Purpose of This PDQ Summary
General Information

Overview of Childhood Hodgkin Lymphoma Epidemiology Pathobiology Clinical Presentation

Cellular Classification and Biologic Correlates

Classical Hodgkin Lymphoma Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Prognostic Factors in Childhood and Adolescent Hodgkin Lymphoma
Staging and Diagnostic Evaluation

Pretreatment Staging         Subclassification of stage         Stage I         Stage II         Stage III         Stage IV Early Chemotherapy Response Assessment End of Chemotherapy Re-evaluation

Treatment Approach for Children and Adolescents with Hodgkin Lymphoma

Chemotherapy for Childhood/Adolescent Hodgkin Lymphoma Radiation Therapy for Children and Adolescents with Hodgkin Lymphoma         Volume considerations         Radiation dose         Technical considerations         Current role of LD-IFRT in childhood and adolescent Hodgkin lymphoma Accepted Treatment Strategies for Newly Diagnosed Children and Adolescent Patients with Hodgkin Lymphoma         Nodular lymphocyte-predominant Hodgkin lymphoma Treatment Strategies Under Clinical Investigation for Childhood/Adolescent Hodgkin Lymphoma         Low-risk classical Hodgkin lymphoma         Intermediate-risk classical Hodgkin lymphoma         High-risk classical Hodgkin lymphoma         Early stage nodular lymphocyte-predominant Hodgkin lymphoma Current Clinical Trials

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

Current Clinical Trials

Late Effects from Childhood/Adolescent Hodgkin Lymphoma Therapy

Male Gonadal Toxicity Female Infertility Thyroid Abnormalities Cardiac Toxicity Secondary Malignancies

Get More Information From NCI
Changes to This Summary (11/13/2008)
More Information

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood Hodgkin lymphoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

• Incidence and presenting symptoms.
• Cellular classification and biologic correlates.
• Prognosis.
• Staging and diagnostic evaluation.
• Treatment options.
• Late treatment effects.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the 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 and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less-technical language, and in Spanish.

Back to Top

General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. 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 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.[1] 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.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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 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.)

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 nonmorbid therapy for these patients. Contemporary treatment programs use a risk-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field irradiation. Prognostic factors used in determining chemotherapy intensity include stage, presence or absence of B symptoms and/or bulk disease. The option of omitting radiation following chemotherapy is only considered in patients achieving complete response to initial chemotherapy.

Hodgkin lymphoma comprises 6% of childhood cancers. In the United States, the incidence of Hodgkin lymphoma is age-related and is highest among 15 to 19 year olds (29 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.[2] In non-European Union countries, there is a similar rate in young adults but a much higher incidence in childhood.[3,4] The male to female ratio varies markedly by age in the pediatric population. Children younger than 5 years show a strong male predominance (M/F = 5.3) and children aged 15 to 19 show a slight female predominance (M/F = 0.8).[5]Lymphomas and reticuloendothelial neoplasms (ICCC II) For children and adolescents in the United States, there is an increased risk of Hodgkin lymphoma in families with higher parental incomes and higher education level. There is a lower incidence of Hodgkin lymphoma in families with large numbers of children.[4]

Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Reed-Sternberg [R-S] cells) or large mononuclear cell variants (lymphocytic and histiocytic [L & H] cells) in an inflammatory milieu. This inflammatory milieu consists of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts in different proportions depending on the histologic subtype. It has been conclusively shown that R-S cells and/or L & H cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from preapoptotic germinal center B cells that cannot synthesize immunoglobulin.[6,7] The R-S cell appears to be resistant to apoptotic stimuli. Deregulation of the nuclear transcription factor NFkB in the R-S cells may explain this resistance to apoptosis.

Epstein-Barr virus (EBV) genetic material can be detected in R-S cells from some patients with Hodgkin lymphoma. EBV positivity is most commonly observed in tumors with mixed-cellularity histology and is almost never seen in patients with lymphocyte-predominant histology.[8-12] EBV positivity is more common in children younger than 10 years [8,12] compared to adolescents and young adults.[9,10] The incidence of EBV tumor cell positivity for Hodgkin lymphoma in developed countries is 15% to 25% in adolescents and young adults.[11-13] There is a very high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma seen in developing countries, and these cases are generally EBV-positive (approximately 90%). EBV serologic status is not a prognostic factor for failure-free survival in pediatric and young adult Hodgkin lymphoma patients.[8,11-14] 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.[15] Although rare, Hodgkin lymphoma can be familial.

Approximately 80% of patients present with painless adenopathy, commonly in the supraclavicular or cervical area. Enlarged nodes are generally firm and have a rubbery texture. 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 presentation, in part, reflecting the tendency of these patients to have either mixed cellularity or lymphocyte-predominant histology. Approximately 25% of patients may have systemic symptoms such as fever, night sweats, and weight loss that are secondary to release of lymphokines and cytokines by R-S cells. Approximately 20% of patients will have bulky adenopathy (maximum mediastinal diameter greater than one-third of the chest diameter and/or a node or nodal aggregate larger than 10 cm). Approximately 80% to 85% of children and adolescents with Hodgkin lymphoma have involvement of lymph nodes and/or the spleen only (stages I–III). The remaining 15% 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.[16,17]

References

1. 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.  [PUBMED Abstract]
   
   
2. Ries LAG, Harkins D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2003. Bethesda, Md: National Cancer Institute, 2006. Also available online. Last accessed October 07, 2008. 
   
   
3. Macfarlane GJ, Evstifeeva T, Boyle P, et al.: International patterns in the occurrence of Hodgkin's disease in children and young adult males. Int J Cancer 61 (2): 165-9, 1995.  [PUBMED Abstract]
   
   
4. Grufferman S, Gilchrist GS, Pollock BH, et al.: Socioeconomic status, the Epstein-Barr virus and risk of Hodgkin's disease in children. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-054, 40, 2001. 
   
   
5. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review 1973-1995. Bethesda, Md: National Cancer Institute, 1998. 
   
   
6. Bräuninger A, Schmitz R, Bechtel D, et al.: Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer 118 (8): 1853-61, 2006.  [PUBMED Abstract]
   
   
7. Mathas S: The pathogenesis of classical Hodgkin's lymphoma: a model for B-cell plasticity. Hematol Oncol Clin North Am 21 (5): 787-804, 2007.  [PUBMED Abstract]
   
   
8. Armstrong AA, Alexander FE, Cartwright R, et al.: Epstein-Barr virus and Hodgkin's disease: further evidence for the three disease hypothesis. Leukemia 12 (8): 1272-6, 1998.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. Makar RR, Saji T, Junaid TA: Epstein-Barr virus expression in Hodgkin's lymphoma in Kuwait. Pathol Oncol Res 9 (3): 159-65, 2003.  [PUBMED Abstract]
    
    
11. 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.  [PUBMED Abstract]
    
    
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 Abstract]
    
    
13. Jarrett RF, Stark GL, White J, et al.: Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based study. Blood 106 (7): 2444-51, 2005.  [PUBMED Abstract]
    
    
14. Herling M, Rassidakis GZ, Vassilakopoulos TP, et al.: Impact of LMP-1 expression on clinical outcome in age-defined subgroups of patients with classical Hodgkin lymphoma. Blood 107 (3): 1240; author reply 1241, 2006.  [PUBMED Abstract]
    
    
15. Hjalgrim H, Askling J, Rostgaard K, et al.: Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 349 (14): 1324-32, 2003.  [PUBMED Abstract]
    
    
16. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002.  [PUBMED Abstract]
    
    
17. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.  [PUBMED Abstract]
    
    

Back to Top

Cellular Classification and Biologic Correlates

Hodgkin lymphoma can be divided into two broad pathologic classes:[1,2]

• Classical Hodgkin lymphoma.
• Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL).

Classical Hodgkin lymphoma is divided into four subtypes:

• Lymphocyte-rich classical Hodgkin lymphoma (LRCHL).
• Nodular sclerosis Hodgkin lymphoma (NSHL).
• Mixed-cellularity Hodgkin lymphoma (MCHL).
• Lymphocyte-depleted Hodgkin lymphoma (LDHL).

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

The hallmark of classic Hodgkin lymphoma is the R-S cell.[3] This is a binucleated or multinucleated giant cell that is often characterized by a bilobed nucleus, with two large nucleoli, giving an owl’s eye appearance to the cells. A striking characteristic is the rarity (about 1%) of the malignant R-S cell in specimens and the abundant reactive cellular infiltrate of lymphocytes, macrophages, granulocytes, and eosinophils. R-S cells generally do not express B-cell antigens such as CD45, CD19, and CD79A. Almost all patients express CD30, and approximately 70% of patients express CD15. CD20 is expressed in approximately 5% to 10% of cases.[4-6] R-S cells show constitutive activation of the nuclear factor kappa B pathway, which may prevent apoptosis and provide a survival advantage. Most cases of classic Hodgkin lymphoma are characterized by expression of tumor necrosis factor receptors (TNF-R) and their ligands, as well as an unbalanced production of Th2 cytokines and chemokines. Activation of TNF-R results in constitutive activation of nuclear factor kappa B.[7]

The histologic features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines, chemokines, and products of the TNF-R family [8] secreted by the R-S cells. Interleukin-5 could be responsible for the eosinophilia in MCHL, and transforming growth factor-beta for the fibrosis in the NSHL subtype.

• In the United States, NSHL histology accounts for approximately 85% of Hodgkin lymphoma cases in older children and adolescents but only 50% of cases in younger children. This subtype is distinguished by the presence of collagenous bands that divide the lymph node into nodules, which often contain an R-S 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 R-S cells present.



• In the United States, MCHL histology is more common in younger children than in adolescents or adults. In a Children's Cancer Group (CCG) study, MCHL accounted for 30% of cases in children younger than 10 years. R-S cells are frequent in a background of abundant normal reactive cells (lymphocytes, plasma cells, eosinophils, and histiocytes). This subtype can be confused with non-Hodgkin lymphoma.



• LRCHL may have a nodular appearance, but immunophenotypic analysis allows distinction between this form of Hodgkin lymphoma and nodular lymphocyte-predominant disease.[9] LRCHL cells express CD15 and CD30 while NLPHL almost never expresses CD15.

This pathologic class of 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. These cells may or may not express CD30. The OCT-2 and BOB.1 oncogenes are both expressed in NLPHL; they are not expressed in the cells of patients with classical Hodgkin lymphoma.[10] While diffuse subtypes may exist with lymphocytic and histiocytic cells set against a diffuse background consisting of reactive T-cells, reliable discrimination from non-Hodgkin lymphoma is problematic.[11] In addition, a purely diffuse subtype would be classified as diffuse large B-cell lymphoma or T-cell-rich B-cell lymphoma. Even NLPHL can be difficult to distinguish from progressive transformation of germinal centers and/or T-cell-rich B-cell lymphoma.[12] NLPHL is most common in males younger than 18 years.[13] In the CCG 5942 study, NLPHL accounted for approximately 18% of cases in children younger than 10 years and 8% of cases in children older than or equal to 10 years. Approximately 80% of these patients were male.[14] Patients with NLPHL generally present with localized, nonbulky disease and infrequently involve the mediastinum.[13] Almost all patients are asymptomatic.

References

1. Pileri SA, Ascani S, Leoncini L, et al.: Hodgkin's lymphoma: the pathologist's viewpoint. J Clin Pathol 55 (3): 162-76, 2002.  [PUBMED Abstract]
   
   
2. Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999.  [PUBMED Abstract]
   
   
3. Küppers R, Schwering I, Bräuninger A, et al.: Biology of Hodgkin's lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002.  [PUBMED Abstract]
   
   
4. Portlock CS, Donnelly GB, Qin J, et al.: Adverse prognostic significance of CD20 positive Reed-Sternberg cells in classical Hodgkin's disease. Br J Haematol 125 (6): 701-8, 2004.  [PUBMED Abstract]
   
   
5. von Wasielewski R, Mengel M, Fischer R, et al.: Classical Hodgkin's disease. Clinical impact of the immunophenotype. Am J Pathol 151 (4): 1123-30, 1997.  [PUBMED Abstract]
   
   
6. Tzankov A, Zimpfer A, Pehrs AC, et al.: Expression of B-cell markers in classical Hodgkin lymphoma: a tissue microarray analysis of 330 cases. Mod Pathol 16 (11): 1141-7, 2003.  [PUBMED Abstract]
   
   
7. Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002.  [PUBMED Abstract]
   
   
8. Re D, Küppers R, Diehl V: Molecular pathogenesis of Hodgkin's lymphoma. J Clin Oncol 23 (26): 6379-86, 2005.  [PUBMED Abstract]
   
   
9. Anagnostopoulos I, Hansmann ML, Franssila K, et al.: European Task Force on Lymphoma project on lymphocyte predominance Hodgkin disease: histologic and immunohistologic analysis of submitted cases reveals 2 types of Hodgkin disease with a nodular growth pattern and abundant lymphocytes. Blood 96 (5): 1889-99, 2000.  [PUBMED Abstract]
   
   
10. Stein H, Marafioti T, Foss HD, et al.: Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 97 (2): 496-501, 2001.  [PUBMED Abstract]
    
    
11. Boudová L, Torlakovic E, Delabie J, et al.: Nodular lymphocyte-predominant Hodgkin lymphoma with nodules resembling T-cell/histiocyte-rich B-cell lymphoma: differential diagnosis between nodular lymphocyte-predominant Hodgkin lymphoma and T-cell/histiocyte-rich B-cell lymphoma. Blood 102 (10): 3753-8, 2003.  [PUBMED Abstract]
    
    
12. Kraus MD, Haley J: Lymphocyte predominance Hodgkin's disease: the use of bcl-6 and CD57 in diagnosis and differential diagnosis. Am J Surg Pathol 24 (8): 1068-78, 2000.  [PUBMED Abstract]
    
    
13. Hall GW, Katzilakis N, Pinkerton CR, et al.: Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma - a Children's Cancer and Leukaemia Group report. Br J Haematol 138 (6): 761-8, 2007.  [PUBMED Abstract]
    
    
14. Mauz-Körholz C, Gorde-Grosjean S, Hasenclever D, et al.: Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma. Cancer 110 (1): 179-85, 2007.  [PUBMED Abstract]
    
    

Back to Top

Prognostic Factors in Childhood and Adolescent Hodgkin Lymphoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

As the treatment of Hodgkin lymphoma has improved, factors that influence outcome have diminished in importance. 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 are their use in determining the aggressiveness of therapy. For example, in a report from the German-Austrian Pediatric multicenter trial DAL-HD-90, bulk disease was not a prognostic factor for outcome on multivariate analysis. However, in this study boost irradiation doses were given to patients who had post-chemotherapy residual disease, which could have obfuscated the relevance of bulky disease at presentation.[1] This underscores the complexity in determining prognostic factors.

Pretreatment factors associated with an adverse outcome in one or more studies include advanced stage of disease, the presence of B symptoms, the presence of bulk disease, extranodal extension, male sex, and elevated erythrocyte sedimentation rate. Examples from selected multi-institutional studies are discussed here. In the German Pediatric Oncology and Hematology Group (GPOH) GPOH-95 study, B symptoms, histology, and male sex were adverse prognostic factors for event-free survival on multivariate analysis.[2] 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 11,500/mm³ or higher; and hemoglobin lower than 11.0g/dL were significant prognostic factors for inferior disease-free survival and overall survival. Prognosis was also associated with the number of adverse factors.[3] In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome.[4]

There is some controversy as to whether histology is an important prognostic factor.[5] Serum markers that have been associated with an adverse outcome include soluble vascular cell adhesion molecule-1,[6] tumor necrosis factor,[7] soluble CD30,[8] beta-2 microglobulin,[9] transferrin, and serum IL-10 level.[10] High levels of caspase 3 in Reed-Sternberg (R-S) cells have been associated with a favorable outcome.[11]

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.[12-14] Positron emission tomography (PET) scanning is being evaluated as a method to assess early response in pediatric Hodgkin lymphoma. Fluorodeoxyglucose (FDG)-PET avidity after two cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[15,16][Level of evidence: 2Diii][17] Further studies are required to assess the magnitude of the prognostic effect with different chemotherapy regimens and to determine whether improved outcome can be achieved by altering the therapeutic strategy based on early PET response.

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. Nonetheless, as therapy becomes increasingly tailored to prognostic factors and therapeutic response, overall outcome should become less affected by these parameters.

References

1. 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.  [PUBMED Abstract]
   
   
2. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.  [PUBMED Abstract]
   
   
3. 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. 
   
   
4. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002.  [PUBMED Abstract]
   
   
5. Shankar AG, Ashley S, Radford M, et al.: Does histology influence outcome in childhood Hodgkin's disease? Results from the United Kingdom Children's Cancer Study Group. J Clin Oncol 15 (7): 2622-30, 1997.  [PUBMED Abstract]
   
   
6. Christiansen I, Sundström C, Enblad G, et al.: Soluble vascular cell adhesion molecule-1 (sVCAM-1) is an independent prognostic marker in Hodgkin's disease. Br J Haematol 102 (3): 701-9, 1998.  [PUBMED Abstract]
   
   
7. Warzocha K, Bienvenu J, Ribeiro P, et al.: Plasma levels of tumour necrosis factor and its soluble receptors correlate with clinical features and outcome of Hodgkin's disease patients. Br J Cancer 77 (12): 2357-62, 1998.  [PUBMED Abstract]
   
   
8. Nadali G, Tavecchia L, Zanolin E, et al.: Serum level of the soluble form of the CD30 molecule identifies patients with Hodgkin's disease at high risk of unfavorable outcome. Blood 91 (8): 3011-6, 1998.  [PUBMED Abstract]
   
   
9. Chronowski GM, Wilder RB, Tucker SL, et al.: An elevated serum beta-2-microglobulin level is an adverse prognostic factor for overall survival in patients with early-stage Hodgkin disease. Cancer 95 (12): 2534-8, 2002.  [PUBMED Abstract]
   
   
10. Bohlen H, Kessler M, Sextro M, et al.: Poor clinical outcome of patients with Hodgkin's disease and elevated interleukin-10 serum levels. Clinical significance of interleukin-10 serum levels for Hodgkin's disease. Ann Hematol 79 (3): 110-3, 2000.  [PUBMED Abstract]
    
    
11. Dukers DF, Meijer CJ, ten Berge RL, et al.: High numbers of active caspase 3-positive Reed-Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease predict favorable clinical outcome. Blood 100 (1): 36-42, 2002.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. Weiner MA, Leventhal B, Brecher ML, et al.: Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 15 (8): 2769-79, 1997.  [PUBMED Abstract]
    
    
14. Landman-Parker J, Pacquement H, Leblanc T, et al.: Localized childhood Hodgkin's disease: response-adapted chemotherapy with etoposide, bleomycin, vinblastine, and prednisone before low-dose radiation therapy-results of the French Society of Pediatric Oncology Study MDH90. J Clin Oncol 18 (7): 1500-7, 2000.  [PUBMED Abstract]
    
    
15. Hutchings M, Loft A, Hansen M, et al.: FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 107 (1): 52-9, 2006.  [PUBMED Abstract]
    
    
16. Gallamini A, Hutchings M, Rigacci L, et al.: Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J Clin Oncol 25 (24): 3746-52, 2007.  [PUBMED Abstract]
    
    
17. Dann EJ, Bar-Shalom R, Tamir A, et al.: Risk-adapted BEACOPP regimen can reduce the cumulative dose of chemotherapy for standard and high-risk Hodgkin lymphoma with no impairment of outcome. Blood 109 (3): 905-9, 2007.  [PUBMED Abstract]
    
    

Back to Top

Staging and Diagnostic Evaluation

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.

Stage is a critical determinant in the selection of treatment. Initial evaluation of the child with Hodgkin lymphoma includes history, physical examination, anatomic imaging (including chest x-ray; computed tomographic [CT] scan of chest, abdomen, and pelvis; functional imaging including positron emission tomography [PET] scan),[1-3] and laboratory studies. The posteroanterior and lateral chest radiograph remains important since the criterion for bulky mediastinal lymphadenopathy is defined by the ratio of the measurement of the mediastinal lymph nodes to the maximal measurement of the chest cavity on an upright chest radiograph; mediastinal ratios 33% or higher are considered bulky. CT scans help delineate the status of intrathoracic lymph node groups (including the hila and cardiophrenic angle), lung parenchyma, pericardium, pleura, and the chest wall, demonstrating abnormalities in about one-half of patients with unremarkable chest radiographs. Definition of disease involvement of intrathoracic tissues by CT will often dictate more aggressive therapy than would otherwise have been administered. Distinguishing normal (or hyperplastic) thymus from nodes in children can be problematic. Bone marrow biopsy should be performed in patients with advanced disease (stage III or stage IV) and/or symptoms (fever, weight loss, or night sweats).[4] PET scans are reliable in assessing bone involvement. Stage is determined by anatomic evidence of disease by CT scanning in conjunction with functional imaging. A suspected anatomic lesion which is PET-negative should not be considered involved unless biopsy-proven. Areas of PET positivity, which do not correspond to an anatomic lesion, (by clinical examination or CT scan) should be disregarded in staging. Functional imaging (Fluorodeoxyglucose [FDG]-PET scan) is sensitive in determining initial sites of involvement, particularly in the neck and mediastinum. PET scanning may be particularly useful in demonstrating unsuspected areas of involvement in the spleen and bone. FDG-PET has advantages over gallium-67 because the scan is a 1-day procedure with higher resolution, better dosimetry, and less intestinal activity.[1] FDG-PET is now the recommended functional imaging procedure for initial staging.[5,6]

Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.[7-10] Although this is less likely to be problematic in Hodgkin lymphoma than in non-Hodgkin lymphoma, appropriate planning of the surgical approach is essential. After a careful physiologic and radiographic evaluation of the patient has been carried out, the least invasive procedure should be used to establish the diagnosis of lymphoma. If at all possible, the diagnosis should be established by lymph node biopsy. 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. In cases where general anesthesia may pose a risk, a CT or ultrasound-guided core needle biopsy should be considered. This procedure can frequently be carried out using light sedation and local anesthesia. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy are the procedures of choice when other diagnostic modalities fail to establish the diagnosis. A formal thoracotomy is rarely indicated for the diagnosis of Hodgkin lymphoma. If a diagnostic operative procedure cannot be performed because of the risk of general anesthesia or heavy sedation and if needle biopsy is not feasible, then preoperative treatment with localized radiation therapy should be considered. Because preoperative treatment may hinder an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risks of general anesthesia or heavy sedation are thought to be alleviated.

The staging classification currently used for Hodgkin lymphoma was adopted at the Ann Arbor Conference held in 1971 [11] and revised in 1989.[12]

Hodgkin lymphoma can be subclassified into A and B categories: A is for those patients who are asymptomatic, and B is for those patients with any of the following specific symptoms:

• Unexplained loss of more than 10% of body weight in the 6 months before diagnosis.



• Unexplained fever with temperatures above 38° C for more than 3 days.



• Drenching night sweats.

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.

Involvement of a single lymph node region or, in the case of stage I(E), direct extension from that node to an adjacent extralymphatic region.

Involvement of two or more lymph node regions (number to be stated) on the same side of the diaphragm, or extension from any one of these lymph nodes to an extralymphatic adjacent organ, or stage II(E).

Involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by extension to an adjacent extralymphatic organ, (stage III[E]), involvement of the spleen (stage III[S+]), or both (stage III[E+S]).

Noncontiguous involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement.

Early response assessment can be based on volume reduction of disease, functional imaging status, or both. Significant reduction in disease volume and PET negativity at an early stage (after one or two cycles of chemotherapy) is associated with a favorable outcome. Use of early response assessment to alter therapy remains investigational. In the current Children's Oncology Group (COG) intermediate-risk Hodgkin lymphoma trial, only anatomic reduction in disease is used for stratification into rapid and slow responder groups. In the trial which will follow, functional imaging will be used to determine response.

Restaging is carried out at the end of chemotherapy. The purpose of restaging is to assess the degree of response to initial chemotherapy. Although complete response can be defined as absence of disease by clinical examination and/or imaging studies, complete response in Hodgkin lymphoma trials is often defined by greater than a 70% to 80% reduction of disease and a change from initial positivity to negativity on either gallium or PET scanning.[13] This definition is necessary in Hodgkin lymphoma because fibrotic residual is common, particularly in the mediastinum. In some studies such patients are designated as having an unconfirmed complete response.

There is a growing consensus that PET scanning is more accurate than gallium scanning in detecting viable Hodgkin lymphoma in posttherapy residual masses.[1,14] Timing of PET scanning after completing therapy is an important issue. For patients treated with chemotherapy alone, PET scanning should be performed a minimum of 3 weeks post therapy completion. For patients whose last treatment modality was radiation therapy, PET scanning should be performed 8 to 12 weeks post radiation.[15] A study testing the sensitivity and specificity of conventional imaging (CT or magnetic resonance imaging) and PET scans in children with Hodgkin lymphoma showed that side-by-side comparison or image fusion could improve the staging accuracy over either modality alone.[3] Currently, PET scanning is acceptable; however, caution should be used in making the diagnosis of relapsed disease based solely on imaging because false-positive results are not uncommon.[16-19]

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.  [PUBMED Abstract]
   
   
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. Furth C, Denecke T, Steffen I, et al.: Correlative imaging strategies implementing CT, MRI, and PET for staging of childhood Hodgkin disease. J Pediatr Hematol Oncol 28 (8): 501-12, 2006.  [PUBMED Abstract]
   
   
4. Mahoney DH Jr, Schreuders LC, Gresik MV, et al.: Role of staging bone marrow examination in children with Hodgkin disease. Med Pediatr Oncol 30 (3): 175-7, 1998.  [PUBMED Abstract]
   
   
5. Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's lymphoma. Pediatr Radiol 34 (3): 190-8, 2004.  [PUBMED Abstract]
   
   
6. Hernandez-Pampaloni M, Takalkar A, Yu JQ, et al.: F-18 FDG-PET imaging and correlation with CT in staging and follow-up of pediatric lymphomas. Pediatr Radiol 36 (6): 524-31, 2006.  [PUBMED Abstract]
   
   
7. Azizkhan RG, Dudgeon DL, Buck JR, et al.: Life-threatening airway obstruction as a complication to the management of mediastinal masses in children. J Pediatr Surg 20 (6): 816-22, 1985.  [PUBMED Abstract]
   
   
8. King DR, Patrick LE, Ginn-Pease ME, et al.: Pulmonary function is compromised in children with mediastinal lymphoma. J Pediatr Surg 32 (2): 294-9; discussion 299-300, 1997.  [PUBMED Abstract]
   
   
9. Shamberger RC, Holzman RS, Griscom NT, et al.: Prospective evaluation by computed tomography and pulmonary function tests of children with mediastinal masses. Surgery 118 (3): 468-71, 1995.  [PUBMED Abstract]
   
   
10. Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.  [PUBMED Abstract]
    
    
11. Carbone PP, Kaplan HS, Musshoff K, et al.: Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31 (11): 1860-1, 1971.  [PUBMED Abstract]
    
    
12. Lister TA, Crowther D, Sutcliffe SB, et al.: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 7 (11): 1630-6, 1989.  [PUBMED Abstract]
    
    
13. Weihrauch MR, Re D, Scheidhauer K, et al.: Thoracic positron emission tomography using 18F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease. Blood 98 (10): 2930-4, 2001.  [PUBMED Abstract]
    
    
14. Bangerter M, Moog F, Buchmann I, et al.: Whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin's disease. Ann Oncol 9 (10): 1117-22, 1998.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. Nasr A, Stulberg J, Weitzman S, et al.: Assessment of residual posttreatment masses in Hodgkin's disease and the need for biopsy in children. J Pediatr Surg 41 (5): 972-4, 2006.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. Meany HJ, Gidvani VK, Minniti CP: Utility of PET scans to predict disease relapse in pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 48 (4): 399-402, 2007.  [PUBMED Abstract]
    
    

Back to Top

Treatment Approach for Children and Adolescents with Hodgkin Lymphoma

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. Current approaches use chemotherapy with or without LD-IFRT.[1] The volume of radiation and the intensity/duration of chemotherapy are determined by prognostic factors at presentation, including presence of constitutional symptoms, disease stage, and bulk.

Devising the ideal therapeutic approach for children with Hodgkin lymphoma is complicated by their risk for late adverse effects. In particular, radiation therapy doses used in adults can cause profound musculoskeletal growth retardation and increase the risk for cardiovascular disease [2] and secondary solid malignancies in children.[3] Further complicating the treatment of children are gender-specific differences in chemotherapy-induced gonadal injury. The desire to cure young children with minimal side effects has stimulated attempts to reduce the intensity of chemotherapy (particularly alkylating agents) and radiation dose and volume. Because of differences in age-related child developmental status and the gender-related sensitivity to chemotherapy toxicity, no single treatment approach is ideal for all pediatric and young adult patients.

Pediatric oncologists agree that standard-dose radiation therapy, particularly applied to large volumes including critical organs, such as the mantle field, has unacceptable toxicity, including growth disturbance in prepubertal children, increased risk for breast cancer in young females,[3] and cardiovascular complications.[2] Therefore, all children and adolescents treated in pediatric cancer centers generally receive combination chemotherapy as initial treatment. Intensity and duration of initial chemotherapy is generally based on stage, the presence or absence of symptoms at diagnosis and the presence or absence of bulk disease.[4-6]

The general treatment strategy that is used to treat children and adolescents with Hodgkin lymphoma is chemotherapy for all patients, with or without radiation. An exception to this general approach is selected patients with stage I, completely resected, nodular lymphocyte-predominant Hodgkin lymphoma, whose initial treatment may be surgery alone. The number of cycles and intensity of chemotherapy may be determined by the rapidity and degree of response, as is the radiation dose and volume.

Drugs utilized as frontline therapy for children and adolescents with Hodgkin lymphoma include:

Alkylating Agents

• cyclophosphamide
• mechlorethamine
• procarbazine

Vinca Alkyloids

• vincristine
• vinblastine

Steroids

• prednisone
• dexamethasone

Antimetabolites

• methotrexate
• cytosine arabinoside

Other Agents

• doxorubicin
• bleomycin
• dacarbazine
• etoposide

When regimens containing alkylating agents were shown to be associated with an increased risk for therapy-related leukemia,[7] non-alkylator-containing regimens such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) were developed. Doxorubicin, however, is associated with cardiac damage and bleomycin can produce pulmonary fibrosis.[8] Hybrid regimens that utilized lower total cumulative doses of alkylators, doxorubicin, and bleomycin were then developed. The COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, and vinblastine) hybrid is an example of this type of regimen.[9] In an effort to decrease risk for male infertility, etoposide has been substituted for procarbazine in the initial courses of therapy in studies of the German pediatric Hodgkin lymphoma group.[10] DBVE (doxorubicin, bleomycin, vincristine, etoposide) and DBVE-PC (prednisone, cyclophosphamide) have been used in Pediatric Oncology Group (POG) trials.[11,12] Although etoposide is associated with an increased risk for therapy-related acute myeloid leukemia (AML) with 11q23 abnormalities,[13] the risk is very low in those treated with DBVE or DBVE-PC without dexrazoxane.[14] Procarbazine is no longer used in frontline Hodgkin lymphoma trials by the Children's Oncology Group (COG) due to its long-term gonadal toxicity in males.

Investigators have evaluated a regimen of vincristine, doxorubicin, methotrexate, and prednisone (VAMP) to treat children and adolescents with Hodgkin lymphoma.[15] Results were good for patients with low-stage disease without B symptoms or bulky disease. VAMP combined with COP was inadequate for the treatment of patients with advanced disease.[16]

Certain protocols have used dexrazoxane with doxorubicin in an effort to lower cardiopulmonary toxicity.[12,17] There remains controversy about the risk of treatment-related AML (tAML) in Hodgkin lymphoma patients receiving dexrazoxane concurrent with etoposide.[11,18] Listed below (Table 1) are the combination chemotherapy regimens that have been utilized for children and young adults with Hodgkin lymphoma:

As discussed in the previous sections, most newly diagnosed children will be treated with risk-adapted chemotherapy alone or in combination with LD-IFRT. LD-IFRT involves the use of meticulous and judiciously designed fields to achieve local control of disease and to minimize damage to normal tissue.

The appropriate treatment volume is often protocol-specific but generally includes the initially involved lymph node region(s). Additional considerations relate to the location of disease (e.g., pericardium, and chest wall). In early-stage Hodgkin lymphoma, the definition of IFRT depends on the anatomy of the region in terms of lymph node distribution, patterns of disease extension into regional areas, and consideration for match line problems should disease recur. Traditional definitions of lymph node regions can be helpful but may not be sufficient. For example, the cervical and supraclavicular (SCV) lymph nodes are generally treated when abnormal nodes are located anywhere within this area; this is consistent with the anatomic definition of lymph node regions used for staging purposes. The hila are irradiated when the mediastinum is involved, however, despite the fact that the hila and mediastinum are separate lymph node regions. Similarly, the SCV lymph nodes are often treated when the axilla or mediastinum is involved, and the ipsilateral external iliac nodes are often treated when the inguinal nodes are involved. In both these situations, however, care must be taken to shield relevant normal tissues as much as possible (such as the breast when the axilla or mediastinum is involved and ovaries when the inguinal nodes are involved). Moreover, the decision to treat the axilla or mediastinum without the SCV lymph nodes and the inguinal nodes without the iliac nodes may be appropriate, depending on the size and distribution of involved nodes at presentation.

By implication, when it is necessary to treat the pelvis, special attention must be given to the ovaries and testes. The ovaries should be relocated, marked with surgical clips, laterally along the iliac wings, or centrally behind the uterus in order to permit appropriate shielding. Ideally, the ovaries should be exposed to less than 3 Gy to preserve fertility. The testes may be incidentally exposed to 5% to 10% of the administered pelvic dose, which may be sufficient to cause transient azoospermia, depending on the total pelvic dose. Multi-leaf collimation or custom blocking should be used when feasible to block the primary beam; scatter dose to the testes can be minimized with the patient treated in a frog-legged position with a “clamshell” testicular shield. In a very young child (younger than 5 years of age), consideration may be given to treating bilateral areas (e.g., both sides of the neck) to avoid growth asymmetry. Growth asymmetry, however, is less of a concern with low radiation doses; unilateral fields are usually appropriate if the disease is unilateral.

Field definition for radiation therapy in unfavorable, and advanced Hodgkin lymphoma is variable and protocol dependent. Although IFRT remains the standard when patients are treated with combined modality therapy, restricting radiation therapy to areas of initial bulk disease (generally defined as ≥5 cm at the time of disease presentation) or postchemotherapy residual disease (generally defined as ≥2 cm or more, or residual positron emission tomography [PET] avidity), is under investigation. The rationale for this is to limit radiation exposure to large portions of the body in patients who often have multifocal disease, including organ invasion. Large volume radiation therapy can compromise organ function and may limit the intensity of retrieval therapy if relapse occurs. However, as previously stated, the current standard of therapy does include post-chemotherapy IFRT for patients with intermediate or advanced disease based on data from the Children's Cancer Study Group [9] and the German-Austrian Childhood Hodgkin studies.[20]

An example of definitions for IFRT is shown in the following table (Table 2), with more restricted definitions increasingly common and protocol-specific.

The dose of radiation is also variously defined and often protocol-specific. In general, doses of 15 Gy to 25 Gy are used, with modifications based on patient age, the presence of bulk or residual (postchemotherapy) disease, and normal tissue concerns. In some situations, a boost of 5 Gy is appropriate. The dose may be determined by the response obtained to initial combination chemotherapy. In most trials conducted before 1995, patients achieving a complete response (CR) to initial chemotherapy received LD-IFRT (15–25 Gy). In some studies, patients with partial responses (PR) received higher radiation doses.

A linear accelerator with a beam energy of 6 mV is desirable because of its penetration, well-defined edge, and homogeneity throughout an irregular treatment field. Excellent immobilization techniques are necessary for young children to ensure accuracy and reproducibility. Treatment of involved supradiaphragmatic fields or a mantle field requires precision because of the distribution of lymph nodes and the critical adjacent normal tissues. These fields can be simulated with the arms up over the head or with arms down and hands on the hips. The former position pulls the axillary lymph nodes away from the lungs, allowing greater lung shielding; however, the axillary lymph nodes then move into the vicinity of the humeral heads, which should be blocked in growing children. Thus, the position chosen involves weighing concerns about lymph nodes, lung, and humeral heads. Attempts should be made to exclude or position breast tissue under the lung/axillary blocking. When the decision is made to include some or all of a critical organ (such as liver, kidney, or heart) in the radiation field, then normal tissue constraints are critical depending on chemotherapy used and patient age. For example, the possible indications for whole heart irradiation (10 – 15 Gy) are pericardial involvement, as suggested by a large pericardial effusion or frank pericardial invasion with tumor. Whole lung irradiation, (10 – 15 Gy) with partial transmission blocks, are a consideration in the setting of overt pulmonary nodules. For example, the German Pediatric Hematology Oncology (GPOH) HD-95 trial administered ipsilateral whole lung radiation therapy to patients who had not achieved a complete response in the lungs to the first two cycles of chemotherapy.

Evaluating late effects associated with treatment for Hodgkin lymphoma is difficult. Because late effects may take 10 years to 30 years or more to become clinically apparent, it is often the case that a regimen associated with a given late effect is no longer utilized by the time the late effect becomes apparent. The type and incidence of late effects associated with modern combination chemotherapy and LD-IFRT regimens are unknown.

Because all children and adolescents with Hodgkin lymphoma receive chemotherapy, a question commanding significant attention is whether patients who achieve an initial CR to chemotherapy require any radiation therapy. Conversely, the judicious use of LD-IFRT may permit a reduction in the intensity or duration of chemotherapy.

In most pediatric cancers, salvage rates for patients who fail initial therapy are very poor, but this is not the case for patients with pediatric Hodgkin lymphoma who relapse after initial treatment. Studies comparing combination chemotherapy with or without radiation therapy for adults with advanced-stage Hodgkin lymphoma showed that the event-free survival (EFS) was higher for patients who received initial chemotherapy and radiation therapy. Overall survival (OS), however was no different for patients whose initial therapy was chemotherapy alone.[25] Many of the salvage regimens utilized included intensive chemotherapy followed by peripheral blood stem cell transplant. Thus it is not clear whether EFS or OS should be the appropriate endpoint for a trial comparing chemotherapy with or without radiation. In addition, there is an inherent assumption 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. It is not clear how histology, presence of bulk disease, presence of symptoms, or other variables affect the efficacy of postchemotherapy radiation.

In the last decade, two major pediatric trials [9,20] have evaluated the utility of LD-IFRT in the treatment of Hodgkin lymphoma. A trial of the former Children’s Cancer Group (CCG) for children and adolescents with Hodgkin lymphoma compared outcome in patients who achieved an initial CR with chemotherapy followed by LD-IFRT or no further therapy. CR was defined as an absence of residual tumor or residual tumor that showed a reduction in size of 70% or more since diagnosis and a change from gallium positivity to gallium negativity for initial gallium-positive lesions.[9] Patients received risk-adapted chemotherapy (stages I–III, COPP/ABV; stage IV, more intensive therapy). The EFS for the 829 eligible patients was 85% at 5 years. CR was obtained in 83% of patients. Five hundred-one patients were randomized to receive LD-IFRT or no further therapy. In an as-treated analysis, 3-year EFS was 93% ± 1.7% for patients receiving LD-IFRT, and 85% ± 2.3% for patients receiving no further therapy. Three-year survival for patients treated with and without LD-IFRT was 98% and 99%, respectively.[9]

In 1995, the German Pediatric Oncology and Hematology Group (GPOH) initiated a study to assess the effect on EFS and OS of eliminating radiation for all patients achieving complete resolution of disease following chemotherapy.[20] Radiation dose was determined by extent of disease reduction following completion of chemotherapy. Twenty-three percent of patients achieved a CR, defined as complete resolution of all disease. Sixty-two percent of patients achieved a PR (>75% but <95% disease reduction) and received 20 Gy of radiation (30 Gy if <75% disease reduction). More relapses occurred in patients who achieved a CR and received no radiation (21/222, 9.5%) than in patients who achieved a PR and received radiation (43/758, 5.7%). Overall EFS was 92% for patients receiving radiation and 88% for those receiving no radiation (P = .05). For patients with stage IA, IB, and IIA Hodgkin lymphoma who achieved a CR after chemotherapy, EFS was 97%, which is similar to the EFS of 94% in patients achieving a PR who then received radiation therapy. For all other patients, however, EFS after CR to chemotherapy was 79%, compared with 91% for patients who achieved a PR and then received radiation therapy (P = .01). For both groups, survival was 97%.[20,26] In both the German GPOH-95 and CCG-5942 studies, the benefit of radiation therapy on EFS was greater in patients with advanced-stage disease at presentation.

Overall survival of patients who receive chemotherapy alone may be similar to that for patients who receive both chemotherapy and LD-IFRT, despite a difference in EFS. This results from the ability to effectively salvage patients who relapse after initial therapy.[9,20,25] If this potential can be accomplished with relatively nontoxic salvage therapy, then initial treatment with less-intense therapy may be appropriate. If, however, salvage therapy results in a substantial risk for late events such as cardiac failure or secondary malignancies, less-intense initial therapy would be unwise. Thus, it will be important to evaluate prognostic factors that may influence the magnitude of the EFS benefit that derives from the use of LD-IFRT in patients achieving a CR to initial chemotherapy. In the German study, the benefit of radiation therapy was greater in patients with advanced-stage disease at presentation. Other potential prognostic factors may include histology, erythrocyte sedimentation rate, bulk disease, and presence of symptoms.

 [Note: LD-IFRT includes radiation dosages between 15 Gy and 25 Gy.]

Low-Risk Disease (stages I–IIA; no bulk; no B symptoms)

• VAMP × 4 plus LD-IFRT.[15]
• COPP/ABV hybrid × 4 plus LD-IFRT.[9]
• DBVE × 2 to 4 and LD-IFRT (2 vs. 4 cycles based on early response).[14]
• OEPA (males) or OPPA (females) × 2 and LD-IFRT (German studies suggest that these patients may not require radiation therapy if a CR is obtained).[20,26]

Intermediate-Risk Disease (all stage I and II patients not classified as early stage; stage IIIA; stage IVA)

• COPP/ABV × 6 plus LD-IFRT.[9]
• DBVE-PC × 3 or 5 plus LD-IFRT (3 vs. 5 cycles based on early response).[27]
• OPPA/OEPA × 2; COPP × 2 plus LD-IFRT.[20,26]

High-Risk Disease (stages IIIB, IVB)

• DBVE-PC × 3 or 5 plus LD-IFRT (3 vs. 5 cycles based on early response).[12]
• Intensive chemotherapy with cytarabine/etoposide, COPP/ABV or CHOP (2 cycles of each) plus LD-IFRT.[9]
• Escalated dose BEACOPP × 8 plus LD-IFRT.[21]
• OPPA/OEPA × 2; COPP × 4 plus LD-IFRT.[20,26]

Both children and adults treated for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) have a favorable outcome, particularly when the disease is localized (stage I), as it is for most patients.[28-33] A retrospective study that included 210 adults with NLPHL found that only 8 of 32 deaths in these patients could be attributed directly to Hodgkin lymphoma, with most of the remaining deaths being the result of treatment-related toxicity (both acute and long-term).[29] Thus, for both adults and children, treatment for NLPHL focuses on reducing initial therapy to reduce long-term treatment-related morbidity and mortality.

Although current standard therapy for children with NLPHL is chemotherapy plus LD-IFRT, there are reports in which patients have been treated with chemotherapy alone or with complete resection of isolated nodal disease without chemotherapy. In a series of 31 adult patients treated with surgery alone, there were seven deaths (median follow-up, 7 years), but only one death resulted from Hodgkin lymphoma.[34] In another series, 15 of 24 patients with surgery alone relapsed, but all achieved a subsequent remission with radiation and/or chemotherapy. Only two patients died (one from NLPHL).[35] In a single institution pediatric experience, six patients with stage I NLPHL treated with surgery alone remained disease free.[31] The largest experience in children with NLPHL treated with resection alone was reported by the European Network Group on Pediatric Hodgkin Lymphoma. In this report of 58 children, survival was 100% with a median follow-up of 43 months. The overall progression-free survival rate in children who achieved CR with surgery was 67% (however, the follow-up is relatively short), while all seven patients with residual disease after initial surgery developed recurrences. Importantly, significant upstaging at recurrence and histologic transformation to a more aggressive B-cell lymphoma were not observed among patients with Stage IA disease treated initially with only resection.

The following are examples of national/international and/or institutional clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

• COG-AHOD0431 : Patients with stage I or IIA and no bulk disease (mediastinal mass <1/3 maximum chest diameter; extramediastinal mass <6 cm) receive three cycles of doxorubicin (Adriamycin), vincristine, prednisone and cyclophosphamide (AVPC). These patients do not receive etoposide or bleomycin. Patients who attain a CR following three cycles of chemotherapy receive no further therapy. Patients with a PR receive LD-IFRT. Patients who relapse after chemotherapy alone and who, at the time of relapse are stage I or IIA without bulk, continue on the study and receive a salvage regimen consisting of alternating courses of ifosfamide / vinorelbine, and dexamethasone, etoposide, cisplatin, and cytosine arabinoside followed by LD-IFRT.



• In the German Pediatric Oncology Group (GPOH) 2003 trial, patients with stage I or IIA disease (regardless of bulk) receive two cycles of either vincristine, etoposide, prednisone, doxorubicin (OEPA- males) or vincristine, procarbazine, prednisone, doxorubicin (OPPA- females). Patients who have a negative PET scan receive no further therapy, while those that are PET scan-positive receive LD-IFRT.

The following are examples of national clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

The COG Intermediate Risk Trial (COG-AHOD0031) (stages I and II with either B symptoms or bulk, stage II AE, stage IIIA and stage IVA) is evaluating early response after two cycles of ABVE-PC to determine subsequent treatment. Response assessment is based solely on anatomic imaging:

• Patients who achieve a rapid response to two cycles of ABVE-PC receive an additional two cycles of the same chemotherapy. Complete responders then are randomized to receive or not receive LD-IFRT. Partial responders receive LD-IFRT. The hypothesis is that rapid response delineates a subgroup of patients who will not require LD-IFRT.



• Patients who show a slow response to two cycles of ABVE-PC are randomized to receive two further cycles of ABVE-PC or two cycles of ABVE-PC and two additional cycles of a noncross-resistant combination (dexamethasone, etoposide, cisplatin, cytarabine [ARA-C] - {DECA}) prior to LD-IFRT. The hypothesis is that additional noncross-resistant chemotherapy prior to LD-IFRT improves EFS for patients with slow initial disease resolution.



• In the GPOH 2003 trial, following OPPA or OEPA, patients in treatment group 2 are randomized to two additional cycles of COPP or COPDIC, in which dacarbazine replaces procarbazine in an effort to reduce gonadal toxicity while maintaining efficacy.[36]



• A consortium of institutions in the United States are evaluating the Stanford V regimen.

The following are examples of national clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

• In the GPOH 2003 trial, following OPPA or OEPA, patients in treatment group 3 are randomized to four additional cycles of COPP or COPDIC, in which dacarbazine replaces procarbazine in an effort to reduce gonadal toxicity while maintaining efficacy.[36]



• A consortium of institutions in the United States are evaluating the Stanford V regimen.

The following is an example of a national clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

• COG-AHOD03P1 : In this ongoing COG study, patients with stage I, completely resected disease are observed without further treatment. Patients with stage I or IIA disease with no bulk disease and residual disease following initial biopsy, receive three cycles of vincristine, doxorubicin and cyclophosphamide chemotherapy. Patients showing a complete response receive no further therapy; patients with a partial response receive LD-IFRT.



• Other patients with NLPHL are treated on stage appropriate intermediate or high risk classical Hodgkin lymphoma protocols.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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

1. Schwartz CL: The management of Hodgkin disease in the young child. Curr Opin Pediatr 15 (1): 10-6, 2003.  [PUBMED Abstract]
   
   
2. Bhatia S, Robison LL, Oberlin O, et al.: Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 334 (12): 745-51, 1996.  [PUBMED Abstract]
   
   
3. Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 11 (7): 1208-15, 1993.  [PUBMED Abstract]
   
   
4. Thomson AB, Wallace WH: Treatment of paediatric Hodgkin's disease. a balance of risks. Eur J Cancer 38 (4): 468-77, 2002.  [PUBMED Abstract]
   
   
5. Hudson MM, Donaldson SS: Treatment of pediatric Hodgkin's lymphoma. Semin Hematol 36 (3): 313-23, 1999.  [PUBMED Abstract]
   
   
6. Oberlin O: Present and future strategies of treatment in childhood Hodgkin's lymphomas. Ann Oncol 7 (Suppl 4): 73-8, 1996.  [PUBMED Abstract]
   
   
7. Kaldor JM, Day NE, Clarke EA, et al.: Leukemia following Hodgkin's disease. N Engl J Med 322 (1): 7-13, 1990.  [PUBMED Abstract]
   
   
8. Mefferd JM, Donaldson SS, Link MP: Pediatric Hodgkin's disease: pulmonary, cardiac, and thyroid function following combined modality therapy. Int J Radiat Oncol Biol Phys 16 (3): 679-85, 1989.  [PUBMED Abstract]
   
   
9. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002.  [PUBMED Abstract]
   
   
10. Gerres L, Brämswig JH, Schlegel W, et al.: The effects of etoposide on testicular function in boys treated for Hodgkin's disease. Cancer 83 (10): 2217-22, 1998.  [PUBMED Abstract]
    
    
11. Tebbi CK, London WB, Friedman D, et al.: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25 (5): 493-500, 2007.  [PUBMED Abstract]
    
    
12. Schwartz CL, Tebbi CK, Constine LS: Response based therapy for pediatric Hodgkin's disease (HD): Pediatric Oncology Group (POG) protocols 9425/9426. [Abstract] Med Pediatr Oncol 37 (3): A-P219, 263, 2001. 
    
    
13. Smith MA, Rubinstein L, Anderson JR, et al.: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17 (2): 569-77, 1999.  [PUBMED Abstract]
    
    
14. Tebbi CK, Mendenhall N, London WB, et al.: Treatment of stage I, IIA, IIIA1 pediatric Hodgkin disease with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: a Pediatric Oncology Group (POG) study. Pediatr Blood Cancer 46 (2): 198-202, 2006.  [PUBMED Abstract]
    
    
15. Donaldson SS, Link MP, Weinstein HJ, et al.: Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease. J Clin Oncol 25 (3): 332-7, 2007.  [PUBMED Abstract]
    
    
16. Hudson MM, Krasin M, Link MP, et al.: Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease. J Clin Oncol 22 (22): 4541-50, 2004.  [PUBMED Abstract]
    
    
17. Tebbi C, Schwartz C, London W, et al.: Hematologic effects of dexrazoxane used with DBVE regimen for treatment of early-stage Hodgkin's disease in children. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-083, 49, 2001. 
    
    
18. Cvetković RS, Scott LJ: Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy. Drugs 65 (7): 1005-24, 2005.  [PUBMED Abstract]
    
    
19. Behrendt H, Brinkhuis M, Van Leeuwen EF: Treatment of childhood Hodgkin's disease with ABVD without radiotherapy. Med Pediatr Oncol 26 (4): 244-8, 1996.  [PUBMED Abstract]
    
    
20. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.  [PUBMED Abstract]
    
    
21. Kelly KM, Hutchinson RJ, Sposto R, et al.: Feasibility of upfront dose-intensive chemotherapy in children with advanced-stage Hodgkin's lymphoma: preliminary results from the Children's Cancer Group Study CCG-59704. Ann Oncol 13 (Suppl 1): 107-11, 2002.  [PUBMED Abstract]
    
    
22. Schwartz CL: Special issues in pediatric Hodgkin's disease. Eur J Haematol Suppl (66): 55-62, 2005.  [PUBMED Abstract]
    
    
23. Chow LM, Nathan PC, Hodgson DC, et al.: Survival and late effects in children with Hodgkin's lymphoma treated with MOPP/ABV and low-dose, extended-field irradiation. J Clin Oncol 24 (36): 5735-41, 2006.  [PUBMED Abstract]
    
    
24. Hudson M, Constine LS: Hodgkin's disease. In: Halperin EC, Constine LS, Tarbell NJ, et al.: Pediatric Radiation Oncology. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2004, pp 223-60. 
    
    
25. Loeffler M, Brosteanu O, Hasenclever D, et al.: Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group. J Clin Oncol 16 (3): 818-29, 1998.  [PUBMED Abstract]
    
    
26. Dörffel W, Lüders H, Rühl U, et al.: Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin's disease in children and adolescents: analysis and outlook. Klin Padiatr 215 (3): 139-45, 2003 May-Jun.  [PUBMED Abstract]
    
    
27. Schwartz CL, Constine LS, London W, et al.: POG 9425: response-based, intensively timed therapy for intermediate/high stage (IS/HS) pediatric Hodgkin's disease. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1555, 2002. 
    
    
28. Nogová L, Reineke T, Brillant C, et al.: Lymphocyte-predominant and classical Hodgkin's lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 26 (3): 434-9, 2008.  [PUBMED Abstract]
    
    
29. Diehl V, Sextro M, Franklin J, et al.: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 17 (3): 776-83, 1999.  [PUBMED Abstract]
    
    
30. Mauz-Körholz C, Gorde-Grosjean S, Hasenclever D, et al.: Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma. Cancer 110 (1): 179-85, 2007.  [PUBMED Abstract]
    
    
31. Murphy SB, Morgan ER, Katzenstein HM, et al.: Results of little or no treatment for lymphocyte-predominant Hodgkin disease in children and adolescents. J Pediatr Hematol Oncol 25 (9): 684-7, 2003.  [PUBMED Abstract]
    
    
32. Sandoval C, Venkateswaran L, Billups C, et al.: Lymphocyte-predominant Hodgkin disease in children. J Pediatr Hematol Oncol 24 (4): 269-73, 2002.  [PUBMED Abstract]
    
    
33. Hall GW, Katzilakis N, Pinkerton CR, et al.: Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma - a Children's Cancer and Leukaemia Group report. Br J Haematol 138 (6): 761-8, 2007.  [PUBMED Abstract]
    
    
34. Miettinen M, Franssila KO, Saxén E: Hodgkin's disease, lymphocytic predominance nodular. Increased risk for subsequent non-Hodgkin's lymphomas. Cancer 51 (12): 2293-300, 1983.  [PUBMED Abstract]
    
    
35. Hansmann ML, Zwingers T, Böske A, et al.: Clinical features of nodular paragranuloma (Hodgkin's disease, lymphocyte predominance type, nodular). J Cancer Res Clin Oncol 108 (3): 321-30, 1984.  [PUBMED Abstract]
    
    
36. Körholz D, Claviez A, Hasenclever D, et al.: The concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin's disease: evolution in the tradition of the DAL/GPOH studies. Klin Padiatr 216 (3): 150-6, 2004 May-Jun.  [PUBMED Abstract]
    
    

Back to Top

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

Treatment failure in children and adolescents with Hodgkin lymphoma can be divided into three groups:

• Primary progressive disease.
• Relapse limited to the site(s) of initial involvement (in patients treated with chemotherapy alone).
• Other relapse.

The presence of B symptoms and extranodal disease at the time of relapse are adverse prognostic features.[1] In one study from the German Pediatric Oncology Group (GPOH), patients with an early relapse (defined as occurring between 3–12 months from the end of therapy) had a 10-year event-free survival (EFS) of 55% and a 5-year overall survival (OS) of 78%. Patients with a late relapse (defined as occurring more than 12 months from the end of therapy) had a 10-year EFS and OS of 86% and 90%, respectively.[2] In the GPOH and the former Children’s Cancer Group (CCG) Hodgkin lymphoma trials, most relapses occurred in patients who received chemotherapy alone as primary treatment, and most of the relapses were limited to sites of initial involvement.[3,4] Patients with favorable disease at diagnosis (i.e., stage IA or stage IIA; no bulk; no B symptoms), with relapse confined to an area of initial involvement after chemotherapy and no radiation, can generally be salvaged with further chemotherapy and low-dose involved-field radiation therapy (LD-IFRT). For some postpubertal patients, standard-dose radiation may be an option.[5] For patients who are initially treated for low-stage disease without dose-intensive therapy, the salvage rates without hematopoietic stem cell transplant are very high.[2] For all other patients, treatment of relapse/progression includes induction chemotherapy,[6-10] and high-dose chemotherapy with hematopoietic stem cell transplant (HSCT).[11-13] Overall outcome is better following the use of autologous versus allogeneic stem cells because of the increased mortality associated with allogeneic transplant.[14] Following autologous HSCT, the projected survival rate is 45% to 70% and progression-free survival (PFS) is 30% to 65%.[15] Adverse prognostic features for outcome after autologous HSCT include extranodal disease at relapse, mediastinal mass at time of transplant, advanced stage at relapse, primary refractory disease, and a positive PET scan prior to autologous HSCT.[15,16] For patients who fail following autologous HSCT or for patients who cannot mobilize sufficient numbers of autologous stem cells, allogeneic HSCT has been used with encouraging results.[14,17-19] Whether such patients should receive further irradiation to previously radiated sites of relapse remains unclear.

A number of chemotherapy drugs not generally used in the initial treatment of Hodgkin lymphoma have documented activity against recurrent Hodgkin lymphoma including:

• moderate- or high-dose cytarabine
• carboplatin/cisplatin
• ifosfamide
• etoposide
• vinorelbine
• gemcitabine
• vinblastine [20]

Combination regimens used in the treatment of progressive/recurrent Hodgkin lymphoma include:

• ICE (ifosfamide, carboplatin, and etoposide) [8]
• DECAL (dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase) [7]  [Note: These are results from a combined Hodgkin and non-Hodgkin lymphoma study. For Hodgkin lymphoma, DECA is the combination regimen currently used.]
• Ifosfamide and vinorelbine [9]
• Vinorelbine/gemcitabine [21]
• IEP–ABVD–COPP (ifosfamide, etoposide, prednisone–doxorubicin, bleomycin, vinblastine, dacarbazine–cyclophosphamide, vincristine, procarbazine, prednisone) [2]
• APE (cytosine arabinoside, cisplatin, etoposide) [22]
• For patients with CD20-positive disease, rituximab can be given alone or in combination with the above chemotherapy.

The most commonly utilized preparative regimen for peripheral blood stem cell transplant is the BEAM regimen (carmustine [BCNU], etoposide, cytarabine, melphalan). Carmustine may produce significant pulmonary toxicity. Other noncarmustine-containing preparative regimens include thiotepa and etoposide, combined with either cyclophosphamide, carboplatin, or melphalan. Busulfan has also been utilized in certain preparative regimens.

LD-IFRT to sites of recurrent disease should be given if these sites have not been previously irradiated. LD-IFRT is generally administered after high-dose chemotherapy and stem cell rescue.[23] Patients treated with HSCT may experience relapse as late as 5 years after the procedure; they should be monitored for relapse as well as late treatment sequelae.

Salvage rates for patients with primary refractory Hodgkin lymphoma are poor even with peripheral blood stem cell transplant and radiation. In one large series of patients, however, salvage after primary refractory Hodgkin lymphoma was attained with aggressive second-line therapy (high-dose chemoradiotherapy) and autologous stem cell transplantation. The OS rate was 49% at 5 years.[24] In a 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 EFS and OS rates of 41% and 51%, respectively.[2] Chemosensitivity to standard dose second-line chemotherapy predicted for a better survival (66% OS), and those who remained refractory did poorly (17% OS).[25] Salvage rates for patients who relapse after chemotherapy and LD-IFRT are approximately 30% to 50%. The salvage rate will probably be higher for patients who relapse after chemotherapy alone, particularly if the relapse is confined to a site of initial disease involvement.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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

1. Moskowitz CH, Nimer SD, Zelenetz AD, et al.: A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood 97 (3): 616-23, 2001.  [PUBMED Abstract]
   
   
2. Schellong G, Dörffel W, Claviez A, et al.: Salvage therapy of progressive and recurrent Hodgkin's disease: results from a multicenter study of the pediatric DAL/GPOH-HD study group. J Clin Oncol 23 (25): 6181-9, 2005.  [PUBMED Abstract]
   
   
3. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002.  [PUBMED Abstract]
   
   
4. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.  [PUBMED Abstract]
   
   
5. Wirth A, Corry J, Laidlaw C, et al.: Salvage radiotherapy for Hodgkin's disease following chemotherapy failure. Int J Radiat Oncol Biol Phys 39 (3): 599-607, 1997.  [PUBMED Abstract]
   
   
6. Aparicio J, Segura A, Garcerá S, et al.: ESHAP is an active regimen for relapsing Hodgkin's disease. Ann Oncol 10 (5): 593-5, 1999.  [PUBMED Abstract]
   
   
7. Kobrinsky NL, Sposto R, Shah NR, et al.: Outcomes of treatment of children and adolescents with recurrent non-Hodgkin's lymphoma and Hodgkin's disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children's Cancer Group Study CCG-5912. J Clin Oncol 19 (9): 2390-6, 2001.  [PUBMED Abstract]
   
   
8. Cairo MS, Shen V, Krailo MD, et al.: Prospective randomized trial between two doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and etoposide in children with recurrent or refractory solid tumors: a children's cancer group report. J Pediatr Hematol Oncol 23 (1): 30-8, 2001.  [PUBMED Abstract]
   
   
9. Bonfante V, Viviani S, Santoro A, et al.: Ifosfamide and vinorelbine: an active regimen for patients with relapsed or refractory Hodgkin's disease. Br J Haematol 103 (2): 533-5, 1998.  [PUBMED Abstract]
   
   
10. Zinzani PL, Bendandi M, Stefoni V, et al.: Value of gemcitabine treatment in heavily pretreated Hodgkin's disease patients. Haematologica 85 (9): 926-9, 2000.  [PUBMED Abstract]
    
    
11. Santoro A, Bredenfeld H, Devizzi L, et al.: Gemcitabine in the treatment of refractory Hodgkin's disease: results of a multicenter phase II study. J Clin Oncol 18 (13): 2615-9, 2000.  [PUBMED Abstract]
    
    
12. Jones RJ, Piantadosi S, Mann RB, et al.: High-dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin's disease. J Clin Oncol 8 (3): 527-37, 1990.  [PUBMED Abstract]
    
    
13. Baker KS, Gordon BG, Gross TG, et al.: Autologous hematopoietic stem-cell transplantation for relapsed or refractory Hodgkin's disease in children and adolescents. J Clin Oncol 17 (3): 825-31, 1999.  [PUBMED Abstract]
    
    
14. Peniket AJ, Ruiz de Elvira MC, Taghipour G, et al.: An EBMT registry matched study of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation. Bone Marrow Transplant 31 (8): 667-78, 2003.  [PUBMED Abstract]
    
    
15. Lieskovsky YE, Donaldson SS, Torres MA, et al.: High-dose therapy and autologous hematopoietic stem-cell transplantation for recurrent or refractory pediatric Hodgkin's disease: results and prognostic indices. J Clin Oncol 22 (22): 4532-40, 2004.  [PUBMED Abstract]
    
    
16. Jabbour E, Hosing C, Ayers G, et al.: Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma. Cancer 109 (12): 2481-9, 2007.  [PUBMED Abstract]
    
    
17. Cooney JP, Stiff PJ, Toor AA, et al.: BEAM allogeneic transplantation for patients with Hodgkin's disease who relapse after autologous transplantation is safe and effective. Biol Blood Marrow Transplant 9 (3): 177-82, 2003.  [PUBMED Abstract]
    
    
18. Claviez A, Klingebiel T, Beyer J, et al.: Allogeneic peripheral blood stem cell transplantation following fludarabine-based conditioning in six children with advanced Hodgkin's disease. Ann Hematol 83 (4): 237-41, 2004.  [PUBMED Abstract]
    
    
19. Sureda A, Schmitz N: Role of allogeneic stem cell transplantation in relapsed or refractory Hodgkin's disease. Ann Oncol 13 (Suppl 1): 128-32, 2002.  [PUBMED Abstract]
    
    
20. Little R, Wittes RE, Longo DL, et al.: Vinblastine for recurrent Hodgkin's disease following autologous bone marrow transplant. J Clin Oncol 16 (2): 584-8, 1998.  [PUBMED Abstract]
    
    
21. Ozkaynak MF, Jayabose S: Gemcitabine and vinorelbine as a salvage regimen for relapse in Hodgkin lymphoma after autologous hematopoietic stem cell transplantation. Pediatr Hematol Oncol 21 (2): 107-13, 2004.  [PUBMED Abstract]
    
    
22. Wimmer RS, Chauvenet AR, London WB, et al.: APE chemotherapy for children with relapsed Hodgkin disease: a Pediatric Oncology Group trial. Pediatr Blood Cancer 46 (3): 320-4, 2006.  [PUBMED Abstract]
    
    
23. Wadhwa P, Shina DC, Schenkein D, et al.: Should involved-field radiation therapy be used as an adjunct to lymphoma autotransplantation? Bone Marrow Transplant 29 (3): 183-9, 2002.  [PUBMED Abstract]
    
    
24. Morabito F, Stelitano C, Luminari S, et al.: The role of high-dose therapy and autologous stem cell transplantation in patients with primary refractory Hodgkin's lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL). Bone Marrow Transplant 37 (3): 283-8, 2006.  [PUBMED Abstract]
    
    
25. Moskowitz CH, Kewalramani T, Nimer SD, et al.: Effectiveness of high dose chemoradiotherapy and autologous stem cell transplantation for patients with biopsy-proven primary refractory Hodgkin's disease. Br J Haematol 124 (5): 645-52, 2004.  [PUBMED Abstract]
    
    

Back to Top

Late Effects from Childhood/Adolescent Hodgkin Lymphoma Therapy

Children and adolescent survivors of Hodgkin lymphoma are at risk for numerous late complications of treatment. Alkylating agents and etoposide have been associated with acute myeloid leukemia (AML) and myelodysplastic syndromes. Doxorubicin can lead to cardiomyopathy and bleomycin can cause pulmonary fibrosis. Steroid use can produce avascular necrosis. Radiation therapy can lead to thyroid dysfunction, most commonly compensated hypothyroidism, increased risk for myocardial atherosclerotic heart disease, and is associated with solid tumor development in radiation fields. The therapy for pediatric Hodgkin lymphoma has changed dramatically over the past 20 years. High-dose radiation therapy is no longer utilized and current chemotherapy regimens utilize lower doses of alkylating agents. Hybrid regimens allow for lower doses of anthracycline and bleomycin as well. Thus, much of the current late effects literature is not necessarily applicable to patients receiving modern therapy. (Refer to the PDQ Late Effects of Treatment for Childhood Cancer summary for a full discussion of the late effects of cancer treatment in children and adolescents.)

Male gonadal toxicity is a complex issue in Hodgkin lymphoma. Gonadal toxicity may manifest as infertility; lack of sexual development; small, atrophic testicles; and sexual dysfunction. Infertility caused by azoospermia is the most common manifestation of gonadal toxicity. Some pubertal male patients will have impaired spermatogenesis before they begin therapy.[1,2] The prepubertal testicle is likely equally or slightly less sensitive to chemotherapy compared with the pubertal testicle. Chemotherapy regimens that include no alkylating agents such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine), DBVE (doxorubicin, bleomycin, vincristine, etoposide), OEPA (vincristine [Oncovin], etoposide, prednisone, doxorubicin [Adriamycin]), or VAMP (vincristine, doxorubicin [Adriamycin], methotrexate, prednisone) are not associated with male infertility. Until recently, most male patients received chemotherapy regimens that included alkylating agents. Many regimens included more than one alkylating agent, usually procarbazine in conjunction with either cyclophosphamide (i.e., COPP [cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine]), chlorambucil, or nitrogen mustard (MOPP).

The German Pediatric Oncology and Hematology Group Hodgkin Study (GPOH-95) utilized OEPA for two cycles for all males.[3] Males with advanced-stage disease received an additional two or four cycles of COPP (each cycle, 1,500 mg/m² of procarbazine and 1,000 mg/m² of cyclophosphamide). Males receiving only two cycles of OEPA had normal basal levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and only rare patients had elevated levels following gonadotropin-releasing hormone (GnRH) stimulation. Basal levels of FSH, however, were elevated in 27.5% and 36.4% in patients receiving two and four COPP cycles, respectively. Stimulated FSH levels were abnormal in 83.3% and 66.7% of patients receiving two and four COPP cycles, respectively. Semen analysis was not performed in this study. Four cycles of COPP/ABV as given in the recently completed Children’s Cancer Group (CCG) study have a higher alkylator dose compared with two cycles of COPP as given in the German trial (CCG: cyclophosphamide 2,400 mg/m² and procarbazine 4,200 mg/m² versus GPOH: cyclophosphamide 2,000 mg/m² and procarbazine 3,000 mg/m²). In a small study of 11 male patients with Hodgkin lymphoma who received COPP/ABV chemotherapy (4 to 6 cycles), nine patients were azoospermic. One of the patients who was normospermatic received only a 400 mg/m² cumulative procarbazine dose because of an allergic reaction.[4] The concern for male fertility is also being addressed in the German GPOH 2003 trial by replacing procarbazine with dacarbazine (COPDIC).[5]

A regimen used by the former Pediatric Oncology Group (POG) included cyclophosphamide but no procarbazine (ABVE-PC). In this regimen, cyclophosphamide was given at 800 mg/m²/course for three to five cycles. A few studies have evaluated male fertility following cyclophosphamide-containing regimens given to children and young adults with sarcomas and other cancers.[6-8] The studies have suggested that the incidence of sterility will be low if the cyclophosphamide dose is less than 4.0 g/m². The level of inhibin B in blood seems to be inversely correlated with FSH levels.[9] Some patients with normal FSH levels may have azoospermia on semen analysis.

There are few published data concerning the incidence of ovarian failure following chemotherapy for female children and young adults with Hodgkin lymphoma. It appears that the ovaries of children and adolescents are less sensitive to the effects of alkylating agents than are the ovaries of older women. Most females will attain menses (prepubertal at treatment) or regain normal menses (pubertal at treatment) unless pelvic radiation therapy is given without oophoropexy. The incidence of early menopause in young female survivors of Hodgkin lymphoma is currently being studied, and may be as high as 37%.[10,11] A small study of patients treated with ABVD, suggests that there is no effect on fertility.[12] Another study of 12 female childhood Hodgkin lymphoma survivors showed that VAMP chemotherapy and low dose involved-field radiation seems to have a minimal impact on female fertility as 14 healthy babies were born to these women.[13]

The largest database for thyroid abnormalities is that of the Childhood Cancer Survivor Study. The cohort of 13,674 patients included 1,791 survivors of childhood Hodgkin lymphoma.[14] For patients with full data, 92 patients received chemotherapy alone, and 1,210 patients received radiation therapy (with or without chemotherapy). Only 15% of patients receiving radiation had doses less than 20 Gy. By self-report, hypothyroidism occurred within 20 years from diagnosis in 7.6% of unirradiated patients, 30% of those receiving less than 35 Gy and 50% of those receiving more than 35 Gy. Although no thyroid cancers were noted in patients receiving less than 25 Gy, overall, there was an 18-fold increased risk of thyroid cancer in survivors of pediatric Hodgkin lymphoma. The risk of hypothyroidism in white patients is 2.5 times the risk in black patients.[15] In a study of 47 survivors of pediatric Hodgkin lymphoma who received neck irradiation (22.5–40Gy), ultrasonography revealed atrophy in 45 patients and goiters in two patients. Twenty patients had a focal abnormality (15 multiple, 5 solitary). Five patients had a lesion larger than 1 cm. Ten patients underwent surgery, and five patients had thyroid carcinoma diagnosed.[16]

Hodgkin lymphoma survivors exposed to doxorubicin or thoracic radiation therapy are at risk for long-term cardiac toxicity. The risks to the heart are related to cumulative anthracycline dose, method of administration, amount of radiation delivered to different depths of the heart, volume and specific areas of the heart irradiated, total and fractional irradiation dose, age at exposure, latency period, and gender.

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.[17] Late effects of radiation to the heart include:[18-20]

• Delayed pericarditis.
• Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
• Myopathy.
• Coronary artery disease (CAD).
• Functional valve injury.
• Conduction defects.

In a study of 635 patients treated for childhood Hodgkin lymphoma, the actuarial risk of pericarditis requiring pericardiectomy was 4% at 17 years posttreatment (occurring only in children treated with higher radiation doses). Only 12 patients died of cardiac disease, including seven deaths from acute myocardial infarction; however, these deaths occurred only in children treated with 42 Gy to 45 Gy. Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.[21] Cardiac radiation using sophisticated treatment planning and careful blocking to doses 25 Gy or less is generally safe, and 40 Gy may be administered to small cardiac regions. The risk of delayed CAD after lower radiation doses, however, requires additional study of patients followed for longer periods of time to definitively ascertain lifetime risk. Nontherapeutic risk factors for CAD such as family history, obesity, hypertension, smoking, diabetes, and hypercholesterolemia are likely to impact the frequency of disease.[19] Increased risk of doxorubicin-related cardiomyopathy is associated with female sex, cumulative doses higher than 200 mg/m² to 300 mg/m², younger age at time of exposure, and increased time from exposure.[22-37]

Prevention or amelioration of anthracycline-induced cardiomyopathy is of utmost importance because the continued usage of anthracyclines is required in cancer therapy. Dexrazoxane (DZR) is a bisdioxopiperazine compound that readily enters cells and is subsequently hydrolyzed to form a chelating agent. Studies to date of cancer survivors treated with anthracyclines have not demonstrated the benefit of enalapril in preventing progressive cardiac toxicity.[38,39] Dexrazoxane has been shown to prevent cardiac toxicity in adults and children treated with anthracyclines,[40-44]however, the use of dexrazoxane in combination with etoposide in treating children with Hodgkin lymphoma remains controversial.[45,46] Studies suggest that dexrazoxane is safe and it does not interfere with chemotherapeutic efficacy. There is a single-study experience suggesting that there could be an increase in malignancies when multiple topoisomerase inhibitors are administered in close proximity; however, at this time, this should not preclude treatment with dexrazoxane.[45,46]

In two closed POG therapeutic phase III studies for Hodgkin lymphoma,[47,48] myocardial toxicity is being measured clinically and sequentially over time by echocardiography and electrocardiography, as well as by the determination of levels of cardiac troponin T, a protein that is elevated after myocardial damage.[40,49-53]

A number of series evaluating the incidence of malignancies in survivors of childhood and adolescent Hodgkin lymphoma have been published.[54-60] Most cover a span of approximately 30 years (1960–1990). Many of the patients included in these series received high-dose radiation therapy and high-dose alkylating agent chemotherapy regimens, which are no longer utilized. In a large study of 1,380 long-term survivors of childhood Hodgkin lymphoma, there was an 18.5-fold increased risk of developing a second cancer compared to the general population. The cumulative incidence of developing a second cancer was 10.6% at 20 years and 26.3% at 30 years.[60] 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. There is a 3.2-fold increase in the risk of developing breast cancer for females who received 4 Gy and an 8-fold increase in risk for females who received 40 Gy. Female patients treated with both radiation therapy and alkylating agent chemotherapy have a lower relative risk for developing breast cancer than women receiving radiation therapy alone.[61] Secondary hematologic malignancy (most commonly AML and myelodysplasia) is related to the use of alkylating agents, anthracycline, and etoposide,[62] and there remains controversy about the risk of treatment-related AML (tAML) in Hodgkin lymphoma patients receiving dexrazoxane concurrent with etoposide.[45,46] Second solid tumors are seen in patients receiving radiation are consistently noted. In one study, there was a significantly higher rate of second malignancies in females, which remained when breast cancer cases were censored. In a study from the Netherlands, relative risk for a second malignancy was 4.9, 6.7, and 12.8 for patients diagnosed at ages 31 to 40 years, 21 to 30 years and younger than 20 years, respectively.[55] Patients treated for recurrence of Hodgkin lymphoma had a higher rate of second malignancy than did patients in continuous first remission. The latency period for a hematologic malignancy (median, 3.2 years) was significantly shorter than that for a second solid tumor (median, 14.3 years).[56] In one study, 40 of 43 (83%) second solid tumors arose in areas that had received at least 35 Gy of radiation.[58]

References

1. Fitoussi, Eghbali H, Tchen N, et al.: Semen analysis and cryoconservation before treatment in Hodgkin's disease. Ann Oncol 11 (6): 679-84, 2000.  [PUBMED Abstract]
   
   
2. Viviani S, Ragni G, Santoro A, et al.: Testicular dysfunction in Hodgkin's disease before and after treatment. Eur J Cancer 27 (11): 1389-92, 1991.  [PUBMED Abstract]
   
   
3. Gerres L, Brämswig JH, Schlegel W, et al.: The effects of etoposide on testicular function in boys treated for Hodgkin's disease. Cancer 83 (10): 2217-22, 1998.  [PUBMED Abstract]
   
   
4. Hobbie WL, Ginsberg JP, Ogle SK, et al.: Fertility in males treated for Hodgkins disease with COPP/ABV hybrid. Pediatr Blood Cancer 44 (2): 193-6, 2005.  [PUBMED Abstract]
   
   
5. Körholz D, Claviez A, Hasenclever D, et al.: The concept of the GPOH-HD 2003 therapy study for pediatric Hodgkin's disease: evolution in the tradition of the DAL/GPOH studies. Klin Padiatr 216 (3): 150-6, 2004 May-Jun.  [PUBMED Abstract]
   
   
6. Kenney LB, Laufer MR, Grant FD, et al.: High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer 91 (3): 613-21, 2001.  [PUBMED Abstract]
   
   
7. Meistrich ML, Wilson G, Brown BW, et al.: Impact of cyclophosphamide on long-term reduction in sperm count in men treated with combination chemotherapy for Ewing and soft tissue sarcomas. Cancer 70 (11): 2703-12, 1992.  [PUBMED Abstract]
   
   
8. Aubier F, Patte C, de Vathaire F, et al.: [Male fertility after chemotherapy during childhood] Ann Endocrinol (Paris) 56 (2): 141-2, 1995.  [PUBMED Abstract]
   
   
9. Cicognani A, Cacciari E, Pasini A, et al.: Low serum inhibin B levels as a marker of testicular damage after treatment for a childhood malignancy. Eur J Pediatr 159 (1-2): 103-7, 2000 Jan-Feb.  [PUBMED Abstract]
   
   
10. Haukvik UK, Dieset I, Bjøro T, et al.: Treatment-related premature ovarian failure as a long-term complication after Hodgkin's lymphoma. Ann Oncol 17 (9): 1428-33, 2006.  [PUBMED Abstract]
    
    
11. Byrne J: Infertility and premature menopause in childhood cancer survivors. Med Pediatr Oncol 33 (1): 24-8, 1999.  [PUBMED Abstract]
    
    
12. Hodgson DC, Pintilie M, Gitterman L, et al.: Fertility among female hodgkin lymphoma survivors attempting pregnancy following ABVD chemotherapy. Hematol Oncol 25 (1): 11-5, 2007.  [PUBMED Abstract]
    
    
13. Donaldson SS, Link MP, Weinstein HJ, et al.: Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease. J Clin Oncol 25 (3): 332-7, 2007.  [PUBMED Abstract]
    
    
14. Sklar C, Whitton J, Mertens A, et al.: Abnormalities of the thyroid in survivors of Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin Endocrinol Metab 85 (9): 3227-32, 2000.  [PUBMED Abstract]
    
    
15. Metzger ML, Hudson MM, Somes GW, et al.: White race as a risk factor for hypothyroidism after treatment for pediatric Hodgkin's lymphoma. J Clin Oncol 24 (10): 1516-21, 2006.  [PUBMED Abstract]
    
    
16. Shafford EA, Kingston JE, Healy JC, et al.: Thyroid nodular disease after radiotherapy to the neck for childhood Hodgkin's disease. Br J Cancer 80 (5-6): 808-14, 1999.  [PUBMED Abstract]
    
    
17. Fajardo LF, Eltringham JR, Steward JR: Combined cardiotoxicity of adriamycin and x-radiation. Lab Invest 34 (1): 86-96, 1976.  [PUBMED Abstract]
    
    
18. Hancock SL, Tucker MA, Hoppe RT: Factors affecting late mortality from heart disease after treatment of Hodgkin's disease. JAMA 270 (16): 1949-55, 1993.  [PUBMED Abstract]
    
    
19. King V, Constine LS, Clark D, et al.: Symptomatic coronary artery disease after mantle irradiation for Hodgkin's disease. Int J Radiat Oncol Biol Phys 36 (4): 881-9, 1996.  [PUBMED Abstract]
    
    
20. Adams MJ, Lipshultz SE, Schwartz C, et al.: Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol 13 (3): 346-56, 2003.  [PUBMED Abstract]
    
    
21. Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 11 (7): 1208-15, 1993.  [PUBMED Abstract]
    
    
22. Ewer MS, Jaffe N, Ried H, et al.: Doxorubicin cardiotoxicity in children: comparison of a consecutive divided daily dose administration schedule with single dose (rapid) infusion administration. Med Pediatr Oncol 31 (6): 512-5, 1998.  [PUBMED Abstract]
    
    
23. Giantris A, Abdurrahman L, Hinkle A, et al.: Anthracycline-induced cardiotoxicity in children and young adults. Crit Rev Oncol Hematol 27 (1): 53-68, 1998.  [PUBMED Abstract]
    
    
24. Green DM, Grigoriev YA, Nan B, et al.: Congestive heart failure after treatment for Wilms' tumor: a report from the National Wilms' Tumor Study group. J Clin Oncol 19 (7): 1926-34, 2001.  [PUBMED Abstract]
    
    
25. Krischer JP, Epstein S, Cuthbertson DD, et al.: Clinical cardiotoxicity following anthracycline treatment for childhood cancer: the Pediatric Oncology Group experience. J Clin Oncol 15 (4): 1544-52, 1997.  [PUBMED Abstract]
    
    
26. Lipshultz SE, Sanders SP, Goorin AM, et al.: Monitoring for anthracycline cardiotoxicity. Pediatrics 93 (3): 433-7, 1994.  [PUBMED Abstract]
    
    
27. Lipshultz SE, Lipsitz SR, Mone SM, et al.: Female sex and drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332 (26): 1738-43, 1995.  [PUBMED Abstract]
    
    
28. Lipshultz S, Lipsitz S, Sallan S, et al.: Chronic progressive left ventricular systolic dysfunction and afterload excess years after doxorubicin therapy for childhood acute lymphoblastic leukemia. [Abstract] Proceedings of the American Society of Clinical Oncology 19: A-2281, 580a, 2000. 
    
    
29. Lipshultz SE, Giantris AL, Lipsitz SR, et al.: Doxorubicin administration by continuous infusion is not cardioprotective: the Dana-Farber 91-01 Acute Lymphoblastic Leukemia protocol. J Clin Oncol 20 (6): 1677-82, 2002.  [PUBMED Abstract]
    
    
30. Nysom K, Holm K, Lipsitz SR, et al.: Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 16 (2): 545-50, 1998.  [PUBMED Abstract]
    
    
31. Silber JH, Jakacki RI, Larsen RL, et al.: Increased risk of cardiac dysfunction after anthracyclines in girls. Med Pediatr Oncol 21 (7): 477-9, 1993.  [PUBMED Abstract]
    
    
32. Steinherz LJ, Graham T, Hurwitz R, et al.: Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Childrens Cancer Study Group. Pediatrics 89 (5 Pt 1): 942-9, 1992.  [PUBMED Abstract]
    
    
33. Steinherz LJ, Steinherz PG, Tan C: Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol 24 (6): 352-61, 1995.  [PUBMED Abstract]
    
    
34. Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25 (4 Suppl 10): 72-85, 1998.  [PUBMED Abstract]
    
    
35. Zinzani PL, Gherlinzoni F, Piovaccari G, et al.: Cardiac injury as late toxicity of mediastinal radiation therapy for Hodgkin's disease patients. Haematologica 81 (2): 132-7, 1996 Mar-Apr.  [PUBMED Abstract]
    
    
36. Pein F, Sakiroglu O, Dahan M, et al.: Cardiac abnormalities 15 years and more after adriamycin therapy in 229 childhood survivors of a solid tumour at the Institut Gustave Roussy. Br J Cancer 91 (1): 37-44, 2004.  [PUBMED Abstract]
    
    
37. Adams MJ, Lipsitz SR, Colan SD, et al.: Cardiovascular status in long-term survivors of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol 22 (15): 3139-48, 2004.  [PUBMED Abstract]
    
    
38. Silber JH, Cnaan A, Clark BJ, et al.: Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines. J Clin Oncol 22 (5): 820-8, 2004.  [PUBMED Abstract]
    
    
39. Lipshultz SE, Lipsitz SR, Sallan SE, et al.: Long-term enalapril therapy for left ventricular dysfunction in doxorubicin-treated survivors of childhood cancer. J Clin Oncol 20 (23): 4517-22, 2002.  [PUBMED Abstract]
    
    
40. Herman EH, Zhang J, Rifai N, et al.: The use of serum levels of cardiac troponin T to compare the protective activity of dexrazoxane against doxorubicin- and mitoxantrone-induced cardiotoxicity. Cancer Chemother Pharmacol 48 (4): 297-304, 2001.  [PUBMED Abstract]
    
    
41. Lipshultz SE, Rifai N, Dalton VM, et al.: The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351 (2): 145-53, 2004.  [PUBMED Abstract]
    
    
42. Swain SM, Whaley FS, Gerber MC, et al.: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15 (4): 1318-32, 1997.  [PUBMED Abstract]
    
    
43. Venturini M, Michelotti A, Del Mastro L, et al.: Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14 (12): 3112-20, 1996.  [PUBMED Abstract]
    
    
44. Wexler LH: Ameliorating anthracycline cardiotoxicity in children with cancer: clinical trials with dexrazoxane. Semin Oncol 25 (4 Suppl 10): 86-92, 1998.  [PUBMED Abstract]
    
    
45. Tebbi CK, London WB, Friedman D, et al.: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25 (5): 493-500, 2007.  [PUBMED Abstract]
    
    
46. Cvetković RS, Scott LJ: Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy. Drugs 65 (7): 1005-24, 2005.  [PUBMED Abstract]
    
    
47. Schwartz CL, Constine LS, London W, et al.: POG 9425: response-based, intensively timed therapy for intermediate/high stage (IS/HS) pediatric Hodgkin's disease. [Abstract] Proceedings of the American Society of Clinical Oncology 21: A-1555, 2002. 
    
    
48. Tebbi CK, Mendenhall N, Schwartz C, et al.: Response dependent treatment of stages IA, IIA, and IIIA1micro Hodgkin's disease with DBVE and low dose involved field irradiation with or without dexrazoxane. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-100, 56, 2001. 
    
    
49. Hamm CW: Cardiac biomarkers for rapid evaluation of chest pain. Circulation 104 (13): 1454-6, 2001.  [PUBMED Abstract]
    
    
50. Heeschen C, Goldmann BU, Terres W, et al.: Cardiovascular risk and therapeutic benefit of coronary interventions for patients with unstable angina according to the troponin T status. Eur Heart J 21 (14): 1159-66, 2000.  [PUBMED Abstract]
    
    
51. Herman EH, Zhang J, Lipshultz SE, et al.: Correlation between serum levels of cardiac troponin-T and the severity of the chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 17 (7): 2237-43, 1999.  [PUBMED Abstract]
    
    
52. Lipshultz SE, Rifai N, Sallan SE, et al.: Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 96 (8): 2641-8, 1997.  [PUBMED Abstract]
    
    
53. Mathew P, Suarez W, Kip K, et al.: Is there a potential role for serum cardiac troponin I as a marker for myocardial dysfunction in pediatric patients receiving anthracycline-based therapy? A pilot study. Cancer Invest 19 (4): 352-9, 2001.  [PUBMED Abstract]
    
    
54. Beaty O 3rd, Hudson MM, Greenwald C, et al.: Subsequent malignancies in children and adolescents after treatment for Hodgkin's disease. J Clin Oncol 13 (3): 603-9, 1995.  [PUBMED Abstract]
    
    
55. van Leeuwen FE, Klokman WJ, Veer MB, et al.: Long-term risk of second malignancy in survivors of Hodgkin's disease treated during adolescence or young adulthood. J Clin Oncol 18 (3): 487-97, 2000.  [PUBMED Abstract]
    
    
56. Green DM, Hyland A, Barcos MP, et al.: Second malignant neoplasms after treatment for Hodgkin's disease in childhood or adolescence. J Clin Oncol 18 (7): 1492-9, 2000.  [PUBMED Abstract]
    
    
57. Metayer C, Lynch CF, Clarke EA, et al.: Second cancers among long-term survivors of Hodgkin's disease diagnosed in childhood and adolescence. J Clin Oncol 18 (12): 2435-43, 2000.  [PUBMED Abstract]
    
    
58. Wolden SL, Lamborn KR, Cleary SF, et al.: Second cancers following pediatric Hodgkin's disease. J Clin Oncol 16 (2): 536-44, 1998.  [PUBMED Abstract]
    
    
59. Sankila R, Garwicz S, Olsen JH, et al.: Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology. J Clin Oncol 14 (5): 1442-6, 1996.  [PUBMED Abstract]
    
    
60. Bhatia S, Yasui Y, Robison LL, et al.: High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group. J Clin Oncol 21 (23): 4386-94, 2003.  [PUBMED Abstract]
    
    
61. Travis LB, Hill DA, Dores GM, et al.: Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 290 (4): 465-75, 2003.  [PUBMED Abstract]
    
    
62. Le Deley MC, Leblanc T, Shamsaldin A, et al.: Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d'Oncologie Pédiatrique. J Clin Oncol 21 (6): 1074-81, 2003.  [PUBMED Abstract]
    
    

Back to Top

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 9:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office

Suite 3036A

6116 Executive Boulevard, MSC8322

Bethesda, MD 20892-8322

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use our “Best Bets” search box in the upper right hand corner of each Web page. The results that are most closely related to your search term will be listed as Best Bets at the top of the list of search results.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237), TTY at 1-800-332-8615.

Back to Top

Changes to This Summary (11/13/2008)

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.

Editorial changes were made to this summary.

Back to Top

More Information

About PDQ

• PDQ® - NCI's Comprehensive Cancer Database.

  Full description of the NCI PDQ database.

Additional PDQ Summaries

• PDQ® Cancer Information Summaries: Adult Treatment

  Treatment options for adult cancers.

• PDQ® Cancer Information Summaries: Pediatric Treatment

  Treatment options for childhood cancers.

• PDQ® Cancer Information Summaries: Supportive and Palliative Care

  Side effects of cancer treatment, management of cancer-related complications and pain, and psychosocial concerns.

• PDQ® Cancer Information Summaries: Screening/Detection (Testing for Cancer)

  Tests or procedures that detect specific types of cancer.

• PDQ® Cancer Information Summaries: Prevention

  Risk factors and methods to increase chances of preventing specific types of cancer.

• PDQ® Cancer Information Summaries: Genetics

  Genetics of specific cancers and inherited cancer syndromes, and ethical, legal, and social concerns.

• PDQ® Cancer Information Summaries: Complementary and Alternative Medicine

  Information about complementary and alternative forms of treatment for patients with cancer.

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

Back to Top