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 produces less 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.[3] In developing countries, there is a similar rate in young adults but a much higher incidence in childhood.[4]

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.[5]
• 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).[6,7]
• 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.[5] Early exposure to common infections in early childhood appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity.[8,9]

  -

  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.[10] 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.[8]

  -

  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.[11]

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.[24,25]
• Nonspecific constitutional symptoms including fatigue, anorexia, weight loss, pruritus, night sweats, and fever occur in approximately 25% of patients.[24,25]
• 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.[26]

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.[27]
• Presence of B symptoms.[24,25]
• Presence of bulky disease.[24]
• Extranodal extension.
• Elevated erythrocyte sedimentation rate.
• Leukocytosis (white blood cell count of 11,500/mm³ or higher).[27]
• Anemia (hemoglobin lower than 11.0 g/dL).
• Male gender.[25,27]
• Response to initial treatment with chemotherapy.[28,29]

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

• In the Society for Paediatric Oncology and Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]) GPOH-95 study, B symptoms, histology, and male gender were adverse prognostic factors for event-free survival on multivariate analysis.[25]
• In 320 children with clinically staged Hodgkin lymphoma treated in the Stanford-St. Jude-Dana Farber Cancer Institute consortium, male gender; stage IIB, IIIB, or IV disease; white blood cell count of 11,500/mm³ or higher; and hemoglobin lower than 11.0 g/dL were significant prognostic factors for inferior disease-free survival and overall survival (OS). Prognosis was also associated with the number of adverse factors.[27]
• In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome.[24]
• One single-institutional study showed that African American patients had a higher relapse rate than did white patients, but OS was similar.[30]

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.[28,29,31] Positron emission tomography (PET) scanning is being evaluated as a method to assess early response in pediatric Hodgkin lymphoma.[32] Fluorodeoxyglucose-PET avidity after two cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[33-35] 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. [PMC free article: PMC4136455] [PubMed: 24853691]
2. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PubMed: 15173520]
3. 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 December 08, 2015.
4. 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: 7705942]
5. Grufferman S, Delzell E: Epidemiology of Hodgkin's disease. Epidemiol Rev 6: 76-106, 1984. [PubMed: 6092122]
6. 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 December 08, 2015.
7. 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 December 08, 2015.
8. 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: 15247136]
9. 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: 21170962]
10. 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: 9378561]
11. 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. [PMC free article: PMC3571233] [PubMed: 23171883]
12. 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: 15961758]
13. 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: 24937173]
14. 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: 15941916]
15. 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: 18391697]
16. 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: 9697883]
17. 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: 16434497]
18. 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. [PMC free article: PMC3643756] [PubMed: 23386127]
19. 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: 14523140]
20. 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: 3592132]
21. 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: 11418480]
22. Biggar RJ, Jaffe ES, Goedert JJ, et al.: Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108 (12): 3786-91, 2006. [PMC free article: PMC1895473] [PubMed: 16917006]
23. 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: 10889594]
24. 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: 12228196]
25. 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: 11728679]
26. 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: 4052959]
27. 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: 12743158]
28. 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: 10735898]
29. 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. [PMC free article: PMC4220044] [PubMed: 25311218]
30. 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: 18323551]
31. 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: 9256118]
32. 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: 23151729]
33. 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: 16150944]
34. 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: 17646666]
35. 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: 17018856]

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]

• 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.[21-23]
• 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.[21,22]

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: 16385563]
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: 17908620]
3. Re D, Küppers R, Diehl V: Molecular pathogenesis of Hodgkin's lymphoma. J Clin Oncol 23 (26): 6379-86, 2005. [PubMed: 16155023]
4. Küppers R, Schwering I, Bräuninger A, et al.: Biology of Hodgkin's lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002. [PubMed: 12078890]
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: 15180859]
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. [PMC free article: PMC1858022] [PubMed: 9327746]
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: 14614054]
8. Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002. [PubMed: 12036854]
9. Pileri SA, Ascani S, Leoncini L, et al.: Hodgkin's lymphoma: the pathologist's viewpoint. J Clin Pathol 55 (3): 162-76, 2002. [PMC free article: PMC1769601] [PubMed: 11896065]
10. Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999. [PubMed: 10462322]
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: 10961891]
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: 21054151]
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. [PMC free article: PMC3257012] [PubMed: 22086417]
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: 19455461]
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: 17760808]
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: 25863756]
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: 22994199]
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: 11154228]
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: 12881319]
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: 10935647]
21. 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: 19933914]
22. 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: 20332141]
23. Appel BE, Chen L, Buxton A, et al.: Impact of low-dose involved-field radiation therapy on pediatric patients with lymphocyte-predominant Hodgkin lymphoma treated with chemotherapy: a report from the Children's Oncology Group. Pediatr Blood Cancer 59 (7): 1284-9, 2012. [PMC free article: PMC3468707] [PubMed: 22847767]

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.

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] 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.[16] Staging is independent of the imaging modality used.

Extralymphatic disease resulting from direct extension of an involved lymph node region is designated E. Extralymphatic disease can cause confusion in staging. For example, the designation E is not appropriate for cases of widespread disease or diffuse extralymphatic disease (e.g., large pleural effusion that is cytologically positive for Hodgkin lymphoma), which should be considered stage IV. If pathologic proof of noncontiguous involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Current practice is to assign a clinical stage on the basis of findings of the clinical evaluation; however, pathologic confirmation of noncontiguous extralymphatic involvement is strongly suggested for assignment to stage IV.

Risk Stratification

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

Figure

Figure 1. Variation in risk stratification across pediatric Hodgkin study groups and protocols. E, extranodal extension; X, bulky disease (peripheral >6 cm and mediastinal bulk); mX, mediastinal bulk (≥0.33 mediastinal to thoracic ratio); (more...)

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.

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: 23047832]
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. [PMC free article: PMC4979083] [PubMed: 25113753]
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: 20625128]
4. Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's lymphoma. Pediatr Radiol 34 (3): 190-8, 2004. [PubMed: 14745528]
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: 16622665]
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: 11843811]
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: 16150944]
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: 21559977]
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: 21437590]
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: 20646867]
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: 24351400]
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: 22957898]
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. [PMC free article: PMC4400730] [PubMed: 17897276]
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: 18422997]
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: 5121694]
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: 2809679]
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: 26304892]
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: 16794504]
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: 9256118]
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. [PMC free article: PMC2744567] [PubMed: 19584400]
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. [PMC free article: PMC4220044] [PubMed: 25311218]
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. [PMC free article: PMC3062352] [PubMed: 21079154]
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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, gender, and histological subtype may also be considered in treatment planning.

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.[30]

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.

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

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

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.[55,56] 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.[57,58] Subsequent need for mediastinal radiation can further enhance the risk of a variety of late cardiac events.[57-59] 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

Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I childhood Hodgkin lymphoma, stage II childhood Hodgkin lymphoma, stage III childhood Hodgkin lymphoma and stage IV childhood Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

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53. 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: 19933914]
54. 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: 20332141]
55. 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: 21774708]
56. 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: 21990405]
57. 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: 22473161]
58. 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. [PMC free article: PMC3383117] [PubMed: 22124095]
59. 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. [PMC free article: PMC3266843] [PubMed: 19996459]

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%.[42]
• 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.[43] Chemosensitivity to standard-dose second-line chemotherapy predicted a better survival (66% OS), and those who remained refractory did poorly (17% OS).[44]
• Another group has reported the PFS post-HCT for chemosensitive patients as 80% compared with 0% for those with chemoresistant disease.[26]

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

The following is an example of a national and/or institutional clinical trial that is currently being conducted or is under analysis. Information about ongoing clinical trials is available from the NCI website.

1. AHOD1221 (NCT01780662) (Brentuximab Vedotin and Gemcitabine Hydrochloride in Treating Younger Patients With Relapsed or Refractory Hodgkin Lymphoma): Both brentuximab vedotin and gemcitabine are active as single agents against Hodgkin lymphoma.[15,17,24,45,46] The objectives of this phase I/II trial include the following:

   • Determine the maximum tolerated doses of brentuximab vedotin and gemcitabine hydrochloride when given together to pediatric patients with relapsed or refractory Hodgkin lymphoma.
   • Define the incidence of adverse events at the maximum tolerated doses of the two agents.
   • Determine the objective response rate for the brentuximab vedotin and gemcitabine regimen.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials that are now accepting patients with recurrent/refractory childhood Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

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. [PMC free article: PMC2936658] [PubMed: 20564743]
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: 11157476]
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: 16135485]
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: 22757721]
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: 12228196]
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: 11728679]
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: 11196267]
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. [PMC free article: PMC4478135] [PubMed: 25833390]
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. [PMC free article: PMC4465390] [PubMed: 25308760]
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. [PMC free article: PMC2668553] [PubMed: 19224841]
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: 24754633]
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: 16200630]
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. [PMC free article: PMC3030464] [PubMed: 20624787]
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: 17938252]
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: 21047225]
16. Sea: ADCETRIS (Brentuximab Vedotin): Prescribing Information. Bothell, Wa: Seattle Genetics, 2012. Available online. Last accessed December 08, 2015.
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. [PMC free article: PMC3646316] [PubMed: 22454421]
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. [PMC free article: PMC4335079] [PubMed: 25533035]
19. 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: 23784872]
20. 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: 10416011]
21. 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: 11331317]
22. 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: 9827930]
23. 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: 10980630]
24. 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: 10893294]
25. 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: 10071273]
26. 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. [PMC free article: PMC2932472] [PubMed: 20367182]
27. 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: 18978738]
28. 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: 12692607]
29. 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: 15542804]
30. 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: 18724297]
31. 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. [PMC free article: PMC3072756] [PubMed: 20637881]
32. 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: 17162217]
33. 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: 17497648]
34. 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: 12652468]
35. 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: 14625790]
36. 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: 12078894]
37. 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: 11099321]
38. 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: 12393626]
39. 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. [PMC free article: PMC2929570] [PubMed: 19135949]
40. 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. [PMC free article: PMC2635413] [PubMed: 19066328]
41. 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: 11859389]
42. 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: 16327815]
43. 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: 19734949]
44. 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: 14871252]
45. Fosså A, Santoro A, Hiddemann W, et al.: Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol 17 (12): 3786-92, 1999. [PubMed: 10577850]
46. Gopal AK, Ramchandren R, O'Connor OA, et al.: Safety and efficacy of brentuximab vedotin for Hodgkin lymphoma recurring after allogeneic stem cell transplantation. Blood 120 (3): 560-8, 2012. [PMC free article: PMC3731651] [PubMed: 22510871]

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 gender, 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 gender (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 gender 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]

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 guidelines 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

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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: 11169946]
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: 4428015]
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: 15390272]
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: 6547167]
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: 1423201]
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: 16492690]
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: 16818852]
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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Hodgkin Lymphoma Treatment are:

• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Alan Scott Gamis, MD, MPH (Children's Mercy Hospital)
• Thomas G. Gross, MD, PhD (National Cancer Institute)
• Melissa Maria Hudson, MD (St. Jude Children's Research Hospital)
• Kenneth L. McClain, MD, PhD (Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/lymphoma/hp/child-hodgkin-treatment-pdq. Accessed <MM/DD/YYYY>.

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Based on the strength of the available evidence, treatment options may be described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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