santoro A, et al.: Testicular dysfunction in Hodgkin’s disease before and after treatment. Eur J Cancer 27 (11): 1389-92, 1991. [PUBMED Abstract]
6. Howell SJ, Shalet SM: Effect of cancer therapy on pituitary-testicular axis. Int J Androl 25 (5): 269-76, 2002. [PUBMED Abstract]
7. Kenney LB, Laufer MR, Grant FD, et al.: High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 91 (3): 613-21, 2001. [PUBMED Abstract]
8. Rowley MJ, Leach DR, Warner GA, et al.: Effect of graded doses of ionizing radiation on the human testis. Radiat Res 59 (3): 665-78, 1974. [PUBMED Abstract]
9. Hobbie WL, Ginsberg JP, Ogle SK, et al.: Fertility in males treated for Hodgkins disease with COPP/ABV hybrid. Pediatr Blood Cancer 44 (2): 193-6, 2005. [PUBMED Abstract]
10. da Cunha MF, Meistrich ML, Fuller LM, et al.: Recovery of spermatogenesis after treatment for Hodgkin’s disease: limiting dose of MOPP chemotherapy. J Clin Oncol 2 (6): 571-7, 1984. [PUBMED Abstract]
11. Meistrich ML, Wilson G, Brown BW, et al.: Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 70 (11): 2703-12, 1992. [PUBMED Abstract]
12. Chemaitilly W, Mertens AC, Mitby P, et al.: Acute ovarian failure in the childhood cancer survivor study. J Clin Endocrinol Metab 91 (5): 1723-8, 2006. [PUBMED Abstract]
13. Sklar CA, Mertens AC, Mitby P, et al.: Premature menopause in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 98 (13): 890-6, 2006. [PUBMED Abstract]
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