Childhood Hodgkin Lymphoma

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of childhood Hodgkin's lymphoma.

Childhood Hodgkin Lymphoma

General Information

This cancer treatment information summary provides an overview of the prognosis, diagnosis, classification, staging, treatment, and potential late therapy effects of childhood Hodgkin lymphoma.

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. These summaries are updated regularly according to the latest published research findings by an Editorial Board of pediatric oncology specialists.

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 othersto 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.^2,3 Thus, new strategies utilizing chemotherapy and lower-dose radiation were developed.⁴ 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 intensity varying by stage) and low-dose involved-field irradiation.

Hodgkin lymphoma comprises 6% of childhood cancers. A striking male:female predominance is found among young children, with a ratio of 4:1 for 3- to 7-year-olds, and 3:1 for 7- to 9-year-olds. For patients older than 10 years, the ratio is 1.3:1 (a ratio more similar to that of adults).⁵ In the United States, Hodgkin lymphoma is uncommon in children younger than 10 years. Younger children have a higher incidence of lymphocyte-predominant and mixed cellularity histology and a lower incidence of nodular-sclerosing histology than adolescents and adults. The incidence of Hodgkin lymphoma continues to increase during the early teen and adolescent years. In one clinical trial for children and adolescents with Hodgkin lymphoma, 3% of patients were aged between 0 and 4 years, and 12% of patients were between 5 and 9 years, 44% of patients were between 10 and 14 years, and 41% were older than 15 years.⁶ In non-European Union countries, there is a similar rate in young adults but a much higher incidence in childhood.^7,8 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.^8,

Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Reed-Sternberg [R-S] cells) or large mononuclear cell variants (Hodgkin’s 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.⁹ It has been conclusively shown that R-S cells and/or Hodgkin cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from preapoptotic germinal center B cells that cannot synthesize immunoglobulin.^{10 11} 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 the resistance to apoptosis.

Epstein-Barr virus (EBV) genetic material can often be detected in R-S or Hodgkin cells. In the United States, EBV positivity is most common in children younger than 10 years. EBV positivity is most commonly found in tumors with mixed-cellularity histology and is extremely rare in patients with lymphocyte-predominant histology. The incidence of EBV tumor cell positivity is only 15% to 20% in adolescents and young adults. EBV serologic status is not a prognostic factor for outcome in pediatric Hodgkinlymphoma.^12,13 Patients with a prior history of serologically confirmed infectious mononucleosis have a 4-fold increased risk of developing EBV-positive Hodgkin lymphoma; these patients are not at increased risk for EBV-negative Hodgkin lymphoma.¹⁴ 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. Many patients have some degree of mediastinal involvement at presentation. 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 or Hodgkin cells. Approximately 20% of patients will have a mediastinal mass whose maximum diameter is 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.^6,15,

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.

² Donaldson SS, Kaplan HS: Complications of treatment of Hodgkin's disease in children. Cancer Treat Rep 66 (4): 977-89, 1982.

³ Mauch PM, Weinstein H, Botnick L, et al.: An evaluation of long-term survival and treatment complications in children with Hodgkin's disease. Cancer 51 (5): 925-32, 1983.

⁴ Donaldson SS, Link MP: Hodgkin's disease. Treatment of the young child. Pediatr Clin North Am 38 (2): 457-73, 1991.

⁵ Spitz MR, Sider JG, Johnson CC, et al.: Ethnic patterns of Hodgkin's disease incidence among children and adolescents in the United States, 1973-82. J Natl Cancer Inst 76 (2): 235-9, 1986.

⁶ 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.

⁷ 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.

⁸ 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.

⁹ Pileri SA, Ascani S, Leoncini L, et al.: Hodgkin's lymphoma: the pathologist's viewpoint. J Clin Pathol 55 (3): 162-76, 2002.

¹⁰ Kanzler H, Küppers R, Hansmann ML, et al.: Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med 184 (4): 1495-505, 1996.

¹¹ Diehl V, von Kalle C, Fonatsch C, et al.: The cell of origin in Hodgkin's disease. Semin Oncol 17 (6): 660-72, 1990.

¹² 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.

¹³ Claviez A, Tiemann M, Krams M, et al.: Lack of prognostic significance of Epstein-Barr virus infection in children and adolescents with Hodgkin's disease. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-058, 41, 2001.

¹⁴ 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.

¹⁵ 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.

Cellular Classification and Biologic Correlates

Hodgkin lymphoma can be divided into 2 broad pathologic classes:^1,2,

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

Classical Hodgkin Lymphoma

Classical Hodgkin lymphoma is divided into 4 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 2 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 2 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. Patients with completely resected stage I LRCHL require chemotherapy with or without radiation therapy, while patients with completely resected stage I NLPHL may be followed without postsurgical chemotherapy or radiation therapy.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

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.

¹ Pileri SA, Ascani S, Leoncini L, et al.: Hodgkin's lymphoma: the pathologist's viewpoint. J Clin Pathol 55 (3): 162-76, 2002.

² Harris NL: Hodgkin's lymphomas: classification, diagnosis, and grading. Semin Hematol 36 (3): 220-32, 1999.

³ Küppers R, Schwering I, Bräuninger A, et al.: Biology of Hodgkin's lymphoma. Ann Oncol 13 (Suppl 1): 11-8, 2002.

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.

⁵ Skinnider BF, Mak TW: The role of cytokines in classical Hodgkin lymphoma. Blood 99 (12): 4283-97, 2002.

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.

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.

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.

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.^13,14,15 Positron emission tomography (PET) scanning is being evaluated as a method to assess early response in pediatric Hodgkin lymphoma. Fluorodeoxyglucose (FDG)-PET avidity after 2 cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.¹⁶

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Staging and Diagnostic Evaluation

Stage is a critical determinant in the selection of treatment. Evaluation of the child with Hodgkinlymphoma includes history, physical examination, imaging (including chest x-rays; computed tomographic [CT] scans of chest, abdomen, and pelvis; gallium scan and/or positron emission tomography [PET] scan),^1,2,3,4 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 aspiration and biopsy should be performed in patients with advanced disease (stage III or stage IV) and/or symptoms (fever, weight loss, or night sweats).⁵ Bone scans are performed in patients with bone pain or elevated alkaline phosphatase. In the past, lymphangiograms were commonly used to evaluate involvement of the abdominal lymph nodes in patients with Hodgkin lymphoma; however, more false-positives occur in children than in adults, and the studies are technically more difficult to perform.⁶ Lymphangiography is no longer used in the staging of children. Gallium scanning is sensitive in determining initial sites of involvement, particularly in the neck and mediastinum. It is also helpful in determining whether residual mass lesions in the chest following chemotherapy represent active disease or scarring.⁷ Fluorodeoxyglucose (FDG)-PET has advantages over gallium-67 because the scan is a 1-day procedure with higher resolution, better dosimetry, and less intestinal activity.^1,2,8 FDG-PET is now the recommended procedure for initial and follow-up staging, though gallium scan remains an acceptable alternative.⁹ FDG-PET detects more disease sites above and below the diaphragm on staging compared to gallium scan and may have particular utility in the evaluation of the spleen.¹⁰

A negative posttherapy PET scan is predictive for continuing remission; however, there is a significant incidence of false-positive or equivocal PET scans following completion of treatment.^11,12 When standard-dose radiation therapy was an acceptable treatment strategy for patients with early-stage Hodgkin lymphoma, exploratory laparotomy with splenectomy was performed to determine the presence and extent of abdominal involvement. There is generally no role for staging laparotomies in the current treatment of pediatric Hodgkin lymphoma patients.

Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.^{13,14 15,16} 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. When the diagnostic procedures described above are not fruitful, a CT or ultrasound-guided core needle biopsy should be considered. This procedure can frequently be carried out using light sedation and local anesthesia, before more invasive procedures are undertaken. If a significant pleural effusion is present, thoracentesis should be considered, though cytologic diagnosis is rarely made in Hodgkin lymphoma. 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 ¹⁷ and revised in 1989.^18,

Subclassification of Stage

Hodgkinlymphoma 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.

Stage I

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.

Stage II

Involvement of 2 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).

Stage III

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)].

Stage IV

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

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.^19,20 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.^1,2,8 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. A study testing the sensitivity and specificity of conventional imaging (CT or MRI) 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. These results confirm the need to do both conventional imaging and PET scans to correctly stage Hodgkin disease.⁴ 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.^11,12,21,

¹ Hueltenschmidt B, Sautter-Bihl ML, Lang O, et al.: Whole body positron emission tomography in the treatment of Hodgkin disease. Cancer 91 (2): 302-10, 2001.

² 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.

³ 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.

⁴ 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.

⁵ 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.

⁶ Dudgeon DL, Kelly R, Ghory MJ, et al.: The efficacy of lymphangiography in the staging of pediatric Hodgkin's disease. J Pediatr Surg 21(3): 233-235, 1986.

⁷ Castellani MR, Cefalo G, Terenziani M, et al.: Gallium scan in adolescents and children with Hodgkin's disease (HD). Treatment response assessment and prognostic value. Q J Nucl Med 47 (1): 22-30, 2003.

⁸ 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.

⁹ Hudson MM, Krasin MJ, Kaste SC: PET imaging in pediatric Hodgkin's lymphoma. Pediatr Radiol 34 (3): 190-8, 2004.

¹⁰ Friedberg JW, Fischman A, Neuberg D, et al.: FDG-PET is superior to gallium scintigraphy in staging and more sensitive in the follow-up of patients with de novo Hodgkin lymphoma: a blinded comparison. Leuk Lymphoma 45 (1): 85-92, 2004.

¹¹ 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.

¹² 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.

¹³ 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.

¹⁴ 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.

¹⁵ 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.

¹⁶ Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.

¹⁷ 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.

¹⁸ 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.

¹⁹ 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.

²⁰ 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.

²¹ 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.

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, 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.^{4,5 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.

Chemotherapy for Childhood/Adolescent Hodgkin Lymphoma

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,^11,12 however, the finding of increased risk for treatment-related AML (tAML) in patients receiving dexrazoxane concurrent with etoposide may limit this use for etoposide-containing regimens.¹⁴ 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:

Table 1: Combination Chemotherapy Regimens Commonly Used for Children and Young Adults with Hodgkin Lymphoma

Chemotherapy Regimen Corresponding AgentsABVD ^17,doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazineABVE (DBVE) ^14,doxorubicin (Adriamycin), bleomycin, vincristine, etoposideVAMP ¹⁵ vincristine, doxorubicin (Adriamycin), methotrexate, prednisoneOPPA +/- COPP (females) ^18,vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazineOEPA +/- COPP (males) ^18,vincristine (Oncovin), etoposide, prednisone, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazineCOPP/ABV ^9,cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin), bleomycin, vinblastineBEACOPP (advanced stage) ^19,bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazineCOP(P) (with or without prednisone)cyclophosphamide, vincristine (Oncovin), ± prednisone, procarbazineCHOPcyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin), prednisoneABVE-PC (DBVE-PC) ^12,doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone, cyclophosphamideMOPP/ABV ²⁰ mechlorethamine, vincristine (Oncovin), procarbazine, prednisone, doxorubicin (Adriamycin), bleomycin, vinblastine

Radiation Therapy for Children and Adolescents 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.

Volume Considerations

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.

Table 2: Sample Definitions of Sites and Corresponding Radiation Treatment Fields*

Involved node(s)Radiation field* Adapted from Hudson ^21,^ Upper cervical region not treated if supraclavicular involvement is extension of the mediastinal disease.** Prechemotherapy volume is treated except for lateral borders of the mediastinal field, which is postchemotherapy.CervicalNeck and Infraclavicular/Supraclavicular ^SupraclavicularNeck and Infraclavicular/Supraclavicular ± AxillaAxillaAxilla ± Infraclavicular/SupraclavicularMediastinumMediastinum, Hila, Infraclavicular/Supraclavicular **^HilaHila, MediastinumSpleenSpleen ± Para-aorticsPara-aorticsPara-aortics ± SpleenIliacIpsilateral Iliac ± Inguinal + FemoralInguinalInguinal + Femoral ± IliacFemoralInguinal + Femoral ± Iliac

Radiation Dose

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 to initial chemotherapy received LD-IFRT (15-25 Gy). In some studies, patients with partial responses received higher radiation doses.

Technical Considerations

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.

Current Role of LD-IFRT in Childhood and Adolescent Hodgkin Lymphoma

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 complete response 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 or slightly better for patients whose initial therapy was chemotherapy alone.²² 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, 2 major pediatric trials ^{9 18} 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 complete response with chemotherapy followed by LD-IFRT or no further therapy. Complete response 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. Complete response was obtained in 83% of patients. Five hundred and 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.¹⁸ Radiation dose was determined by extent of disease reduction following completion of chemotherapy. Twenty-three percent of patients achieved a complete response, defined as complete resolution of all disease. Sixty-two percent of patients achieved a partial response (>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 complete response and received no radiation (21/222, 9.5%) than in patients who achieved a partial response 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 complete response (CR) after chemotherapy, EFS was 97%, which is similar to the EFS of 94% in patients achieving a partial response (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%.^18,23 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.^9,18,22 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 complete response 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.

Accepted Treatment Strategies for Children and Adolescent Patients with Hodgkin Lymphoma

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 complete response is obtained).^18,23,

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).^24,
• OPPA/OEPA × 2; COPP × 2 plus LD-IFRT.^18,23,

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.^19,
• OPPA/OEPA × 2; COPP × 4 plus LD-IFRT.^18,23,

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Although current standard therapy for children with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is chemotherapy plus LD-IFRT, patients have been successfully treated with chemotherapy alone or complete resection of isolated nodal disease. There have been a number of reports in the literature of patients with completely resected stage I NLPHL who received no further therapy. In a series of 31 adult patients treated with surgery alone, there were 7 deaths (median follow-up, 7 years), but only one death resulted from Hodgkin lymphoma.²⁵ In another series, 15 of 24 patients with surgery alone relapsed, but all achieved a subsequent remission with radiation and/or chemotherapy. Only 2 patients died (one from NLPHL).²⁶ Some of these patients may have had lymphocyte-rich classic Hodgkin lymphoma.²⁷ In the GPOH-95 trial, 14 patients with completely resected stage I NLPHL received no further therapy; 4 of these patients have relapsed.²⁸ In a French study of children with NLPHL, 10 patients with completely resected stage I disease received no further therapy, 3 patients relapsed, but all were salvaged.²⁹ In another study, all 6 patients with stage I NLPHL treated with surgery alone remained disease free.³⁰ However, in another small series of seven pediatric patients with stage I disease (five patients) and stage II disease (two patients) treated with chemotherapy alone, there were four relapses.^31,

Treatment Strategies Under Clinical Investigation for Childhood/Adolescent Hodgkin Lymphoma

Low-Risk Disease

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 :³² 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 3 cycles of doxorubicin (Adriamycin), vincristine, prednisone and cyclophosphamide (AVPC). These patients do not receive etoposide or bleomycin. Patients who attain a complete response following 3 cycles of chemotherapy receive no further therapy. Patients with a partial response 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 2 cycles of chemotherapy will not receive radiation therapy, even if radiographic abnormalities persist at the end of treatment.^33,

Intermediate-Risk Disease

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.

The COG Intermediate Risk Trial (stages I and II with either B symptoms or bulk, stage II AE, stage IIIA and stage IVA) will evaluate early response after 2 cycles of ABVE-PC to determine subsequent treatment:^34,

• Patients who achieve a rapid response to 2 cycles of ABVE-PC will receive an additional 2 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 2 cycles of ABVE-PC will be randomized to receive 2 additional cycles of ABVE-PC or 2 cycles of ABVE-PC and 2 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.^33,

Nodular Lymphocyte-Predominant Hodgkin Lymphoma

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 :³⁵ A COG study is evaluating surgery alone for patients with stage I completely resected NLPHL. Other patients with stage I or stage II disease receive 3 cycles of vincristine, prednisone, doxorubicin, and cyclophosphamide. Patients showing a complete response receive no further therapy; other patients receive LD-IFRT. Patients with advanced-stage disease are treated on stage-appropriate protocols that include all histologies.

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

¹ Schwartz CL: The management of Hodgkin disease in the young child. Curr Opin Pediatr 15 (1): 10-6, 2003.

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.

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.

⁴ Thomson AB, Wallace WH: Treatment of paediatric Hodgkin's disease. a balance of risks. Eur J Cancer 38 (4): 468-77, 2002.

⁵ Hudson MM, Donaldson SS: Treatment of pediatric Hodgkin's lymphoma. Semin Hematol 36 (3): 313-23, 1999.

⁶ Oberlin O: Present and future strategies of treatment in childhood Hodgkin's lymphomas. Ann Oncol 7 (Suppl 4): 73-8, 1996.

⁷ Kaldor JM, Day NE, Clarke EA, et al.: Leukemia following Hodgkin's disease. N Engl J Med 322 (1): 7-13, 1990.

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.

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.

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.

¹¹ 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.

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.

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.

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.

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.

¹⁷ 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.

¹⁸ 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.

¹⁹ 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.

²⁰ 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.

²¹ 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.

²² 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.

²³ Dörffel W, Lüders H, Rühl U, et al.: Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin's disease in children and adolescents: analysis and outlook. Klin Padiatr 215 (3): 139-45, 2003 May-Jun.

²⁴ 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.

²⁵ 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.

²⁶ 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.

²⁷ Sandoval C, Venkateswaran L, Billups C, et al.: Lymphocyte-predominant Hodgkin disease in children. J Pediatr Hematol Oncol 24 (4): 269-73, 2002.

²⁸ Seyyedi S, Luders H, Marciniak H, et al.: Nodular lymphocyte predominant Hodgkin's disease (NLPHD) - results of the German multicenter trial GPOH-HD 95. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-065, 43, 2001.

²⁹ Pellegrino B, Terrier-Lacombe MJ, Oberlin O, et al.: Lymphocyte-predominant Hodgkin's lymphoma in children: therapeutic abstention after initial lymph node resection--a Study of the French Society of Pediatric Oncology. J Clin Oncol 21 (15): 2948-52, 2003.

³⁰ 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.

³¹ van Grotel M, Lam KH, de Man R, et al.: High relapse rate in children with non-advanced nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL or nodular paragranuloma) treated with chemotherapy only. Leuk Lymphoma 47 (8): 1504-10, 2006.

³² Keller FG, Children's Oncology Group: Phase III Study of Doxorubicin Hydrochloride, Vincristine, Prednisone, and Cyclophosphamide Followed by Radiotherapy and/or Response-Directed Chemotherapy in Children and Adolescents With Newly Diagnosed Low-Risk Hodgkin's Lymphoma, COG-AHOD0431, Clinical trial, Active.

³³ 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.

³⁴ Friedman DL, Children's Oncology Group: Phase III Randomized Study of Response-Based Chemotherapy With Doxorubicin, Bleomycin, Vincristine, Etoposide, Prednisone, and Cyclophosphamide With or Without Dexamethasone, Etoposide, Cytarabine, Cisplatin, and/or Radiotherapy in Children With Newly Diagnosed Intermediate-Risk Hodgkin's Lymphoma, COG-AHOD0031, Clinical trial, Active.

³⁵ Appel BE, Children's Oncology Group: Treatment of Children with Newly Diagnosed, Low Stage, Lymphocyte Predominant Hodgkin's Disease, COG-AHOD03P1, Clinical trial, Active.

Primary Progressive/Recurrent Hodgkin Lymphoma in Children and Adolescents

Treatment failure in children and adolescents with Hodgkin lymphoma can be divided into 3 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 and 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 7 8 9 10} and high-dose chemotherapy with hematopoietic stem cell transplant (HSCT).^{11 12 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, and primary refractory disease.¹⁵ 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.^14,17,18,19 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 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,

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.^23,24 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).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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

²³ 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.

²⁴ 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.

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.

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 late effects literature is probably no longer relevant. (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

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 2 cycles for all males.³ Males with advanced-stage disease received an additional 2 or 4 cycles of COPP (each cycle, 1,500 mg/m2 of procarbazine and 1,000 mg/m2 of cyclophosphamide). Males receiving only 2 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 2 and 4 COPP cycles, respectively. Stimulated FSH levels were abnormal in 83.3% and 66.7% of patients receiving 2 and 4 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 2 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), 9 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 3 to 5 cycles. A few studies have evaluated male fertility following cyclophosphamide-containing regimens given to children and young adults with sarcomas and other cancers.^6,7,8 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.

Female Infertility

There are few published data concerning the incidence of ovarian failure following chemotherapy for female children and young adults with Hodgkin’s 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’s lymphoma is currently being studied.^10,

Thyroid Abnormalities

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.¹¹ 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.¹² In a study of 47 survivors of pediatric Hodgkin lymphoma who received neck irradiation (2,250-4,000 cGy), ultrasonography revealed atrophy in 45 patients and goiters in 2 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 5 patients had thyroid carcinoma diagnosed.^13,

Cardiac Toxicity

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.¹⁴ Late effects of radiation to the heart include:^15,16,17

• Delayed pericarditis.
• Pancarditis, which includes pericardial and myocardial fibrosis, with or without endocardial fibroelastosis.
• Myopathy.
• Coronary artery disease.
• 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 7 deaths from acute myocardial infarction; however, these deaths only occurred in children treated with 42 Gy to 45 Gy. Among children treated with 15 Gy to 26 Gy, none developed radiation-associated cardiac problems.¹⁸ 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.¹⁶ 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.^{19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,}

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.^35,36 Dexrazoxane has been shown to prevent cardiac toxicity in adults and children treated with anthracyclines.^{37,38,39,40,41,}

In 2 closed POG therapeutic phase III studies for Hodgkin lymphoma,^42,43 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 (cTnT), a protein that is elevated after myocardial damage.^{37,44,45,46,47,48,}

Secondary Malignancies

A number of series evaluating the incidence of malignancies in survivors of childhood and adolescent Hodgkin lymphoma have been published.^{49,50,51,52,53,54,55} 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.⁵⁵ 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.⁵⁶ Secondary hematologic malignancy (most commonly AML and myelodysplasia) is related to the use of alkylating agents, anthracycline, and etoposide,⁵⁷ while second solid tumors are seen in patients receiving radiation therapy. Certain common themes were consistently noted. 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, 21 to 30 and younger than 20 years, respectively.⁵⁰ 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).⁵¹ In one study, 40 of 43 (83%) second solid tumors arose in areas that had received at least 35 Gy of radiation.^53,

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.

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.

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.

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.

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.

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.

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.

⁸ Aubier F, Patte C, de Vathaire F, et al.: [Male fertility after chemotherapy during childhood] Ann Endocrinol (Paris) 56 (2): 141-2, 1995.

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.

¹⁰ Byrne J: Infertility and premature menopause in childhood cancer survivors. Med Pediatr Oncol 33 (1): 24-8, 1999.

¹¹ 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.

¹² 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.

¹³ 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.

¹⁴ Fajardo LF, Eltringham JR, Steward JR: Combined cardiotoxicity of adriamycin and x-radiation. Lab Invest 34 (1): 86-96, 1976.

¹⁵ 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.

¹⁶ 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.

¹⁷ Adams MJ, Lipshultz SE, Schwartz C, et al.: Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol 13 (3): 346-56, 2003.

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¹⁹ 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.

²⁰ 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.

²¹ 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.

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²⁴ 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.

²⁵ 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.

²⁶ 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.

²⁷ 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.

²⁸ 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.

²⁹ 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.

³⁰ 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.

³¹ Grenier MA, Lipshultz SE: Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 25 (4 Suppl 10): 72-85, 1998.

³² 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.

³³ 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.

³⁴ 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.

³⁵ 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.

³⁶ 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.

³⁷ 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.

³⁸ 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.

³⁹ 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.

⁴⁰ 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.

⁴¹ Wexler LH: Ameliorating anthracycline cardiotoxicity in children with cancer: clinical trials with dexrazoxane. Semin Oncol 25 (4 Suppl 10): 86-92, 1998.

⁴² 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.

⁴³ 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.

⁴⁴ Hamm CW: Cardiac biomarkers for rapid evaluation of chest pain. Circulation 104 (13): 1454-6, 2001.

⁴⁵ 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.

⁴⁶ 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.

⁴⁷ 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.

⁴⁸ 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.

⁴⁹ 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.

⁵⁰ 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.

⁵¹ 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.

⁵² 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.

⁵³ Wolden SL, Lamborn KR, Cleary SF, et al.: Second cancers following pediatric Hodgkin's disease. J Clin Oncol 16 (2): 536-44, 1998.

⁵⁴ 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.

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⁵⁶ 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.

⁵⁷ 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.

Changes to This Summary (06/14/2007)

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.

Staging and Diagnostic Evaluation

Added Levine et al. as reference 12.

Revised text to state that caution should be used in making the diagnosis of relapsed disease based solely on imaging because false-positive results are not uncommon (cited Nasr et al. as reference 21).

Treatment Approach for Children and Adolescents with Hodgkin Lymphoma

Added mechlorethamine to the list of drugs used as frontline therapy for children and adolescents with Hodgkin lymphoma.

Added Donaldson et al. as reference 15.

In Table 1, added MOPP/ABV as a chemotherapy regimen (cited Chow et al. as reference 20).

Added text about results of a study of stage I and stage II NLPHL patients treated with chemotherapy alone (cited van Grotel et al. as reference 31).

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 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:

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