Purpose of This PDQ Summary
General Information
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

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 Children and Adolescent Patients with Hodgkin Lymphoma         Nodular lymphocyte-predominant Hodgkin lymphoma Treatment Strategies Under Clinical Investigation for Childhood/Adolescent Hodgkin Lymphoma         Low-risk disease         Intermediate-risk disease         Nodular lymphocyte-predominant Hodgkin lymphoma

Primary Progressive/Recurrent Hodgkin Lymphoma in Children and Adolescents
Late Effects from Childhood/Adolescent Hodgkin Lymphoma Therapy

Male Gonadal Toxicity Female Infertility Thyroid Abnormalities Cardiac Toxicity Secondary Malignancies

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Changes to This Summary (02/14/2008)
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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 ¹.

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.

In the summary, treatments are described as “standard” or “conventional” and “under clinical evaluation.” These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version ², which is written in less-technical language, and in Spanish ³.

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 ⁴ 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. ⁵

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 ⁶ for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

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]
   
   

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 or Hodgkin 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 20% to 30% of cases.[4] R-S/Hodgkin 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.[5]

The histologic features and clinical symptoms of Hodgkin lymphoma have been attributed to the numerous cytokines secreted by the R-S cells, which include interleukin-1 and interleukin-6, and tumor necrosis factor. Interleukin-5 could be responsible for the eosinophilia in MCHL, and transforming growth factor-b for the fibrosis in the NSHL subtype. These cytokines also enable the cells to evade immunologic surveillance as well as promote their own replication.

• NSHL histology accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents but only 45% 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.



• MCHL histology is more common in younger children (about 35%) than in adolescents or adults (10% to 20%). 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 peripheral T-cell lymphoma.



• LRCHL may have a nodular appearance, but immunophenotypic analysis allows distinction between this form of Hodgkin lymphoma and nodular lymphocyte-predominant disease.[6] 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.[7] It is sometimes difficult to distinguish NLPHL from progressive transformation of germinal centers and/or T-cell-rich B-cell lymphoma.[8] NLPHL is most common in males younger than 10 years. Patients with NLPHL generally present with localized, nonbulky disease. 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. 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]
   
   
5. Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002.  [PUBMED Abstract]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   

Prognostic Factors in Childhood and Adolescent Hodgkin Lymphoma

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 determination of prognostic factors is that their relevance is influenced by the factors chosen to stratify patients and the treatment administered. 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. Radiation therapy was administered to involved sites, however, with boost doses given to patients who had postchemotherapy residual disease.[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 on multivariate analysis for inferior disease-free survival and overall survival. Prognosis was 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,[10] and serum IL-10 level.[11] High levels of caspase 3 in Reed-Sternberg (R-S) cells have been associated with a favorable outcome.[12]

The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important and is being used to determine subsequent therapy.[13-15] 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.[16] In this setting, visual assessment of PET negativity may not be adequate and consideration of standard uptake values may be necessary.[17]

Although prognostic factors will continue to change because of risk stratification and choice of therapy, parameters such as disease stage, bulk, number of involved sites, and systemic symptomatology 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. Hann HW, Lange B, Stahlhut MW, et al.: Prognostic importance of serum transferrin and ferritin in childhood Hodgkin's disease. Cancer 66 (2): 313-6, 1990.  [PUBMED Abstract]
    
    
11. 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]
    
    
12. 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]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. 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]
    
    

Staging and Diagnostic Evaluation

End of Chemotherapy Re-evaluation

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 more than a 70% to 80% reduction of disease and a change from initial positivity to negativity on either gallium or PET scanning.[1,2] 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.

Recently, many centers have switched functional imaging from gallium to PET scanning.[3-5] There is a growing consensus from adult studies that PET scanning may identify more sites of initial disease than gallium scans, and that PET scanning is more accurate than gallium scanning in detecting viable Hodgkin lymphoma in posttherapy residual masses. 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.[6] 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. [7] Currently, either PET or gallium 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.[8-11]

References

1. Brisse H, Pacquement H, Burdairon E, et al.: Outcome of residual mediastinal masses of thoracic lymphomas in children: impact on management and radiological follow-up strategy. Pediatr Radiol 28 (6): 444-50, 1998.  [PUBMED Abstract]
   
   
2. 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]
   
   
3. 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]
   
   
4. Wiedmann E, Baican B, Hertel A, et al.: Positron emission tomography (PET) for staging and evaluation of response to treatment in patients with Hodgkin's disease. Leuk Lymphoma 34 (5-6): 545-51, 1999.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. 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]
   
   
10. 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]
    
    
11. 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]
    
    

Treatment Approach for Children and Adolescents with Hodgkin Lymphoma

In general, the use of combined chemotherapy and radiation broadens the spectrum of potential toxicities, while reducing the severity of individual drug-related or radiation-related toxicities. Current approaches use chemotherapy alone with or without low-dose involved-field radiation therapy (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 increased 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 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 anatomic-disease stage and the presence or absence of symptoms at diagnosis and the presence or absence of bulk disease.[4-6]

The following strategies have been utilized to treat children and adolescents with Hodgkin lymphoma:

• Chemotherapy and LD-IFRT for all patients.



• Chemotherapy alone for selected patients; chemotherapy and LD-IFRT for other patients.



• Initial chemotherapy intensity (number of cycles) determined by early response assessment followed by no further therapy or LD-IFRT.

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

• cyclophosphamide
• procarbazine
• vincristine and/or vinblastine
• prednisone or dexamethasone
• doxorubicin
• bleomycin
• dacarbazine
• etoposide
• methotrexate
• cytosine arabinoside
• mechlorethamine

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 under study 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] Ongoing COG trials are based on the DBVE-PC regimen (now referred to as the ABVE-PC regimen) that use intensive-dose delivery per week but limit cumulative doses.[12] Most patients in the United States are treated with chemotherapy regimens that combine low cumulative doses of alkylating agents, doxorubicin, and bleomycin with or without etoposide. 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. In a very young child (younger than 5 years), 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.

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.

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 in its early stage, 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).[30] 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, patients have been successfully treated with chemotherapy alone or complete resection of isolated nodal disease. 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.[32] The largest experience in children with resection alone for NLPHL 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%, 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 ⁹.

• COG-AHOD0431 ¹⁰ : A COG low-risk Hodgkin lymphoma study is evaluating patients with clinical stage I and IIA disease. Patients with no bulk (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 are stage I or IIA, without bulk, at relapse 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 GPOH 2003 trial, patients are divided into risk groups for treatment stratification. Treatment group one (TG-1) includes patients with stage I and IIA disease; treatment group two (TG-2) includes patients with stage IIB, IIEA, and IIIA disease; treatment group three (TG-3) includes patients with stage IIEB, IIIEA, IIIB, IIIEB, IVA, and IVB disease. Patients in TG-1 who have a negative PET scan at the end of two cycles of chemotherapy will not receive radiation therapy, even if radiographic abnormalities persist at the end of treatment.[36]

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 ⁹.

The COG Intermediate Risk Trial (COG-AHOD0031 ¹¹) (stages I and II with either B symptoms or bulk, stage II AE, stage IIIA and stage IVA) will evaluate early response after two cycles of ABVE-PC to determine subsequent treatment:

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



• Patients who show a slow response to two cycles of ABVE-PC will be randomized to receive two additionalcycles of ABVE-PC or two cycles of ABVE-PC and two 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 will improve EFS for patients with slow initial disease resolution.



• In the German GPOH 2003 trial, patients in treatment groups 2 and 3 will be randomized to COPP or COPDIC, in which dacarbazine will replace procarbazine in an effort to reduce gonadal toxicity while maintaining efficacy.[36]

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 ⁹.

• COG-AHOD03P1 ¹² : A COG study is evaluating surgery alone for stage I patients with NLPHL with total resection of a single, involved lymph node.

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

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. Karayalcin G, Behm FG, Gieser PW, et al.: Lymphocyte predominant Hodgkin disease: clinico-pathologic features and results of treatment--the Pediatric Oncology Group experience. Med Pediatr Oncol 29 (6): 519-25, 1997.  [PUBMED Abstract]
    
    
29. 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]
    
    
30. 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]
    
    
31. 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]
    
    
32. 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]
    
    
33. 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]
    
    
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]
    
    

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 rate without transplant can be 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%.[15,16] 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.[15,17] 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.[14,18-20] 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 [21]

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 [22]
• IEP–ABVD–COPP (ifosfamide, etoposide, prednisone–doxorubicin, bleomycin, vinblastine, dacarbazine–cyclophosphamide, vincristine, procarbazine, prednisone) [2]
• APE (cytosine arabinoside, cisplatin, etoposide) [23]

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 may be given if these sites have not been previously irradiated. LD-IFRT is generally administered after high-dose chemotherapy and stem cell rescue.[24,25] 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. At a median of 10 years of follow-up, EFS, PFS, and OS rates were 45%, 49%, and 48%, respectively. 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).[26] 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.

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. Williams CD, Goldstone AH, Pearce R, et al.: Autologous bone marrow transplantation for pediatric Hodgkin's disease: a case-matched comparison with adult patients by the European Bone Marrow Transplant Group Lymphoma Registry. J Clin Oncol 11 (11): 2243-9, 1993.  [PUBMED Abstract]
    
    
17. 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]
    
    
18. 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]
    
    
19. 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]
    
    
20. 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]
    
    
21. 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]
    
    
22. 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]
    
    
23. 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]
    
    
24. Constine LS, Rapoport AP: Hodgkin's disease, bone marrow transplantation, and involved field radiation therapy: coming full circle from 1902 to 1996. Int J Radiat Oncol Biol Phys 36 (1): 253-5, 1996.  [PUBMED Abstract]
    
    
25. 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]
    
    
26. 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]
    
    

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 ⁶ 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 lympho