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Childhood Hodgkin Lymphoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Childhood Hodgkin Lymphoma Treatment

General Information

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[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 primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

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

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For Hodgkin lymphoma, the 5-year survival rate has increased over the same time from 81% to more than 94% for children and adolescents.[1] Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Overview of Childhood Hodgkin Lymphoma

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

Epidemiology

Hodgkin lymphoma comprises 6% of childhood cancers. In the United States, the incidence of Hodgkin lymphoma is age-related and is highest among adolescents aged 15 to 19 years (29 cases per million per year), with children ages 10 to 14 years, 5 to 9 years, and 0 to 4 years having approximately threefold, eightfold, and 30-fold lower rates, respectively.[3] In non-European Union 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:

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 serologic status is not a prognostic factor for failure-free survival in pediatric and young adult Hodgkin lymphoma patients.[10,13,14,15,17] Patients with a prior history of serologically confirmed infectious mononucleosis have a fourfold increased risk of developing EBV-positive Hodgkin lymphoma; these patients are not at increased risk for EBV-negative Hodgkin lymphoma.[18]

Immunodeficiency and Hodgkin lymphoma

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

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

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.

Prognostic Factors

As the treatment of Hodgkin lymphoma has improved, factors that are associated with outcome have become more difficult to identify. Several factors, however, continue to influence the success and choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and biologic aggressiveness are frequently codependent. Further complicating the identification of prognostic factors is their use in determining the aggressiveness of therapy. For example, in a report from the German-Austrian Pediatric multicenter trial DAL-HD-90, bulky disease was not a prognostic factor for outcome on multivariate analysis. However, in this study, boost irradiation doses were given to patients who had postchemotherapy residual disease, which could have obfuscated the relevance of bulky disease at presentation.[26] This underscores the complexity in determining prognostic factors.

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

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

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. Fluorodeoxyglucose-PET avidity after two cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[32,33,34] Further studies in children are required to assess the role of early response based on PET. The value of PET avidity to predict outcome and whether improved outcome can be achieved by altering the therapeutic strategy based on early PET response is to be determined.

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

References:

  1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
  2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
  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 February 01, 2013.
  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.
  5. Grufferman S, Delzell E: Epidemiology of Hodgkin's disease. Epidemiol Rev 6: 76-106, 1984.
  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 February 01, 2013.
  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 April 04, 2013.
  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.
  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.
  10. 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.
  11. Araujo I, Bittencourt AL, Barbosa HS, et al.: The high frequency of EBV infection in pediatric Hodgkin lymphoma is related to the classical type in Bahia, Brazil. Virchows Arch 449 (3): 315-9, 2006.
  12. Makar RR, Saji T, Junaid TA: Epstein-Barr virus expression in Hodgkin's lymphoma in Kuwait. Pathol Oncol Res 9 (3): 159-65, 2003.
  13. Herling M, Rassidakis GZ, Medeiros LJ, et al.: Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome. Clin Cancer Res 9 (6): 2114-20, 2003.
  14. 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.
  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.
  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.
  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.
  18. 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.
  19. 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.
  20. 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.
  21. Biggar RJ, Jaffe ES, Goedert JJ, et al.: Hodgkin lymphoma and immunodeficiency in persons with HIV/AIDS. Blood 108 (12): 3786-91, 2006.
  22. 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.
  23. 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.
  24. 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.
  25. Gobbi PG, Cavalli C, Gendarini A, et al.: Reevaluation of prognostic significance of symptoms in Hodgkin's disease. Cancer 56 (12): 2874-80, 1985.
  26. Dieckmann K, Pötter R, Hofmann J, et al.: Does bulky disease at diagnosis influence outcome in childhood Hodgkin's disease and require higher radiation doses? Results from the German-Austrian Pediatric Multicenter Trial DAL-HD-90. Int J Radiat Oncol Biol Phys 56 (3): 644-52, 2003.
  27. Smith RS, Chen Q, Hudson M, et al.: Prognostic factors in pediatric Hodgkin's disease. [Abstract] Int J Radiat Oncol Biol Phys 51 (3 Suppl 1): 119, 2001.
  28. Carde P, Koscielny S, Franklin J, et al.: Early response to chemotherapy: a surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity? Ann Oncol 13 (Suppl 1): 86-91, 2002.
  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.
  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.
  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.
  32. 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.
  33. 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.
  34. 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.

Cellular Classification and Biologic Correlates

Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Reed-Sternberg cells) or large mononuclear cell variants (lymphocytic and histiocytic cells) in a background of inflammatory cells consisting of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts. The inflammatory cells are present in different proportions depending on the histologic subtype. It has been conclusively shown that Reed-Sternberg cells and/or lymphocytic and histiocytic cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from germinal center B cells that cannot synthesize immunoglobulin.[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 classic Hodgkin lymphoma is the Reed-Sternberg cell,[4] which has 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:

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:

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

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.
  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.
  3. Re D, Küppers R, Diehl V: Molecular pathogenesis of Hodgkin's lymphoma. J Clin Oncol 23 (26): 6379-86, 2005.
  4. Küppers R, Schwering I, Bräuninger A, et al.: Biology of Hodgkin's lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002.
  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.
  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.
  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.
  8. Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002.
  9. Pileri SA, Ascani S, Leoncini L, et al.: Hodgkin's lymphoma: the pathologist's viewpoint. J Clin Pathol 55 (3): 162-76, 2002.
  10. Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999.
  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.
  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.
  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.
  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.
  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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.

Diagnosis and Staging

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

Pretreatment Staging

The diagnostic and staging evaluation is a critical determinant in the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes the following:[1,2]

Systemic symptoms

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

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

Physical examination

Laboratory studies

Anatomic imaging

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

Definition of bulky disease

The posteroanterior chest radiograph remains important since the criterion for bulky mediastinal lymphadenopathy used in North American protocols 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. This definition is no longer used in some European protocols because it does not influence risk classification.

The criteria for bulky peripheral (nonmediastinal) lymphadenopathy have varied per cooperative group study protocols from aggregate nodal masses exceeding 4 to 6 cm. This disease characteristic has not been consistently used among all groups for risk 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:

Functional imaging

The recommended functional imaging procedure for initial staging is now PET.[4,5] In PET scanning, uptake of the radioactive glucose analog, 18-fluoro-2-deoxyglucose (FDG) correlates with proliferative activity in tumors undergoing anaerobic glycolysis. PET-CT, which integrates functional and anatomic tumor characteristics, is often used for staging and monitoring of pediatric patients with Hodgkin lymphoma. Residual or persistent FDG avidity has been correlated with prognosis and the need for additional therapy in posttreatment evaluation.[6,7,8,9]

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

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

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

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 [13] and revised in 1989.[14] Staging is independent of the imaging modality used.

Table 1. Ann Arbor Staging Classification for Hodgkin Lymphomaa

Stage Description
a Reprinted 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.[15]
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 various pediatric research groups, and often even between different studies conducted by the same group, as summarized in Table 2.

Table 2. Criteria Used for the Classification of Risk Groups in Childhood Hodgkin Lymphoma Clinical Trialsa

Trial Low Risk Intermediate Risk High Risk
E = extralymphatic.
a Adapted from Kelly.[16]
Children's Oncology Group
AHOD0031[17]   IA bulk or E; IB; IIA bulk or E; IIB; IIIA, IVA  
AHOD0431[18] IA, IIA with no bulk    
AHOD0831     IIIB, IVB
C5942[19] IA, IB, IIA with no bulk, no hilar nodes and <4 sites IA, IB, IIA with bulk, hilar nodes or ≥4 sites; III IV
C59704[20]     IIB/IIIB with bulk, IV
P9425/P9426[21] IA, IIA with no bulk IB, IIA, IIIA1 with bulk; IIIA2 IIB, IIIB, IV
 
German Multicenter/Euronet
GPOH-HD 95; GPOH-HD 2002;PHL-C1[3,22,23] 1A/B, IIA IE A/B;IIE A; IIB; IIIA IIE B; IIIE A/B; IIIB; IV
 
Stanford/St. Jude/Dana-Farber Cancer Institute Consortium
HOD05   IB, IIIA, IA/IIA with E, ≥3 sites or bulk  
HOD08 IA, IIA with no bulk, E and <3 sites    
HOD99     IIB, IIIB, IV

Although all major research groups classify patients according to clinical criteria, such as stage and presence of B symptoms, extranodal involvement, or bulky disease, comparison of outcomes across trials is further complicated because of differences in how these individual criteria are defined.

Response Assessment

Further refinement of risk classification may be performed through assessment of response after initial cycles of chemotherapy or at its completion.

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.[24,25] Definitions for interim response are variable and protocol specific, but can range from volume reductions of greater than 50% to the achievement of a complete response with a volume reduction of greater than 95% by anatomic imaging or resolution of FDG-PET avidity.[3,18,21]

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.

Results of selected trials using interim response to titrate therapy

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:

References:

  1. Hueltenschmidt B, Sautter-Bihl ML, Lang O, et al.: Whole body positron emission tomography in the treatment of Hodgkin disease. Cancer 91 (2): 302-10, 2001.
  2. Friedberg JW, Canellos GP, Neuberg D, et al.: A prospective, blinded comparison of positron emission tomography (PET) with gallium/SPECT scintigraphy in the staging and follow-up of patients (pts) with de novo Hodgkin's disease. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-123, 64, 2001.
  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.
  4. Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's lymphoma. Pediatr Radiol 34 (3): 190-8, 2004.
  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.
  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.
  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.
  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.
  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.
  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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010.
  16. Kelly KM: Management of children with high-risk Hodgkin lymphoma. Br J Haematol 157 (1): 3-13, 2012.
  17. Friedman DI, Wolden S, Constine L, et al.: AHOD0031: A phase III study of dose intensive therapy for intermediate risk Hodgkin lymphoma: a report from the Children's Oncology Group. [Abstract] Blood 116 (22): A-766, 2010.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007.
  28. Brepoels L, Stroobants S, De Wever W, et al.: Hodgkin lymphoma: Response assessment by revised International Workshop Criteria. Leuk Lymphoma 48 (8): 1539-47, 2007.
  29. Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007.
  30. Cheson BD: The International Harmonization Project for response criteria in lymphoma clinical trials. Hematol Oncol Clin North Am 21 (5): 841-54, 2007.
  31. 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.
  32. 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.
  33. Levine JM, Weiner M, Kelly KM: Routine use of PET scans after completion of therapy in pediatric Hodgkin disease results in a high false positive rate. J Pediatr Hematol Oncol 28 (11): 711-4, 2006.
  34. Rhodes MM, Delbeke D, Whitlock JA, et al.: Utility of FDG-PET/CT in follow-up of children treated for Hodgkin and non-Hodgkin lymphoma. J Pediatr Hematol Oncol 28 (5): 300-6, 2006.
  35. 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.
  36. 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.

Treatment for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma

Historical Overview of Treatment for Hodgkin Lymphoma

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

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

  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 and restriction of its use in contemporary trials.[1,2,3]
    • 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 as a single modality 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. The cumulative dose of these agents is proactively restricted in pediatric patients to reduce this risk.[10,11,12]
    • 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.
  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 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.
    • 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.[17,18]

Treatment Approaches

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

Risk designation

Risk-adapted treatment paradigms

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

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.[25]

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

General trends in radiation treatment volume are summarized as follows:

Table 3. Sample Definitions of Sites and Corresponding Involved-Field Radiation Therapy Treatment Fieldsa

Involved Node(s) Radiation Field
a Adapted from Hudson.[28]
b Upper cervical region not treated if supraclavicular involvement is extension of the mediastinal disease.
c Prechemotherapy volume is treated except for lateral borders of the mediastinal field, which is postchemotherapy.
Cervical Neck and infraclavicular/supraclavicularb
Supraclavicular Neck and infraclavicular/supraclavicular ± axilla
Axilla Axilla ± infraclavicular/supraclavicular
Mediastinum Mediastinum, hila, infraclavicular/supraclavicularb,c
Hila Hila, mediastinum
Spleen Spleen ± para-aortics
Para-aortics Para-aortics ± spleen
Iliac Ipsilateral iliac ± inguinal + femoral
Inguinal Inguinal + femoral ± iliac
Femoral Inguinal + femoral ± iliac

A breast-sparing radiation-therapy plan using proton therapy is being evaluated to determine if there is a statistically significant reduction in dose.[29] Long-term results are awaited.

Considerations in IFRT Treatment Planning

Traditional definitions of lymph node regions can be helpful for defining IFRT but may not be sufficient. The following issues should be considered in IFRT treatment planning:

Radiation dose

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

Technical considerations

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

Role of LD-IFRT 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-IFRT may permit a reduction in the intensity or duration of chemotherapy below toxicity thresholds that would not be possible if single modality chemotherapy were used, thus decreasing overall acute and late toxicities.

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

Additionally, when considering the role of RT in the initial management of Hodgkin lymphoma, one must carefully consider the endpoint that is being evaluated. Unlike most other pediatric malignancies, Hodgkin lymphoma is often salvageable if initial treatment does not result in a CR or if relapse occurs. For example, studies comparing combination chemotherapy with or without RT in adults with advanced-stage Hodgkin lymphoma showed that EFS was higher for patients who received initial chemotherapy and RT; however, OS was no different for patients whose initial therapy was chemotherapy alone.[35] Among adult Hodgkin lymphoma patients, study results conflict regarding whether adjuvant RT improves OS compared with chemotherapy alone, despite an improvement in EFS, because of the ability to effectively salvage patients who relapse after initial therapy.[36] Thus, it is not clear whether EFS or OS should be the appropriate endpoint for a trial comparing chemotherapy with or without radiation.

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

Chemotherapy

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

Combination chemotherapy regimens used in contemporary trials are summarized in Table 4.

Table 4. Contemporary Chemotherapy Regimens for Children and Adolescents with Hodgkin Lymphoma

Name Drugs Dosage Route Days
IV = intravenous; PO = oral.
COPP [37] 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[37] Dacarbazine substituted for procarbazine in COPP 250 mg/m2 IV 1–3
OPPA[37] 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[37] 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[38] 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[39] 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[32] 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[40] 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

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) [41] for favorable low-stage patients and dose-dense ABVE-PC (prednisone and cyclophosphamide) for unfavorable advanced-stage patients in combination with 21 Gy IFRT.[32]

Key findings from these trials include the following:

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:[14,17]

Another CCG Study (COG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP regimen followed by a gender-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[40][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:[40]

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:

German multicenter trials

In the last 30 years, German investigators have implemented a series of risk-adapted trials evaluating gender-based treatments featuring multiagent chemotherapy with OPPA/COPP and IFRT.

Key findings from these trials include the following:

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.

Table 5. Low-Risk Disease (Stages I–IIA; No Bulky Disease; No B Symptoms)

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.
a Refer toTable 4for more information about the chemotherapy regimens.
b Without bulky mediastinal (defined as one-third or more of intrathoracic ratio measured on an upright posteroanterior chest radiograph) or peripheral lymphadenopathy (defined as 6 cm or more) or B symptoms.
c Without adverse features, defined as one or more of the following: hilar adenopathy, involvement of more than four nodal regions; mediastinal tumor with diameter equal to or larger than one-third of the chest diameter, and node or nodal aggregate with a diameter larger than 10 cm.
d Results fromas-treated analysis.
VAMP (4)[38] 15-25.5, IFRT CS I/IIb 110 89 (10) 96 (10)
VAMP (4)[44] 25.5, IFRT/None CS I/IIb 41/47 88/89 (5) 100/100 (5)
COPP/ABV (4)[14,17] 21, IFRT/None CS IA/B, IIAc 94/113 100/89 (10)d 97/96 (10)d
OEPA/OPPA (2)[18] 20-35, IFRT/None I, IIA 281/113 94/97 (5) N/A
ABVE (2-4)[47] 25.5, IFRT IA, IIA, IIIA1 51 91 (6) 98 (6)

Table 6. Intermediate-Risk Disease (All Stage I and Stage II Patients Not Classified as Early Stage; Stage IIIA; Stage IVA)

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; E = extralymphatic; IFRT = involved-field radiation therapy.
a Refer toTable 4for more information about the chemotherapy regimens.
b With adverse disease features, defined as one or more of the following: hilar adenopathy, involvement of more than four nodal regions; mediastinal tumor with diameter equal to or larger than one-third of the chest diameter, and node or nodal aggregate with a diameter larger than 10 cm.
c Results fromas-treated analysis.
COPP/ABV (6)[17] 21, IFRT/None CS I/IIb, CS IIB, CS III 103/122 84/78 (10)c 100 (3)
OEPA/OPPA (2) + COPP (2)[18] 20–35, IFRT IIE A, IIB, IIIA 212 92 (5) N/A
OEPA/OPPA (2) + COPDAC (2)[37] 20–35, IFRT IIE B, IIIE A/B, IIIB, IVA/B 139 88.3 (5) 98.5 (5)
ABVE-PC (3–5)[32] 21, IFRT IB, IIA, IIIA 53 84 (5) 95 (5)

Table 7. High-Risk Disease (Stages IIIB, IVB)

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; RER = rapid early response; SER = slow early response.
a Refer toTable 4for more information about the chemotherapy regimens.
OEPA/OPPA (2) + COPP (4)[18] 20–35, IFRT IIE B, IIIE A/B, IIIB, IVA/B 265 91 (5) N/A
OEPA/OPPA (2) + COPDAC (4)[37] 20–35, IFRT IIE B, IIIE A/B, IIIB, IVA/B 239 86.9 (5) 94.9 (5)
ABVE-PC (3-5)[32] 21, IFRT IB, IIA, IIIA 163 85 (5) 95 (5)
BEACOPP (4); COPP/ABV (4) (RER; girls)[40] None IIB, IIIB, IV 38 94 (5) 97 (5)
BEACOPP (4); ABVD (2) (RER; boys)[40] 21, IFRT IIB, IIIB, IV 34
BEACOPP (8) (SER)[40] 21, IFRT IIB, IIIB, IV 25

Treatment of Adolescents and Young Adults with Hodgkin Lymphoma

The treatment approach used for adolescents and young adults with Hodgkin lymphoma may vary based on community referral patterns and age restrictions at pediatric cancer centers. In patients with high-risk disease, the standard of care in medical oncology practices typically involves at least six cycles of ABVD chemotherapy that would deliver a cumulative anthracycline dose of 300 mg/m2.[48,49] 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.[50,51] Subsequent need for mediastinal radiation can further enhance the risk of a variety of late cardiac events.[50,51,52] In an effort to optimize disease control and preserve both cardiac and gonadal function, pediatric regimens for low-risk disease most often feature a restricted number of cycles of ABVD or derivative combinations, whereas alkylating agents and etoposide are integrated into anthracycline-containing regimens for those with intermediate- and high-risk disease.

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

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I childhood Hodgkin lymphoma, stage II childhood Hodgkin lymphoma, stage III childhood Hodgkin lymphoma and stage IV childhood Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

References:

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  29. 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.
  30. 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.
  31. Paulino AC, Margolin J, Dreyer Z, et al.: Impact of PET-CT on involved field radiotherapy design for pediatric Hodgkin lymphoma. Pediatr Blood Cancer 58 (6): 860-4, 2012.
  32. 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.
  33. Friedman DI, Wolden S, Constine L, et al.: AHOD0031: A phase III study of dose intensive therapy for intermediate risk Hodgkin lymphoma: a report from the Children's Oncology Group. [Abstract] Blood 116 (22): A-766, 2010.
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  44. 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.
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  47. Schwartz CL: Special issues in pediatric Hodgkin's disease. Eur J Haematol Suppl (66): 55-62, 2005.
  48. 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.
  49. 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.
  50. 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.
  51. 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.
  52. 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.

Treatment of Primary Refractory / Recurrent Hodgkin Lymphoma in Children and Adolescents

The excellent response to frontline therapy among children and adolescents with Hodgkin lymphoma limits opportunities to evaluate second-line (salvage) therapy. Because of the small number of patients that fail primary therapy, no uniform second-line treatment strategy exists for this patient population. Adverse prognostic factors after relapse include the following:[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 following treatment with more intensive conventional chemotherapy.[5,6]

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

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

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.

Current Clinical Trials

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

References:

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  18. 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.
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Late Effects from Childhood / Adolescent Hodgkin Lymphoma Therapy

Children and adolescent survivors of Hodgkin lymphoma are at risk for numerous late complications of treatment related to radiation, specific chemotherapeutic exposures, and surgical staging. 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.

The following table 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.)

Table 8. Treatment Complications Observed in Hodgkin Lymphoma Survivors

Health Effects Predisposing Therapy Clinical Manifestations
Oral/dental Any chemotherapy in a patient who has not developed permanent dentition Dental maldevelopment (tooth/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
Osteonecrosis
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

Female Gonadal Toxicity

Thyroid Abnormalities

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.[19,20]

Radiation-associated cardiovascular toxicity

Selected studies evaluating cardiovascular toxicity associated with radiation

(Refer to the Cardiovascular Disease in Select Cancer Subgroups: Hodgkin lymphoma section in the PDQ summary on Late Effects of Treatment for Childhood Cancer for information on studies evaluating cardiovascular toxicity associated with radiation.)

Anthracycline-related cardiac toxicity

Subsequent Neoplasms

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  48. Taylor AJ, Winter DL, Stiller CA, et al.: Risk of breast cancer in female survivors of childhood Hodgkin's disease in Britain: a population-based study. Int J Cancer 120 (2): 384-91, 2007.
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Changes to This Summary (02 / 01 / 2013)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Diagnosis and Staging

Added text about a Children's Oncology Group study that evaluated surveillance computed tomography (CT) and detection of relapse in intermediate-stage and advanced-stage Hodgkin lymphoma; the routine use of CT at the intervals used in this study did not improve outcome (cited Voss et al. as reference 31).

Treatment for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma

Added text to state that involved-nodal radiation therapy (RT) defines the treatment volume using the prechemotherapy positron emission tomography (PET)/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.

Added text about involved-site RT, the indications for use, and the size of the treatment volumes.

Added text to state that proton therapy is currently being investigated and may further decrease the mean dose to the surrounding normal tissue compared with intensity-modulated RT or 3-dimensional conformal RT, without increasing the volume of normal tissue receiving lower-dose radiation.

Treatment of Primary Refractory/Recurrent Hodgkin Lymphoma in Children and Adolescents

Added Gorde-Grosjean et al. as reference 4.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

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:

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

The lead reviewers for Childhood Hodgkin Lymphoma Treatment are:

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. 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

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childhodgkins/HealthProfessional. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

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Last Revised: 2013-02-01


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