Treatment of Pediatric Hodgkin Lymphoma

Chapter 3 35

Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Contents 3.0 Introduction

3.0 Introduction ...... 35 3.1 Clinical Presentation ...... 36 Treatment for children and adolescents with Hodgkin 3.1.1 Systemic Symptoms ...... 37 lymphoma (HL) aims to achieve cure without long- 3.1.2 Laboratory Evaluation...... 37 term morbidity. Earlier treatment approaches did not 3.1.3 Immunologic Status ...... 38 consider the developmental issues in pediatric patients 3.2 Diff erential Diagnosis ...... 39 that resulted in unacceptable musculoskeletal hypo- 3.3 Diagnostic Evaluation and Staging ...... 40 3.4 Prognostic Factors ...... 43 plasia, cardiovascular and pulmonary dysfunction, 3.5 Combination Chemotherapy ...... 45 and the development of subsequent primary cancers. 3.6 Chemotherapy Alone Versus Combined Recognition of these life-altering and life-threatening Modality Therapy ...... 49 late treatment eff ects motivated the development of 3.7 Risk-Adapted Therapy ...... 51 combined-modality therapy regimens in which cycles 3.7.1 Treatment of Low-Risk Disease ...... 51 3.7.2 Treatment of Intermediate- of chemotherapy replaced a portion of the radiation and High-Risk Disease...... 53 therapy in laparotomy-staged children. Demonstra- 3.8 Principles of Radiation Therapy ...... 54 tion of the eff ectiveness of combined-modality therapy 3.8.1 Volume Considerations ...... 56 in children and progress in diagnostic imaging tech- 3.8.2 Dose Considerations ...... 58 nology eventually permitted the abandonment of sur- 3.8.3 Energy ...... 59 3.9 Summary Recommendations for Primary gical staging. Over time, investigators undertook fur- Disease/Selection of Therapy ...... 59 ther modifi cations that decreased the number of 3.10 Acute Eff ects of Therapy ...... 59 chemotherapy cycles, restricted or eliminated specifi c 3.10.1 Chemotherapy Side-Eff ects ...... 59 agents that predisposed to greater treatment toxicity, 3.10.2 Radiation Side-Eff ects ...... 61 and reduced radiation treatment fi elds and doses. Most 3.11 Future Directions ...... 61 References ...... 61 contemporary trials for children, adolescents, and young adults with HL involve a risk-adapted approach that considers disease-related factors like presence of B symptoms, stage, the number of involved nodal regions, and the presence of tumor bulk in treatment recommendations. In general, patients with favorable disease presentations receive fewer cycles of multiagent chemotherapy alone or combined with low-dose, involved-fi eld radiation than those with advanced and unfavorable clinical presentations. Because of specifi c treatment toxicities that are unique to age and gender, these factors may also infl uence treatment decisions. Th erefore, no single treatment approach is uniformly appropriate for all patients. Instead, therapy duration 36 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Table 3.1 Demographic and clinical characteristics at pre- and intensity are selected to optimize opportunities to sentation of pediatric Hodgkin lymphoma achieve and maintain long-term remission with minimal treatment-related morbidity. Children a, b (%) Adultsb (%) Number of patients 1985 1912 3.1 Clinical Presentation <10 yrs of age 360 (18.1) ≥10 yrs of age 1615 (81.4) Clinical presentations of HL range from the coinci- dental discovery of mediastinal lymphadenopathy >17 yrs of age 10 (0.5) 1912 (100) during an evaluation for an orthopedic injury, to a Gender chronic cough or pruritus, to life-threatening airway Male 1100 (55.4) 1147 (60.0) obstruction or spinal cord compression. In most, the presentation is asymptomatic or less dramatic because Female 885 (44.6) 765 (40.0) of the indolent onset of symptoms. Persistent painless Histology cervical or supraclavicular lymphadenopathy represents the most common presentation of pediatric HL. Lymphocyte 192 (9.7) 96 (5.0) predominant Involved lymph nodes are typically rubbery or fi rm and non-tender, although they may be sensitive to pal- Mixed cellularity 307 (15.5) 325 (17.0) pation if they have grown rapidly. With disease pro- Nodular sclerosis 1431 (72.1) 1377 (72.0) gression, abnormal nodes form large aggregate nodal Not classiﬁ ed and 55 ( 2.8) 115 (6.0) masses that may become fi xed to underlying tissues. lymphocyte depleted Because reactive lymphadenopathy is quite common c in the pediatric age group, oft en several courses of an- Stage timicrobial therapy have been administered before re- I 229 (11.5) 210 (11.0) ferral for biopsy. Th e presence of supraclavicular II 1078 (54.3) 899 (47.0) lymphadenopathy should prompt earlier consideration of a malignant pathogenesis, as opposed to cervical III 391 (19.7) 593 (31.0) nodal abnormalities, which are commonly enlarged in IV 287 (14.5) 210 (11.0) association with pediatric infectious and infl ammatory B symptoms conditions. Cervical nodal disease is accompanied by mediastinal involvement in two-thirds or more of chil- present 564 (28.4) 612 (32.0) dren and adolescents. Intrathoracic HL is oft en asymp- absent 1421 (71.6) 1300 (68.0) tomatic, but may be associated with a nonproductive cough, dyspnea, chest pain, or superior vena cava syn- a Data taken from Ruhl et al. 2001 and Nachman et al. drome. When lymphoma is considered in the diff eren- 2002. tial diagnosis, posteroanterior and lateral thoracic ra- b Data taken from Cleary et al. 1994. diographs should be performed to evaluate for c Data derived from both pathologically and clinically mediastinal lymphadenopathy and airway patency, staged patients. particularly if sedation or general anesthesia is planned for diagnostic procedures. Occasionally, mediastinal involving the peripheral inguinal, femoral, or superfi - lymphadenopathy may be diffi cult to diff erentiate from cial iliac lymph nodes. a large, normal thymus in younger children. Uncom- Th e histologic subtypes of HL (reviewed in Chapter monly, patients present with axillary or inguinal 2) have unique characteristics that are refl ected in their lymphadenopathy. HL limited to infradiaphragmatic clinical presentations. Nodular lymphocyte predomi- sites develops in less than 5% of pediatric cases (Kriko- nant HL usually presents as clinically localized disease rian et al. 1986). Th ese patients usually have lymphoma involving the cervical, axillary, or inguinal-femoral Treatment of Pediatric Hodgkin Lymphoma Chapter 3 37 nodal regions. Th is subtype is more common in male ies, night sweats were not as prognostically signifi cant and younger patients and may be preceded by or coex- as fever and weight loss (Gobbi et al. 1985; Crnkovich ist with progressive transformation of germinal cen- et al. 1986). ters, a pattern of benign lymphoid hyperplasia. Nodu- Other symptoms observed in patients with HL that lar sclerosis HL more frequently involves the cervical, are not defi ned as B symptoms for staging include pru- supraclavicular, and mediastinal lymph nodes. Th e ritus and alcohol-induced pain. Severe pruritus may abundant collagen characteristic of the nodes involved be an important marker of disease activity in some pa- by this subtype contributes to the development of tients with HL (Gobbi et al. 1985). Pruritus, which bulky aggregate nodal masses that may not completely may present months or even a year before lymphade- regress aft er completion of therapy. Nodular sclerosis nopathy is discovered, is usually generalized and may HL is the most common subtype observed in adoles- be associated with extensive excoriations from exces- cents. Mixed cellularity HL frequently presents as ad- sive scratching. Pruritus is more common in women vanced disease with extranodal involvement and has and in patients with advanced disease. Hodgkin-in- the strongest association with Epstein-Barr virus. Th is duced pruritus has been speculated to result from cy- subtype may exhibit an unusual “skip” pattern of clini- tokine production following tumor lysis (Newbold cal staging with radiographically uninvolved lymph 1970). In older patients, alcohol ingestion may pro- node regions in the thoracic cavity contiguous to in- duce severe pain in sites of involved nodes or bony me- volved nodal regions in the neck and abdomen. Mixed tastases, and radiate to the extremities or back. Th e cellularity HL more commonly occurs in children mechanism for this unusual symptom is unknown. younger than 10 years of age. Lymphocyte depleted HL Pruritus and alcohol-induced pain uniformly resolve is very rare in the pediatric age range but may develop when HL responds to therapy. in the setting of acquired immunodefi ciency, e. g., human immunodefi ciency virus infection or chronic im- 3.1.2 Laboratory Evaluation munosuppression following solid organ transplantation. Th is subtype is characterized by widespread Laboratory evaluation in the patient with HL is under- disease involving the bones and bone marrow. Th e re- taken to identify aberrations in hematologic and lationship of age at presentation, stage, gender, and chemical blood parameters that may correlate with histologic subtype is illustrated in Table 3.1. disease extent and confi rm satisfactory renal and hepatic function before initiating therapy. In children, 3.1.1 Systemic Symptoms bone marrow involvement is usually focal, so the presence of extranodal disease in the marrow cannot be Cytokine production by Hodgkin and Reed-Sternberg reliably assessed by blood counts. Nonspecifi c hema- cells is felt to be responsible for many of the clinical tologic abnormalities observed in HL may include features of HL (Table 3.2) (Kadin and Liebowitz 1999). neutrophilic leukocytosis, lymphopenia, eosinophilia, Nonspecifi c systemic symptoms commonly observed and monocytosis. Lymphopenia is more commonly at diagnosis include fatigue, anorexia, and mild weight observed in patients with extensive disease (Tan et al. loss. Approximately 30% of pediatric patients present 1982). Other hematologic manifestations of HL in- with any one of three specifi c constitutional or B symp- clude a normochromic normocytic anemia that is toms that have been correlated with prognosis: unex- typically associated with advanced disease (Ratkin et plained fever with temperatures above 38.0°C orally, al. 1974) and rarely, a Coombs’ positive hemolytic ane- unexplained weight loss of 10% within 6 months pre- mia (Cline and Berlin 1963). ceding diagnosis, and drenching night sweats. Th e Pel- Elevations of acute phase reactants like the erythro- Epstein fever associated with HL is characteristically cyte sedimentation rate (ESR), serum copper, ferritin, intermittent, recurrent over variable intervals of days and C-reactive protein ( CRP) are commonly observed to weeks, more noticeable in the evening, and becomes at presentation of HL. Of these, the ESR and more re- more severe and continuous over time. In some stud- cently, CRP, have been used at diagnosis as prognostic 38 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Table 3.2 Clinical features of Hodgkin lymphoma related to cytokine production

Clinical features of Hodgkin’s disease Cytokines

Constitutional (B) symptoms TNF, LT-α, IL-1, IL-6

Polykaryon formation Interferon-γ , IL-4

Sclerosis TGF-β, LIF, PDGF, IL-1, TNF

Acute phase reactions IL-1, IL-6, IL-11, LIF

Eosinophilia IL-5, granulocyte M-CSF, IL-2, IL-3

Plasmacytosis IL-6, IL-11

Mild thrombocytosis IL-6, IL-11, LIF

T-cell and Hodgkin and Reed-Sternberg cell interaction IL-1, IL-2, IL-6, IL-7, IL-9, TNF, LT-α, CD30L, CD40L, B7 ligands (CD80 and CD86)

Immune deﬁ ciency TGF-β, IL-10

Autocrine growth factors (?) IL-6, IL-9, TNF, LT-α, CD30L, M-CSF

Increased alkaline phosphatase M-CSF

Neutrophil accumulation/activation IL-8, TNF, TGF-β

Abbreviations: IL, interleukin; LIF, leukemia inhibitory factor; LT, lymphotoxin; M-CSF, macrophage colony-stimulating factor; PDGF, platelet-derived growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor Adapted from Kadin and Liebowitz 1999:139 factors and during therapy to nonspecifi cally monitor malignancy (Sonnenblick et al. 1986). ITP may also response (Wieland et al. 2003). Alkaline phosphatase develop in association with autoimmune hemolytic may correlate with the presence of bony metastatic anemia (Xiros et al. 1988). disease; elevations beyond what is appropriate for age should prompt further investigation for skeletal sites 3.1.3 Immunologic Status of extranodal disease. Other chemical parameters that have been used as prognostic factors include hypoal- Active HL is characterized by generalized cellular im- buminemia and elevations of lactate dehydrogenase. mune defi ciency and ineff ective host antitumor re- Autoimmune disorders including nephrotic syn- sponse (Slivnick et al. 1990). Th e universal anergy as- drome, autoimmune hemolytic anemia, autoimmune sociated with HL is considered a primary attribute of neutropenia, and immune thrombocytopenia (ITP) the disease. Mechanisms hypothesized to be responsi- have been observed as paraneoplastic phenomena in ble for impaired cellular immunity include abnormal patients with HL. Of these, ITP is the most commonly T-cell subset populations, prostaglandin E2 mediated reported, occurring in 1−2% of HL cases (Sonnenblick suppression, enhanced sensitivity to suppressor mono- et al. 1986; Xiros et al. 1988; Bradley et al. 1993). cytes and suppressor T cells, inherent T-lymphocyte Th rombocytopenia may develop before, at the same defect, reduced interleukin-2 production and trans- time, or aft er the diagnosis of HL. ITP frequently oc- forming growth factor β (TGF-β) secretion by HRS curs in patients in remission aft er completion of thera- cells (Slivnick et al. 1990). T-cell immune defi cits may py for HL and is not usually associated with relapse. persist in long-term disease-free survivors. Conse- Th e treatment approach and response for ITP in pa- quent to their cellular immunodefi ciency, patients tients with HL is similar to that in patients without with HL exhibit an increased risk of infection with op- Treatment of Pediatric Hodgkin Lymphoma Chapter 3 39

Table 3.3 Immune proﬁ les in Hodgkin lymphoma portunistic pathogens including fungi, viruses, and tuberculosis (Casazza et al. 1966). Even with contem- Activity Untreated active Disease-free porary antimicrobial agents, varicella zoster and hu- disease survivors man papilloma infections commonly occur during Antigen- Normal Transiently and aft er completion of therapy. induced depressed Natural killer cell cytotoxicity is also depressed in antibody newly diagnosed patients with HL, with more pro- production nounced defi cits in patients with advanced and symp- Polymorpho- tomatic disease (Ruco et al. 1982). NK function typi- nuclear cally normalizes aft er treatment in patients who attain function: a complete remission (Liberati et al. 1987). Th e etiolo- Chemotaxis Decreased Decreased gy of depressed NK cell cytotoxicity associated with HL is unknown. Metabolic Decreased Decreased reactivity Humoral immunity is usually intact at diagnosis, but may become transiently depressed following ther- Delayed- apy. In a study evaluating antibody production follow- hypersensitivity skin tests: ing Haemophilus infl uenzae type B in adults who had completed therapy for HL, patients treated with com- Recall antigens Anergic Reactive bination chemotherapy, particularly in association Neoantigens Anergic Anergic with total nodal radiation, exhibited signifi cantly reduced antibody production following immunization E rosette Decreased Decreased formation (Weitzman et al. 1977). Humoral immune defi cits typically recover with increasing time from therapy (Mi- Mitogen- Decreased Decreased nor et al. 1979). In vitro and in vivo studies have pro- induced T-cell proliferation vided insights regarding the mechanism of immune dysregulation in HL. Chemokine and cytokine pro- Mixed lympho- duction (discussed further in Chapter 2) appear to cyte-induced proliferation: contribute to the development of an environment in which Hodgkin and Reed-Sternberg cells can prolifer- Autologous Decreased Decreased ate, escape apoptosis, and evade host immune surveil- Allogeneic Slightly Slightly lance. Table 3.3 summarizes the characteristic immune decreased decreased profi les observed in patients with HL (Slivnick et al. Sensitivity to Enhanced Enhanced 1990). suppressor monocytes Sensitivity to Enhanced Enhanced 3.2 Diﬀ erential Diagnosis suppressor T cells Th e diff erential diagnosis for HL includes other infec- CD4:CD8 ratio Slightly Decreased tious, infl ammatory, and neoplastic conditions pre- decreased senting with lymphadenopathy (Green 1998). A variety of bacterial, viral, and fungal organisms From Slivnick et al. 1990;17:673, with permission. prominently feature lymphadenopathy in their presentation. Th e infectious agents most commonly consid- plasmosis). Pyogenic bacterial lymphadenitis is typi- ered in the diff erential diagnosis of HL are those that cally unilateral, and associated with erythema, pain, present with an indolent course (e. g., atypical myco- and tenderness. Bilateral acute cervical lymphadenitis bacterium, Bartonella henselae, histoplasma, and toxo- is more likely to be viral in etiology. Individuals with 40 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

chronic localized lymphadenopathy should be evalu- Lymphadenopathy is also frequently observed in ated for signs of a persistent regional infection. Tuber- immunodefi ciency syndromes and phagocytic dys- culosis typically presents with localized lymphadenop- function. Suppurative lymphadenitis is a common athy in the mediastinal, mesenteric, anterior cervical complication in children with chronic granulomatous nodes, but generalized lymphadenopathy may be ob- disease and hyper-IgE syndrome. Acquired immuno- served with hematogenous spread of the organism. A defi ciency syndrome associated with chronic human positive tuberculin skin test is helpful in confi rming immunodefi ciency virus (HIV) is characterized by the diagnosis. Nontuberculous mycobacteria may also generalized lymphadenopathy, hepatosplenomegaly, cause cervical or submandibular lymphadenitis that is fever, and failure to thrive. Chronic immunosuppres- typically unilateral. Cat-scratch is a common cause of sion associated with HIV increases the risk of a variety localized, usually painful, lymphadenopathy that may of malignancies, including HL and NHL. Th erefore, persist for weeks to months. A positive exposure his- children with chronic HIV infection should undergo tory and Bartonella henselae titer should facilitate prompt evaluation of lymph node changes suggesting making this diagnosis. the development of a malignant process. Infectious mononucleosis is most oft en accompa- Non-Hodgkin lymphoma (NHL) is the most com- nied by symmetrical cervical lymphadenopathy in as- mon pediatric malignancy that should be considered sociation with pharyngitis. Generalized lymphade- in the diff erential diagnosis of HL. Typically, the nopathy may also occur, and hepatosplenomegaly is growth rate of the aff ected lymph nodes in NHL is common. A positive Epstein-Barr viral titer (IgM frac- more rapid than in HL and more frequently associated tion) establishes the diagnosis of acute infection, but it with abnormal chemical parameters such as elevated should be noted that HL may also present in the set- levels of uric acid or lactic dehydrogenase. Cervical ting of an acute EBV infection. Th erefore, further in- lymphadenopathy is observed in the presentation of vestigation should be undertaken if abnormal lymph- other pediatric malignancies including nasopharyn- adenopathy persists or progresses aft er resolution of geal carcinoma, rhabdomyosarcoma, neuroblastoma, infectious symptoms. Several microbes may simulate and thyroid carcinoma. For further discussion regard- infectious mononucleosis in their presentation. Cyto- ing pathologic features to consider in the diff erential megalovirus infection is associated with generalized diagnosis of HL, see Chapters 8−11. lymphadenopathy, hepatosplenomegaly, and fever. Toxoplasmosis usually causes cervical, suboccipital, supraclavicular, or generalized lymphadenopathy and 3.3 Diagnostic Evaluation and Staging fever. In healthy hosts, these infections are usually self- limited. Table 3.4 summarizes the recommended steps in the Pulmonary histoplasmosis produces mediastinal diagnostic work-up for pediatric HL. Biopsy is re- and hilar lymphadenopathy that may be diffi cult to quired to establish the diagnosis. Lymph node excision clinically distinguish from lymphoma in an asymp- is preferred because the malignant Hodgkin and Reed- tomatic patient. A history of a recent respiratory infec- Sternberg cells can be evaluated within the context of tion, exposure to a high-risk area of fungal spore con- the nodal architecture unique to individual histologic tamination, and positive histoplasma serology are subtypes. If a noninvasive needle biopsy is planned, helpful in avoiding invasive diagnostic procedures. Hi- multiple tissue passes should be performed to facilitate lar adenopathy is also a prominent feature of sarcoid- the assessment of the nodal architecture. Physical ex- osis, a multisystem disorder that may be accompanied amination should include an evaluation of all node- by nonspecifi c constitutional symptoms (fatigue, mal- bearing areas, including Waldeyer’s ring, and measure- aise, anorexia, or weight loss) and characteristic lung, ment of enlarged nodes that can be monitored for eye, and skin fi ndings. Th e diagnosis may be suspected response to therapy. based on clinical presentation, but requires biopsy for Th e goal of the staging evaluation is to identify sites defi nitive confi rmation. and characteristics of disease to permit as accurate a Treatment of Pediatric Hodgkin Lymphoma Chapter 3 41 risk assessment as possible for treatment planning. tion studies are also unreliable indicators of hepatic Historically, cervical lymph nodes have been evaluated disease. Previous studies in children undergoing stag- exclusively by physical examination. Because ongoing ing laparotomy demonstrate that CT fi ndings of intrin- risk-adapted treatment protocols use response as a pa- sic spleen lesions and porta hepatic and celiac lymph- rameter to escalate or truncate therapy, computed to- adenopathy were infrequent but highly predictive of mography ( CT) evaluation of Waldeyer’s ring and cer- lymphomatous involvement (Mendenhall et al. 1993). vical soft tissues is recommended to permit more Defi nitive evaluation of disease involving the liver and accurate assessment of the nodal response. spleen requires histologic assessment, which is no lon- A chest radiograph provides preliminary informa- ger required for contemporary treatment planning. tion about mediastinal involvement and intrathoracic Functional nuclear imaging is an important diag- structures. Mediastinal lymphadenopathy measuring nostic and monitoring modality in patients with HL. 33% or more of the maximum intrathoracic cavity at Earlier investigations established the sensitivity and the dome of the diaphragm on an upright chest radio- predictive value of gallium-67 (67Ga) avidity, particu- graph is designated “bulky” in the risk assessment (Fig. larly in the evaluation of supradiaphragmatic disease 3.1). CT of the chest provides more detailed informa- (Weiner et al. 1991). PET has largely replaced 67Ga im- tion regarding involvement of the intrathoracic lymph aging because of the latter modality’s low resolution nodes, pulmonary parenchyma, chest wall, pleura, and and its suboptimal physiological biodistribution, pericardium that may not be apparent on radiographs which limits evaluation of the abdominal and pelvic (Rostock et al. 1982). Although magnetic resonance lymph nodes (Hueltenschmidt et al. 2001; Bar-Shalom imaging (MRI) is an eff ective tool for evaluating intra- et al. 2003; Hudson et al. 2004). PET provides an as- thoracic structures, thoracic CT is superior to MRI in sessment of proliferative activity in tumors undergo- the evaluation of the pulmonary parenchyma. ing anaerobic glycolysis through uptake of the radio- Since the abandonment of staging laparotomy and active glucose analogue, 18-fl uoro-2-deoxyglucose lymphography, CT is most oft en used to evaluate sites (FDG). PET-CT is both an accurate and cost-eff ective of infradiaphragmatic disease. Oral and intravenous imaging modality that integrates functional and ana- contrast administration is required to accurately delin- tomic tumor characteristics (Jerusalem et al. 1999). eate abdominal/pelvic nodes from other infradiaphrag- Moreover, PET or PET-CT imaging can be completed matic structures and organ involvement. Suboptimal in a single day, has a higher resolution, better dosime- bowel contrast and the lack of retroperitoneal fat in try, less intestinal activity than 67Ga imaging. Like some patients may limit the sensitivity of CT in detect- 67Ga, FDG avidity persisting aft er therapy is prognos- ing abdominal adenopathy (Baker et al. 1990). In these tic of outcome and helpful in determining the need for cases, MRI may provide better evaluation of fat-en- additional therapy (Jerusalem et al. 1999; Spaepen et cased retroperitoneal lymph nodes (Hanna et al. 1993). al. 2001; Friedberg et al. 2004). Th e size of abdominal and pelvic nodes is used to esti- Clinicians should be aware of the limitations of mate lymphomatous involvement. Abdominal nodes FDG-PET in the pediatric setting. Patient cooperation smaller than 1−1.5 cm and pelvic nodes smaller than or sedation is critical to minimize FDG uptake that is 2−25 cm are usually considered normal. Functional unrelated to tumor activity. Interpretation of lympho- imaging with positron emission tomography (PET) matous involvement may be confounded by FDG avid- now enables identifi cation of disease in smaller nodes. ity in normal tissues, e. g., brown fat of cervical mus- Splenic involvement occurs in 30−40% of patients culature. Also, a variety of nonmalignant conditions with HL, whereas hepatic involvement is rare in the pe- including thymic rebound commonly observed aft er diatric age group. Abnormal densities on CT or MRI completion of lymphoma therapy exhibit FDG avidity suggest lymphomatous involvement of the liver and (Kaste et al. 2005). Lastly, tumor activity cannot be as- spleen. Because tumor deposits in these organs may be sessed in diabetic patients with poorly controlled less than 1 cm in diameter, the disease status cannot be blood glucose. Prospective trials evaluating FDG-PET dependably assessed by organ size alone. Liver func- in pediatric HL are ongoing (Korholz et al. 2003). 42 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Bone marrow involvement at initial presentation of er sites of extranodal disease. PET-CT, which assesses pediatric HL is uncommon and rarely occurs as an iso- both cortical bone and bone marrow, may ultimately lated site of extranodal disease. Lymphomatous mar- replace these previously used modalities. row infi ltration may be diff use or focal and is frequent- Th e currently used Ann Arbor staging system, ad- ly accompanied by reversible marrow fi brosis. Bone opted in 1971, is based on the observation that Hodg- marrow aspiration is an inadequate method of assess- kin lymphoma appears to spread along contiguous ment for disease. Bone marrow biopsy should be per- lymph nodes until late in the course of disease (Table formed in any patient with advanced (clinical stage III 3.5) (Carbone et al. 1971). Th e substage classifi cations to IV) or symptomatic (B symptoms) disease, or dur- A, B, and E amend each stage based on defi ned clinical ing restaging of patients with recurrent disease. Bone features. Substage A indicates “asymptomatic” disease. marrow involvement in newly diagnosed stage I to IIA B symptoms include fever exceeding 38°C for 3 con- disease is very rare. Consequently, the low yield from secutive days, drenching night sweats, and an unex- bone marrow biopsy in these patients does not support plained loss of at least 10% of body weight over 6 routine marrow evaluation for this favorable risk months. Substage E denotes extranodal involvement group. arising from extension of disease from contiguous Historically, evaluations undertaken for the assess- nodal regions. Substage S denotes involvement of the ment of sites of skeletal metastases included techne- spleen. tium-99 nuclear imaging and radiography-identifi ed sites of abnormalities. Because of the rarity of bone involvement in pediatric HL, these studies were reserved for children with bone pain, elevations of serum alkaline phosphatase beyond that expected for age, or oth- Table 3.4 Diagnostic evaluation for children with Hodg- kin lymphoma

Physical examination with measurement of lymph nodes

Complete blood cell count with diﬀ erential, erythrocyte sedimentation rate or C-reactive protein, renal and hepatic function tests, alkaline phosphatase level

Lymph node biopsy

Chest radiograph with measurement of ratio of mediastinal mass to maximum intrathoracic cavity at the dome of the diaphragm

Computed tomography of neck and chest

Computed tomography or magnetic resonance imaging of abdomen and pelvis

Bone marrow biopsya

Figure 3.1 Bone scanb Mediastinal bulk is determined by calculating the ratio of maximum diameter of the mediastinal mass to the Gallium or positron emission tomography (PET) scan

maximum diameter of the intrathoracic cavity a measured at the dome of the diaphragm on an Recommended for all children except those with stages IA/IIA. upright chest radiograph. A measurement of 33% or b more is designated “bulky” in the risk assessment Recommended for children with bone pain and elevated alkaline phosphatase. Treatment of Pediatric Hodgkin Lymphoma Chapter 3 43

Table 3.5 Ann Arbor staging classiﬁ cation for Hodgkin lymphoma

Stage Description

I Involvement of a single lymph node region or lymphoid structure, e. g., spleen, thymus, Waldeyer’s ring, or single extralymphatic site (IE)

II Involvement of two or more lymph node regions on the same side of the diaphragm, or localized contiguous involvement of only one extranodal organ/site and lymph node region on the same side of the diaphragm (IIE)

III Involvement of lymph node regions on both sides of the diaphragm (III), which may be accompanied by involvement of the spleen (IIIS) or by localized contiguous involvement of only one extranodal organ site (IIIE) or both (IIISE) III1 With or without involvement of splenic hilar, celiac, or mesenteric nodes

III2 With involvement of para-aortic, iliac, or mesenteric nodes

IV Diﬀ use or disseminated involvement of one or more extranodal organs or tissues, with or without associated lymph node involvement

Designations applicable to any stage

A No symptoms

B Fever (temperature > 38ºC), drenching night sweats, unexplained loss of > 10% of body weight within the preceding 6 months

E Involvement of a single extranodal site that is contiguous or proximal to the known nodal site

1996). Finally, some factors may be prognostic for cer- 3.4 Prognostic Factors tain therapies or for certain stages. Prognostic factors used in various current clinical Advances in the treatment of HL have diminished the trials for children are as follows: importance of prognostic factors. As a corollary, prog- CS I/II disease treated with combined modality nostic factors change as therapy changes and improves. therapy: disease bulk (peripheral and mediasti- Yet, they remain useful as tools for predicting outcome, nal), number of disease sites, B symptoms, eryth- defi ning risk groups for patient stratifi cation, and pro- rocyte sedimentation rate, histologic subtype, gen- viding insight into the disease process (e. g., natural der. history, biology). Prognostic factors in HL can be di- CS III/IV disease but also early stage with B symp- vided into those that are patient-related (e. g. age, gen- toms: disease bulk, B symptoms, histologic subtype, der) and tumor-related (e. g. pathologic subtype, dis- extranodal extension and organ involvement, labo- ease extent). Th ey can also be grouped according to ratory values including anemia, leukocytosis, lym- the time point at which they were recorded: at diagno- phopenia, hypoalbuminemia. sis or during therapy. Th e degree to which prognostic Retrieval therapy with or without high-dose thera- factors are interrelated (e. g., disease stage, bulk, bio- py and hematopoietic cell rescue: intensity of initial logic aggressiveness) and therapy-dependent will de- chemotherapy, treatment with radiation, response termine their general applicability. Defi nitions of the to initial therapy, duration of initial remission, re- prognostic factors will, of course, aff ect their interpret- sponse to salvage therapy, disease stage at relapse, ability (e. g., bulk disease, sites of involvement, age disease bulk at relapse, extranodal relapse, B symp- cutoff s, relevant ranges of laboratory values) (Specht toms at relapse. 44 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Disease extent and biology have been correlated with Laboratory studies, including the erythrocyte sedi- the following prognostic factors currently in use or un- mentation rate, serum ferritin, hemoglobin level, se- der investigation. Th e stage of disease persists as the rum albumin, and serum CD8 antigen levels, have most important prognostic variable. Th e Ann Arbor been reported to predict a worse outcome (Pui et al. staging classifi cation was demonstrated to be prognos- 1989; Specht 1996; Landman-Parker et al. 2000; Smith tic for more than 14,000 patients in the International et al. 2003; Montalban et al. 2004). Th is could refl ect Database on HL (Henry-Amar et al. 1990), and its util- disease biology or bulk. Other investigational serum ity has persisted despite obvious limitations in its pre- markers associated with an adverse outcome include cision. Th ese include its failure to consider other fac- soluble vascular cell adhesion molecule-1 (Christian- tors such as disease burden and biology. Yet, it is used sen et al. 1998), tumor necrosis factor (Warzocha et al. in most trials for patient stratifi cation. Patients with 1998), soluble CD30 (Nadali et al. 1998) and CD 20 advanced stage disease, especially stage IV, have an in- (Tzankov et al. 2003), beta-2-microglobulin (Chro- ferior outlook compared with patients with early stage nowski et al. 2002), transferrin and serum IL-10 (Boh- disease (Henry-Amar et al. 1990; Bader et al. 1993; len et al. 2000), bcl-2 expression (Sup et al. 2005). High Nachman et al. 2002; Smith et al. 2003). levels of caspase 3 in Hodgkin and Reed-Sternberg cel- Disease burden encompasses the bulk of disease as ls has been correlated with a favorable outcome (Du- refl ected by the disease stage, but more specifi cally by kers et al. 2002). A recent study of children suggests the volume of distinct areas of involvement and the that EBV infection may be predictive of an inferior number of disease sites. Large mediastinal adenopathy outcome in those with advanced stage disease or NSHL places a patient at a greater risk for disease recurrence subtype (Claviez et al. 2005). when treated with radiation therapy alone, and also in Histologic subtype is relevant, at least among adults. trials using combined modality therapy. A slightly in- Patients with clinical stage I to II MCHL have an inferior survival rate is also apparent in some studies decreased frequency of subdiaphragmatic relapse, and spite the eff ectiveness of salvage therapy (Gobbi et al. disease subtype independently infl uences survival in 1985; Mauch et al. 1988; Maity et al. 1992; Specht 1996; some reports (Mauch et al. 1988). Grade 2 NSHL his- Nachman et al. 2002; Smith et al. 2003). Of interest, tology has conferred poor outcome in some, but not all however, is the recent DAL-HD-90 trial, in which bulk studies (Schellong 1996; von Wasielewski et al. 2003). disease did not infl uence the outcome (Dieckmann et Patients with LDHL fare poorly. However, a recent re- al. 2003). Escalating radiation doses for patients with port from the United Kingdom Children’s Cancer bulk or residual postchemotherapy disease may have Study Group assessing the relevance of histology in obviated the signifi cance of bulk in this trial. Patients 331 children is revealing. Less than 1% had LDHL, ob- (at least those staged only clinically) with several sites viating any meaningful assessment of its prognostic of involvement, generally defi ned as 4 or more, fare signifi cance. For patients with other histologies treated less well (Mauch et al. 1988; Maity et al. 1992; Specht with combined therapy, no diff erence in outcome was 1996). Patients with stage IV disease who have multi- observed (Shankar et al. 1997). As previously dis- ple organs involved fare especially poorly. cussed, patients with nLPHL have distinctive diff er- Systemic symptoms, which presumably result from ences in disease-free and overall survival (Sandoval et cytokine secretion, refl ect biologic aggressiveness and al. 2002). confer a worse prognosis (Vecchi et al. 1993; Schellong Age is a signifi cant prognostic factor is some stud- 1996; Landman-Parker et al. 2000; Nachman et al. ies. Survival rates for children with HL approach 2002; Smith et al. 2003). Th e constellation of symp- 85−95%. In a report from Stanford, the 5- and 10-year toms appears to be relevant to this observation. Th at is, survival for children with HL less than or equal to 10 patients with night sweats only (at least among patients years of age is 94% and 92%, respectively, compared with PS I and II disease) appear to fare as well as PS I with 93% and 86% for adolescents (aged 11 to 16 years to IIA patients, while those with both fevers and weight old) and 84% and 73% for adults (Cleary et al. 1994). loss have the worst prognosis (Crnkovich et al. 1986). Several features of the youngest patient group may in- Treatment of Pediatric Hodgkin Lymphoma Chapter 3 45

Table 3.6 Prognostic factors identiﬁ ed in pediatric Hodgkin lymphoma trials

Center Patient no. Treatment outcome Prognostic factors (study period)

Associazione Italiana di 215 7-yr FFP: 86% B symptoms Ematologia ed Oncologia (1983–1989) Mediastinal bulka Pediatrica-MH-83 (AIEOP) Histology (Vecchi 1993)

German multicenter DAL 578 5-yr EFS: 91% Histology: Nodular 90 (1990–1995) sclerosis, grade 2 (Schellong 1996) B symptoms

Stanford, 328 5-yr DFS: 83% Male sex Dana Farber & (1990–2000) Stage IIB, IIIB, IV St. Jude Consortium Mediastinal bulka (Smith 2003) WBC > 13.5 × 103/mm3 Hemoglobin < 11.5 gm/dL a Deﬁ ned as mediastinal mass/thoracic cavity ratio > 0.33 on upright chest radiograph Abbreviations: DFS, disease-free survival; EFS, event-free survival; FFP, freedom from progression fl uence their improved prognosis, including higher both improves and becomes increasingly tailored to frequency of LP and MC subtypes and of stage I dis- prognostic factors and therapeutic response, the over- ease, a lower frequency of systemic symptoms, and the all outcome should become less aff ected by those pa- more common use of combined modality therapy. rameters. Multivariate analysis of these data showed that age, stage, histology, and treatment modality (combined radiation and chemotherapy versus radiation alone) 3.5 Combination Chemotherapy were all independent prognostic variables for survival (Cleary et al. 1994). Although children less than 4 Its contiguous nodal pattern of disease dissemination years of age with HL are uncommon, even these chil- permitted HL to be one of the few tumors curable with dren would appear to have an excellent prognosis radiation alone. However, cure was limited to those (Kung 1991). whose entire extent of disease could be detected by Th e rapidity of response to initial therapy is an im- available staging studies and included within radiation portant prognostic variable in many forms of cancer, fi elds. Th e introduction of eff ective chemotherapy for including HL. In some trials, the rapidity of response HL made cure possible for patients with more exten- to chemotherapy is used to determine subsequent sive disease. In addition to treating sites of unrecog- therapy (Bierman et al. 2002; Carde et al. 2002; Lies- nized metastasis, chemotherapy permitted the reduc- kovsky et al. 2004). Early response to therapy as mea- tion of radiation fi elds and total dose, thus reducing sured by FDG-PET imaging is under investigation as a the risk of hypoplasia in growing children. Table 3.7 possible marker of prognosis (Korholz et al. 2003). summarizes the most common regimens used today in Table 3.6 provides examples of factors signifi cant on the treatment of pediatric Hodgkin lymphoma. multivariate analysis in recently published studies with Although single agents induced a response, combi- more than 200 patients. Although prognostic factors nation chemotherapy resulted in sustained disease will continue to be infl uenced by choice of therapy, pa- control that impacted survival rates. MOPP (nitrogen rameters such as disease, bulk, number of involved mustard, vincristine, procarbazine, and prednisone; sites, and systemic symptomatology are likely to re- DeVita et al. 1980) and ABVD (doxorubicin, bleomy- main relevant to the outcome. Nonetheless, as therapy cin, vinblastine, and dacarbazine; Santoro et al. 1982) 46 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

were developed by combining active agents with dif- other (COPP). When the subsequent elimination of ferent mechanisms of action and minimal overlap of procarbazine resulted in a signifi cant increase in ther- toxicity. Similar therapeutic responsiveness to chemo- apeutic failure in higher risk patients, etoposide was therapy made these combinations valuable for the used in lieu of procarbazine (OEPA) in boys in an ef- treatment of both adults and children. When com- fort to preserve testicular function. With this change, bined with radiation, cure rates in the range of 85−90% the gender-based approach produced less gonadal tox- are achievable. Unfortunately, many patients suff er icity while maintaining effi cacy (Bramswig et al. 1990; from adverse long-term eff ects of the chemotherapy. Ruhl et al. 2001). Th e increased vulnerability of children to late treat- Other chemotherapeutic agents may have fewer or ment complications (Donaldson and Kaplan 1982; non-overlapping toxicities. Cytosine arabinoside and Mauch et al. 1983) and their expected long-term sur- etoposide have been incorporated into several regimens vival have motivated the goals of pediatric trials to in an eff ort to reduce gonadal toxicity and enhance an- mitigate these eff ects. titumor activity (Ekert et al. 1993; Nachman et al. 2002). A review of the modern treatment of pediatric HL Non-cross-resistant agents with fewer or diff erent ef- (Th omson and Wallace 2002) is an overview of at- fects have also been studied. Investigators at Stanford, tempts to select optimal combinations of therapy that St. Jude, Boston consortium combined methotrexate might off er maximal effi cacy with minimal toxicity. with vinblastine, doxorubicin, and prednisone to estab- MOPP and ABVD have been used alone, in alternating lish VAMP, an eff ective regimen in low-stage disease fashion, and as a hybrid cycle in children. In adult tri- that does not include alkylating agents (Donaldson et als, regimens including doxorubicin appear to enhance al. 2002). Other combinations including DBVE (doxo- the outcome (Canellos et al. 1992; Duggan et al. 2003). rubicin, bleomycin, vincristine, etoposide), VBVP (vin- Although ABVD does not have the signifi cant risk of blastine, bleomycin, etoposide, prednisone), and OEPA sterility or secondary malignancy associated with (vincristine, etoposide, prednisone, doxorubicin) have MOPP or COPP (cyclophosphamide, vincristine, pro- also successfully eliminated the use of alkylating agents carbazine, prednisone; da Cunha et al. 1984; Bramswig (Landman-Parker et al. 2000; Schwartz et al. 2002; et al. 1990; Lipton et al. 1996; Schellong et al. 1997, Dorff el et al. 2003). VAMP has the advantage of not in- 1999), the combination does carry the risk of anthra- cluding etoposide and its potential leukemogenic eff ect, cycline-induced cardiotoxicity and bleomycin-induced while EBVP avoids the need for anthracycline. OEPA is pulmonary toxicity. Hybrid and alternating regimens the only regimen without an alkylating agent that has have the advantage of administering restricted cumu- been shown to be eff ective for low-stage disease with- lative doses of each eff ective agent. Th e Pediatric On- out radiation, producing 97% event-free survival (EFS) cology Group (POG) achieved excellent results using in IA/IIA patients (Dorff el et al. 2003). ABVD deriva- MOPP alternating with ABVD with low-dose radia- tive regimens including etoposide have not been eff ec- tion as the backbone of therapy for children, limiting tively used in high-stage disease. VEPA (vinblastine, cumulative doses of therapy even for those with the etoposide, prednisone, doxorubicin) combined with re- most advanced disease (Weiner et al. 1997). In a more sponse-based (15–25.5 cGy) involved-fi eld radiation recent study, Nachman et al. relied on the hybrid regi- resulted in only a 70% and 49% 5-year EFS for stages III men COPP/ABV (Nachman et al. 2002). An alterna- and IV HL, respectively (Friedmann et al. 2002). Re- tive approach was pioneered in the German Austrian sults with VEEP (vincristine, etoposide, epirubicin, investigators who attempted to minimize the use of al- prednisolone) and AOPE (doxorubicin, vincristine, kylating agents in an eff ort to reduce the incidence of prednisone, etoposide) and involved-fi eld radiation sterility and secondary malignancy (Schellong et al. (>30 Gy) were also suboptimal for patients with ad- 1999). Using the regimen known as OPPA (vincristine, vanced and unfavorable disease, suggesting that out- procarbazine, prednisone, doxorubicin)/COPP, this comes are compromised for some high-risk patients group replaced nitrogen mustard with doxorubicin in with the elimination of alkylating agents (Sackmann- one cycle (OPPA) and with cyclophosphamide in the Muriel et al. 1997; Shankar et al. 1998). Treatment of Pediatric Hodgkin Lymphoma Chapter 3 47

Table 3.7 Chemotherapy regimens for Hodgkin lymphoma (repeat cycle every 28 days)

Name Drugs Dosage Route Days MOPP & derivatives: MOPP Mechlorethamine 6.0 mg/m2 IV 1, 8 (Donaldson 1987) Vincristine 1.4 mg/m2 IV 1, 8 Procarbazine 100 mg/m2 PO 1–15 Prednisone 40 mg/m2 PO 1–15 COPP Cyclophosphamide 600 mg/m2 IV 1, 8 (Baez 1997) Vincristine 1.4 mg/m2 IV 1, 8 Procarbazine 100 mg/m2 PO 1–15 Prednisone 40 mg/m2 PO 1–15 OPPA Vincristine 1.5 mg/m2 IV 1, 8, 15 (Schellong 1996) Procarbazine 100 mg/m2 PO 1–15 Prednisone 60 mg/m2 PO 1–15 Doxorubicin 40 mg/m2 IV 1, 15 ChlVPP Chlorambucil 6 mg/m2 PO 1–14 (Shankar 1997) Vinblastine 6 mg/m2 PO 1, 8 Procarbazine 100 mg/m2 PO 1–14 Prednisone 40 mg/m2 PO 1–14 ABVD & derivatives: ABVD Doxorubicin 25 mg/m2 IV 1, 15 (Santoro 1982) Bleomycin 10 U/m2 IV 1, 15 Vinblastine 6 mg/m2 IV 1, 15 Dacarbazine 375 mg/m2 IV 1, 15 OEPA Vincristine 1.5 mg/m2 IV 1, 8, 15 (Schellong 1996) Etoposide 125 mg/m2 IV 3–6 Prednisone 60 mg/m2 PO 1–15 Doxorubicin 40 mg/m2 IV 1, 15 VAMP Vinblastine 6 mg/m2 IV 1, 15 (Donaldson 2002) Doxorubicin 25 mg/m2 IV 1, 15 Methotrexate 20 mg/m2 IV 1, 15 Prednisone 40 mg/m2 PO 1–14 VBVP Vinblastine 6 mg/m2 IV 1, 8 (Landman-Parker 2000) Bleomycin 10 U/m2 IV 1 Etoposide 100 mg/m2 IV 1–5 Prednisone 40 mg/m2 PO 1–8 DBVE Doxorubicin 25 mg/m2 IV 1, 15 (Schwartz 2002) Bleomycin 10 U/m2 IV 1, 15 Vincristine 1.5 mg/m2 IV 1, 15 (2 mg max) Etoposide 100 mg/m2 IV 1–5 48 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Table 3.7 Chemotherapy regimens for Hodgkin lymphoma (repeat cycle every 28 days)

Name Drugs Dosage Route Days VEPA Vinblastine 6 mg/m2 IV 1, 15 (Friedmann 2002) Etoposide 200 mg/m2 IV 1, 15 Prednisone 40 mg/m2 PO 1–14 Doxorubicin 25 mg/m2 IV 1, 15 Dose-intensive MOPP/ABVD combination derivatives: COPP/ABV Cyclophosphamide 600 mg/m2 IV 1 (Nachman 2002) Vincristine 1.4 mg/m2 IV 1 Procarbazine 100 mg/m2 PO 1–7 Prednisone 40 mg/m2 PO 1–14 Doxorubicin 35 mg/m2 IV 8 Bleomycin 10 U/m2 IV 8 Vinblastine 6 mg/m2 IV 8 DBVE-PC Doxorubicin 25 mg/m2 IV 1, 2 (Schwartz 2002) Bleomycin 5 U/m2 IV 1 10 U/m2 8 Vincristine 1.4 mg/m2 IV 1, 8 (2.8 mg max) 7 Etoposide 125 mg/m2 IV 1–3 Prednisone 40 mg/m2 PO 1–7 Cyclophosphamide 800 mg/m2 IV 1 BEACOPP Bleomycin 10 U/m2 IV 8 (Kelly 2002) Etoposide 200 mg/m2 IV 1–3 Doxorubicin 35 mg/m2 IV 1 Cyclophosphamide 1200 mg/m2 IV 1 Vincristine 2 mg/m2 IV 8 (2 mg max) Procarbazine 100 mg/m2 PO 1–7 Prednisone 40 mg/m2 PO 1–14 Stanford V Mechlorethamine 6 mg/m2 IV 1, 15 (Horning 2002) Vinblastine 6 mg/m2 IV 1, 15 Doxorubicin 25 mg/m2 IV 1 Etoposide 60 mg/m2 IV 15, 16 Vincristine 1.4 mg/m2 IV 8, 22 (2 mg max) Bleomycin 5 U/m2 IV 8, 22 Prednisone 40 mg/m2 PO Every other day Treatment of Pediatric Hodgkin Lymphoma Chapter 3 49

Dose-intensive regimens designed to improve effi - al. 2003; Kenney et al. 2004; Guibout et al. 2005) and cacy have been used to increase the antitumor eff ect atherosclerotic heart disease (Hancock et al. 1993; Ad- and limit cumulative doses of potentially toxic agents. ams et al. 2003) occurring 10 to 20 years aft er full-dose Adult groups have explored the concept of dose/time radiation has led to the use of combined modality intensifi cation in advanced stage disease. Stanford V therapy with low-dose radiotherapy rather than full- limited the duration and total dose of chemotherapy, dose radiotherapy even for postpubertal adolescents. achieving a 3-year EFS of 87% and a 5-year progres- With rare exceptions, chemotherapy is now recom- sion-free survival of 89% in adults with advanced and mended for all children and adolescents (Hudson unfavorable HL (Horning et al. 2002). BEACOPP and 2002; Hudson and Constine 2004). Chemotherapy escalated BEACOPP are dose-intensive regimens with also has signifi cant long-term eff ects on children and improved effi cacy compared to COPP/ABVE (Diehl et adolescents including sterility/infertility (alkylating al. 2003). Children with advanced-stage disease have agents; Horning et al. 1981; Bramswig et al. 1990; Or- received escalated BEACOPP followed by response- tin et al. 1990; Byrne et al. 1992; Hobbie et al. 2005), directed, gender-specifi c therapy with excellent early secondary leukemia (alkylating agents, etoposide; van outcomes (Kelly et al. 2002). Dose-intensive regimens Leeuwen et al. 2000; Bhatia et al. 2003; Lin and Teitell of short duration can potentially minimize cumulative 2005), pulmonary fi brosis (bleomycin; Marina et al. doses and thus long-term toxicity, although acute tox- 1995; Polliack 1995; Bossi et al. 1997), and cardiomy- icity associated with myelosuppressive and neuropath- opathy (anthracyclines; Kadota et al. 1988; Hancock et ic side-eff ects may be greater than that observed fol- al. 1993; Adams et al. 2004). To avoid these late toxici- lowing conventional chemotherapy administered on a ties, treatment regimens evaluated in children have twice-monthly schedule. Instead of further cumulative focused on the determination of minimal therapies dose escalation, ongoing pediatric trials utilize dose- necessary to eff ect cure. intensive delivery to limit cumulative cytotoxic therapy. Th e current Children’s Oncology Group’s intermediate risk trial features a dose/time-intensive approach 3.6 Chemotherapy Alone Versus Combined with ABVE-PC as the backbone therapy that elimi- Modality Therapy nates procarbazine and restricts doxorubicin and etoposide dose. Similarly, pediatric Hodgkin’s consortium Treatment with combination chemotherapy alone is investigators from St. Jude, Stanford, and Boston are eff ective for pediatric HL and avoids the potential testing Stanford V and response-based (15–25.5 Gy), long-term complications associated with radiation involved-fi eld radiation therapy for children and ado- therapy (Behrendt et al. 1987; Ekert et al. 1988, 1993; lescents with advanced and unfavorable disease. Lon- Lobo-Sanahuja et al. 1994; Baez et al. 1997; Sackmann- ger follow-up is required to determine if outcome will Muriel et al. 1997; van den Berg et al. 1997; Hutchin- be improved with this approach. son et al. 1998; Atra et al. 2002). Th is treatment ap- Overall 5-year survival for pediatric HL approaches proach is preferred in centers that do not have access 90% for most patients, but with prolonged follow-up to the radiation facilities, trained personnel, and diag- beyond 10 years from diagnosis, the risk of death due nostic imaging modalities needed for clinical staging. to disease is almost equaled by the risk of death due to Earlier chemotherapy-alone trials that prescribed other causes, particularly the long-term consequences MOPP and MOPP-derivative combinations supported of therapy (Hudson et al. 1998; Mertens et al. 2001). the therapeutic effi cacy of the combination but did not Chemotherapy with lower dose (15–25 Gy) and limit- provide information about long-term toxicity (Beh- ed fi eld radiation provides excellent disease control rendt et al. 1987; Ekert et al. 1988; Atra et al. 2002). In without cosmetically signifi cant hypoplasia (Land- an eff ort to avoid gonadal and neoplastic complica- man-Parker et al. 2000; Donaldson et al. 2002; Dorff el tions associated with alkylating agent combinations, et al. 2003). Recognition of the risks of breast cancer subsequent trials of chemotherapy alone tested ABVD (Bhatia et al. 2003; Travis et al. 2003; van Leeuwen et or derivative combinations in alternation with MOPP- 50 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

derivative therapy (Lobo-Sanahuja et al. 1994; Sripada prompted early closure of the study. Radiation was as- et al. 1995; Baez et al. 1997; Hutchinson et al. 1998). sociated with a 12% EFS diff erential in those with a Outcomes observed aft er these treatments were com- good response aft er 4–6 cycles of COPP/ABV. Surpris- parable to those achieved with combined modality ingly, this eff ect was apparent in all stages of the dis- regimens, particularly in patients with localized disease, although radiation was most important for those ease presentations. Attempts to reduce toxicity by with stage IV disease and those with B symptoms or eliminating alkylating agents in regimens by using “bulky” disease (Nachman et al. 2002). Due to success- ABVD or derivative therapy produced suboptimal re- ful salvage therapy aft er relapse, the overall survival sults in patients with advanced stage disease (Ekert et estimates did not diff er between the randomized al. 1993; Behrendt et al. 1996; Shankar et al. 1998). Th e groups, but the follow-up of the cohort is still too alternative approach to chemotherapy-alone treatment short. in pediatric patients utilizes combination chemothera- In another prospective trial, German-Austrian pe- py with low-dose radiation delivered to involved sites diatric Hodgkin’s disease investigators assigned radia- of disease. Th e superiority of treatment with combined tion on the basis of the clinical response at the end of modality versus chemotherapy alone continues to be therapy (Dorff el et al. 2003). Radiation was omitted for intensely debated by investigators because of individu- patients responding completely to risk- and gender- al biases regarding chemotherapy- and radiation-re- based OEPA or OPPA/COPP chemotherapy. Interme- lated toxicities. To date, only a few longitudinal, con- diate-risk and high-risk patients with complete re- trolled, randomized trials have been undertaken sponse to chemotherapy had an inferior outcome (Sackmann-Muriel et al. 1981, 1997; Weiner et al. compared with those with >75% response but not CR 1997; Hutchinson et al. 1998; Nachman et al. 2002). (81% vs. 92% EFS; p=0.01), a fi nding attributable to Early studies failed to demonstrate an event-free sur- the radiation given to those with residual disease vival advantage with the addition of radiation to com- (Dorff el et al. 2003). Relapses included involved nodal bination chemotherapy. However, these results are areas in all of the non-radiated group and in 65% of limited in their clinical relevance because some trials those receiving radiation. Th ere was no diff erence in required staging laparotomy with splenectomy for DFS among irradiated and nonirradiated patients as- treatment assignment, administered radiation to ex- signed to the favorable-risk group. Due to the eff ec- tended treatment volumes in combined modality regi- tiveness of retrieval therapy, overall survival was not mens, prescribed an excessive (by contemporary stan- signifi cantly reduced. dards) number of chemotherapy cycles, or utilized the Radiation clearly plays an important role in treating more leukemogenic MOPP combination chemothera- HL, yet with risks of breast cancer and myocardial in- py. farction, identifi cation of the group who can safely be A recent, more clinically pertinent study undertak- treated with chemotherapy alone would be benefi cial. en by the Children’s Cancer Group investigators pro- One hypothesis is that patients with the most chemo- spectively evaluated the benefi t of adding low-dose, therapy-sensitive disease do not need an additional involved-fi eld radiation to hybrid COPP/ABV combi- modality of therapy. Studies that eliminate radiation nation chemotherapy (Nachman et al. 2002). Th e trial for a subset of patients have routinely defi ned the sub- featured a risk-adapted treatment assignment based set as those with complete response at the end of ther- on the presence of B symptoms, hilar adenopathy, me- apy. Th e results of recent studies indicate that early re- diastinal and peripheral lymph node bulk, and the sponse to chemotherapy may appropriately predict number of involved nodal regions. Patients who those who can be treated with reduced or single mo- achieved a complete response to COPP/ABV hybrid dality therapy. Patients in the Pediatric Oncology chemotherapy were eligible for randomization to re- Group (POG) study 8725 with complete response (CR) ceive low-dose, involved-fi eld radiation or no further aft er 3 cycles of MOPP/ABVD had improved outcome, therapy. A signifi cantly higher number of relapses while CR aft er 6 cycles was not predictive of outcome among patients treated with chemotherapy alone (Weiner et al. 1991). Donaldson et al. (2002) used re- Treatment of Pediatric Hodgkin Lymphoma Chapter 3 51 sponse aft er 2 cycles of VAMP to determine radiation cline-induced cardiomyopathy than males (Lipshultz dose (15 Gy vs. 25.5 Gy). Preliminary results of recent- et al. 1991). Th e desire to avoid a particular treatment ly concluded POG studies showed that an early re- toxicity may infl uence an investigator’s preferred treat- sponse could be used to determine an appropriate du- ment approach in a given patient. Overall, however, ration of chemotherapy (Schwartz et al. 2002). Th is most frontline treatment protocols for pediatric HL approach is under investigation in several ongoing tri- limit exposure to agents and modalities, taking into als for pediatric HL. account risks for treatment side-eff ects that are unique Radiation therapy with its long-term risks (hypo- to age and gender. plasia, hypothyroidism, cardiopulmonary fi brosis, Cancer-related factors considered in the risk assess- breast cancer, myocardial ischemia) remains a major ment at diagnosis include the presence of B symptoms, therapeutic modality for the treatment of HL. Th e Ann Arbor stage, number of involved nodal regions, challenge is to identify patients for whom radiation lymph node bulk, and extranodal extension of disease represents a less toxic modality than the chemotherapy to contiguous structures. Histological subtype has an- necessary for an equivalent outcome or for whom ra- ecdotally been used to direct therapy in patients with diation is a unique modality necessary for cure. Opti- localized, completely resected, nodular lymphocyte mistically, the long-term risks previously noted will be predominant HL (Murphy et al. 2003; Pellegrino et al. less substantial in the modern era of lower dose radio- 2003). Th is treatment approach will be prospectively therapy to tailored fi elds. studied in an ongoing Children’s Oncology Group trial. Risk designations using these cancer-related parameters have varied among pediatric investigators, 3.7 Risk-Adapted Therapy but typically defi ne characteristics of low-, intermediate-, and high-risk disease presentations. To optimize the opportunity for long-term disease control and minimize cancer-related morbidity, con- 3.7.1 Treatment of Low-Risk Disease temporary treatment for pediatric HL utilizes a risk- adapted approach that considers host- and cancer-re- A low-risk clinical presentation is uniformly charac- lated factors at diagnosis. Th erapy type and intensity terized by localized (stage I/II) nodal involvement in are largely determined by cancer-related factors, but the absence of B symptoms and lymph node bulk. host-specifi c risks for treatment toxicity may be taken Bulky mediastinal lymphadenopathy is designated into account when equally eff ective alternative mo- when the ratio of the maximum measurement of the dalities are available. Host-related factors that are most mediastinal lymph nodes to the intrathoracic cavity on oft en considered in the context of risk for specifi c an upright chest radiograph is 33% or more. Some treatment-related toxicities are age and gender. Young- studies also consider lymph node bulk outside the meer age at diagnosis increases the risk of musculoskeletal diastinum in the risk assessment; this designation has and soft -tissue deformity aft er radiation therapy and ranged across studies from 4 cm to 10 cm. Likewise, cardiovascular dysfunction aft er mediastinal radiation the number of nodal sites considered as low risk has and anthracycline therapy (Donaldson and Link 1991; been variable, but generally is defi ned as fewer than 3 Adams et al. 2003, 2004). At equivalent doses of alkyl- to 4 involved nodal regions. ating agent chemotherapy, boys exhibit a higher fre- Numerous investigations have demonstrated that quency of gonadal dysfunction than girls (Horning et children and adolescents with low-risk presentations al. 1981; Bramswig et al. 1990; Ortin et al. 1990; Hob- of HL are excellent candidates for reduced therapy. Th e bie et al. 2005). In contrast, teenage girls have a sub- standard treatment approach for low-risk patients in- stantially increased risk of breast cancer following tho- volves 2 to 4 cycles of chemotherapy with low-dose, racic radiation, which is not observed in boys (Bhatia involved-fi eld radiation. Th e most popular multiagent et al. 2003). At equivalent doses of anthracycline che- regimens used for low-risk patients are characterized motherapy, females are at a higher risk for anthracy- by little or no alkylating agent chemotherapy (see Ta- 52 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Table 3.8 Treatment results for selected low-risk pediatric Hodgkin lymphoma

Group or institution Number Stage Chemotherapy Radiation Survival (%) Follow- of (Gy), fi eld up DFS, Overall patients interval EFS, or (years) RFS Combined modality trials: Stanford/St. Jude/ 15 I 3 VAMP/ 3 COP 15–25.5, IF 100 NA 5.8 Boston Consortium 62 II 3 VAMP/ 3 COP 15–25.5, IF 78 NA (Hudson 2004) German Multicenter (Dorff el 281 I-IIA 2 OPPA/OEPA 20–35, IF 94 NA 5 2003) 212 IIEA, IIB, IIIA 2 OPPA/OEPA + 2 92 COPP Stanford/St. Jude/ 110 I/II (without 4 VAMP 15–25.5, 93 99 5 Boston Consortium lymph node IF (Donaldson 2002) bulk)a U.S. Children’s Cancer 294 IA/B, IIA (without 4 COPP/ABV 21, IF 97 100 3 Group (Nachman 2002) adverse features)b French Society of Pediatric 171 I-II 4 VBVP, good 20, IF 91 97.5 5 Oncology (Landman-Parker responders 20, IF 78 5 2000) 27 I-II 4VBVP + 1-2 OPPA, poor responders Royal Marsden (Shankar 1998) 46 I-III 8 VEEP 30–35, IF 82 93 5 Royal Marsden (Shankar 1997) 125 II 6–10 ChlVPP 35, IF 85 92 10 Stanford (Hunger 1994) 44 I-III (some PS) 3 MOPP/ 3 ABVD 15–25.5, 100 100 10 IF St. Jude (Hudson 1993) 58 II/III 4–5 COP(P)/ 3–4 20, IF 96/97 96/100 5 ABVD French Society of Pediatric 79 I-IIA 4 ABVD 20–40, IF 90 6 Oncology (Oberlin 1992) 67 I-IIA 2 MOPP/ 2 ABVD 20–40, IF 87 6 31 IB-IIB 3 MOPP/ 3 ABVD 20–40, EF 92 6 Stanford (Donaldson 1987) 27 PS I, II 6 MOPP 15–25, IF 96 100 5 Chemotherapy-alone trials: German Multicenter 113 I-IIA 2 OPPA/OEPA None 97 NA 5 (Dorff el 2003) 52 IIEA, IIB, IIIA 2 OPPA/OEPA + 2 78 COPP U.S. Children’s Cancer Group 106 IA/B, IIA (without 4 COPP/ABV None 91 100 3 (Nachman 2002) adverse features)b Nicaragua (Baez 1997) 14 I, IIA 6 COPP None 100 100 3 Argentina (Sackmann-Muriel 10 IA, IIA 3 CVPP None 86 NA 6.7 1997) 16 IB, IIB 6 CVPP None 87 6.7 Costa Rica (Lobo-Sanahuja 1994) 52 IA-IIIA 6 CVPP None 90 100 5

Abbreviations: DFS, disease-free survival; EF, extended fi eld; prednisone, Adriamycin; OPPA, Oncovin, procarbazine, EFS, event-free survival; IF, involved fi eld; PS, pathologic prednisolone, and Adriamycin: VAMP, vinblastine, doxorubi- stage; RFS, relapse-free survival. cin, methotrexate, and prednisone; VBVP, vinblastine, ABVD, Adriamycin, bleomycin, vinblastine and dacarbazine; bleomycin, etoposide, and prednisone; VEEP, vincristine, eto- ChlVPP, chlorambucil, vinblastine, procarbazine, and poside, epirubicin, prednisolone. prednisolone; CVPP, cyclophosphamide, vinblastine, a Tumor bulkdefi ned as mediastinal mass to thoracic cavity procarbazine, prednisone; COP(P), cyclophosphamide, Onco- ratio of > 33% or node or nodal aggregate > 6 cm. vin, prednisone, and procarbazine; COPP/ABV, cyclophos- b Adverse features defi ned as hilar adenopathy, involvement phamide, Oncovin, procarbazine, prednisone/Adriamycin, of more than 4 nodal regions, mediastinal tumor > 33% of bleomycin, vinblastine; MOPP, nitrogen mustard, Oncovin, chest diameter, node or nodal aggregate > 10 cm. procarbazine, and prednisone; OEPA, Oncovin, etoposide, Treatment of Pediatric Hodgkin Lymphoma Chapter 3 53 ble 3.8) (Schellong 1996; Landman-Parker et al. 2000; In a prospective study that randomized low-risk pa- Donaldson et al. 2002; Nachman et al. 2002). Pediatric tients who achieved a complete response to 4 cycles of investigators from Stanford, Dana Farber, and St. Jude COPP/ABV hybrid chemotherapy, North American reported excellent outcomes using 4 cycles of vinblas- investigators observed a signifi cantly higher 3-year tine, doxorubicin, methotrexate, and prednisone EFS in patients who received 21 Gy involved-fi eld ra- (VAMP) and low-dose, involved-fi eld radiation thera- diation consolidation (97%) compared with those who py (Donaldson et al. 2002). Five-year event-free sur- were treated with 4 cycles of COPP/ABV chemothera- vival and overall survival for low-risk patients treated py alone (91%; Nachman et al. 2002). Despite this sig- with combined modality including the VAMP regi- nifi cant diff erence, the still very good early treatment men was 93% and 99%, respectively (Donaldson et al. results in the group randomized to chemotherapy 2002). Other groups have demonstrated comparable alone suggests that many patients with low-risk dis- results using regimens prescribing lower doses of an- ease can be cured using this approach. Th is is support- thracyclines. Th ese trials feature regimens that use eto- ed by the results of the most recent GPOH-HD trial, poside in lieu of anthracyclines or alkylators (Schel- which established that the outcome was not compro- long 1996; Landman-Parker et al. 2000; Schwartz et al. mised by omitting involved-fi eld radiation in low-risk 2002; Dorff el et al. 2003), which has been controversial patients who achieved a complete response following among some investigators because of the agent’s asso- treatment with 2 cycles of OPPA or OEPA chemother- ciation with secondary acute myeloid leukemia (s- apy (Dorff el et al. 2003). AML; Smith et al. 1999). French investigators observed a 5-year EFS of 91.5% in favorable-risk patients who 3.7.2 Treatment of Intermediate- and achieved a good response following 4 cycles of vinblas- High-Risk Disease tine, bleomycin, etoposide, and prednisone (VBVP), a regimen including neither alkylating agent nor anthra- Th e intermediate-risk group most oft en includes pa- cycline chemotherapy, followed by 20 Gy to involved tients with stage I/II disease who have one or more un- fi elds (Landman-Parker et al. 2000). Similarly, Ger- favorable features, and sometimes patients with stage man-Austrian trials demonstrated that DFS could be IIIA disease. Patients with localized disease with unfa- maintained with a potential for less gonadal toxicity in vorable features have been treated similarly to those male patients by substituting etoposide for procarba- with advanced stage (III/IV) disease in some risk- zine in the vincristine, prednisone, procarbazine, and adapted pediatric trials or assigned a therapy that is doxorubicin (OPPA) regimen (Schellong 1996; Dorff el intermediate in intensity in others. Th e criterion for et al. 2003). To date, the cumulative dose of etoposide unfavorable disease features has not been consistent in these trials has been associated with only a rare case across trials and may include the presence of B symp- of s-AML (Landman-Parker et al. 2000). Th erefore, toms, lymph node bulk, hilar lymph involvement, in- the benefi ts of reduced gonadal and cardiac toxicity far volvement of 3–4 or more lymph node regions, and outweigh the risk of leukemogenesis with the restrict- extranodal extension to contiguous structures. A high- ed use of etoposide in low-risk HL. risk presentation includes patients with advanced stage In addition to eff orts at reducing chemotherapy-as- IIIB or IVA/B. Th is risk designation earns patients the sociated toxicity, several recent trials have aimed to most dose-intensive chemotherapy assignment thera- eliminate radiation therapy for low-risk patients with py, which in most cases includes low-dose, involved- favorable responses to chemotherapy. St. Jude investi- fi eld radiation consolidation. gators demonstrated that local control was not com- Chemotherapy used for intermediate- and high- promised by reducing involved-fi eld radiation dose to risk HL generally includes derivative combinations of 15 Gy in patients who achieved an early complete re- MOPP and ABVD. Because cyclophosphamide is less sponse to VAMP chemotherapy (Krasin et al. 2005). myelosuppressive and leukemogenic than mechlor- Th eir ongoing consortium trial is investigating wheth- ethamine, COPP has largely replaced MOPP in pediat- er radiation can be eliminated for this favorable group. ric trials (Schellong et al. 1997). Similar to combina- 54 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

tions used in studies of low-risk HL, etoposide has a frontline therapy has not been pursued because the been incorporated in regimens for intermediate- and EFS of these patients is well in excess of 50%. Ongoing high-risk HL with the goal of improving antitumor ac- studies evaluating the relationship of metabolic tumor tivity and reducing cumulative doses of alkylating and activity by PET to early chemotherapy response and anthracycline chemotherapy. Th e standard treatment treatment outcomes may help identify patients who approach prescribes a noncross-resistant chemothera- may benefi t from intensifi cation of therapy with HSCT. py combination on a twice-monthly schedule for a to- To date, consensus has not been established among in- tal of 6 months. Low-dose (15.0 to 25.5 Gy), involved- vestigators regarding prognostic features that justify fi eld radiation therapy may be delivered between the risks of this aggressive approach. Until these issues treatment cycles or, more commonly, following com- are further clarifi ed, HSCT should be reserved for pa- pletion of chemotherapy to consolidate remission. An tients aft er relapse or for those who are refractory to alternative approach utilizes dose-intensive multiagent primary conventional therapy, including alkylating chemotherapy administered at weekly intervals for a agents. period of 3 to 5 months during which myelosuppressive agents are alternated with nonmyelosuppressive agents. Th e abbreviated therapy duration provides the 3.8 Principles of Radiation Therapy advantage of increased dose intensity, reduced therapy duration, decreased cumulative chemotherapy doses, Th e complexity of current treatment strategies and the which should theoretically reduce the potential for the vulnerability of the developing child to both radiation development of chemotherapy resistance and treat- and chemotherapy require a comprehensive under- ment toxicity. Most pediatric trials consolidate with standing of both modalities. Newly diagnosed children low-dose, involved-fi eld radiation to sites of bulky or will be treated with risk-adapted chemotherapy alone or residual disease. combined-modality therapy including low-dose, in- Treatment results for selected intermediate- and volved-fi eld radiation. Th e use of radiation alone, even high-risk pediatric HL are summarized in Table 3.9 for fully grown adolescents with early stage disease, has and are notable for the following observations: Patients been largely abandoned. Th is shift derives from recog- at intermediate risk, i.e., those with clinically localized nition of the cardiopulmonary and musculoskeletal disease (stages I–IIIA) with unfavorable features like morbidities of full-dose radiation and the occurrence of lymph node bulk, extranodal extension, etc., have ex- secondary malignant neoplasms (Donaldson and Ka- cellent treatment outcomes following therapy reduc- plan 1982; Mauch et al. 1983; Donaldson and Link tion to 4 chemotherapy cycles (Schellong 1996; Ruhl et 1991). However, most mature reports demonstrate an al. 2001; Dorff el et al. 2003). Trials in high-risk patients advantage of involved-fi eld radiation in combination evaluating the substitution of nonalkylating agent che- with chemotherapy, and particularly in children with motherapy like methotrexate or etoposide as an alter- advanced stages of disease (Ruhl et al. 2001; Nachman native to alkylating agent chemotherapy observed in- et al. 2002). Th e principles of radiotherapeutic manage- ferior EFS among patients with high-risk clinical ment are generally consistent across institutions (e. g., presentations (Schellong et al. 1992; Shankar et al. high-energy machines, immobilization and simulation 1998; Friedmann et al. 2002; Hudson et al. 2004). Pre- of patients), but the nuances of volume and dose vary liminary results of the North American pediatric co- and will depend on the overall treatment regimen. Th e operative groups support the feasibility of using a radiation oncologist ideally will participate in the initial compacted, dose-intensive therapy approach com- evaluation and ultimate determination of therapy. Most bined with low-dose radiation therapy (Kelly et al. children will be entered into institutional or group stud- 2002). However, long-term follow-up is not yet availa- ies, and understanding (as well as agreeing with) proto- ble to evaluate the effi cacy and treatment sequelae. col requirements is necessary. In the environment of a Th erapy intensifi cation for high-risk pediatric HL us- formal study, a central review of radiation compliance ing hematopoietic stem cell transplantation ( HSCT) as can enhance the quality of therapy. A recent review of Treatment of Pediatric Hodgkin Lymphoma Chapter 3 55

Table 3.9 Treatment results for selected intermediate- and high-risk pediatric Hodgkin lymphoma

Group or institution Number Stage Chemotherapy Radiation Survival (%) Follow-up of (Gy), ﬁ eld DFS, EFS, Overall in ter val patients or RFS (years) Combined modality trials:

German Multicenter (Schellong 179 IIEB, IIIEA/B, IIIB, 2 OEPA/OPPA + 4 20, IF 83/91 98/89 5 1996) IVA/B COPP

German Multicenter (Dorﬀ el 265 IIEA, IIIEA/B, 2 OPPA/OEPA + 4 20–35, IF 90 90 5 2003) IIIB, IVA/B COPP St. Jude (Hudson 1993) 27 IV 4–5 COP(P)/ 3–4 20, IF 85 86 5 ABVD Stanford (Donaldson 1987) 28 III-IV 6 MOPP 15–25.5, IF 84 78 7.5 Stanford (Hunger 1994) 13 III-IV 3 MOPP/ 3 ABVD 15–25.5, IF 69 85 10 Stanford/St. Jude/Boston 56 I/IIa (n=26) 6 VEPA 15–25.5, IF 67.8 81.9 5 Consortium (Friedmann 2002) III/IV (n=30) Stanford/St. Jude/Boston 82 III 3 VAMP/ 3 COP 15–25.5, IF 68.9 92.7 5.8 Consortium (Hudson 2004) IV 68.5 (all) Toronto (Jenkin 1990) 57 IIA-IV 6 MOPP 25–30, EF 80 85 10 U.S. Children’s Cancer Group 54 PS III/IV 6 ABVD 21, EF 87 90 4 (Fryer 1990)

Pediatric Oncology Group (Weiner 80 IIB, IIIA2, IIIB, IV 4 MOPP/4 ABVD 21, EF 80 87 5 1997) (some PS) U.S. Children’s Cancer Group 394 I/IIb, IIB, III 6 COPP/ABV 21, IF 87 95 3 (Nachman 2002) U.S. Children’s Cancer Group 141 CS IV COPP/ABV + 21, IF 90 100 3 (Nachman 2002) CHOP + Ara-C/ VP-16 Chemotherapy-alone trials

German Multicenter (Dorﬀ el 57 IIEA, IIIEA/B, IIIB, 2 OPPA/OEPA + 4 None 80 90 5 2003) IVA/B COPP U.K. Children’s Cancer Study 67 CS IV 6–8 ChlVPP None 55.2 80.8 5 Group (Atra 2002) U.S. Children’s Cancer Group 394 CS I/IIb, CS IIB, 6 COPP/ABV None 83 100 3 (Nachman 2002) CS III U.S. Children’s Cancer Group 141 IV COPP/ABV + None 81 94 3 (Nachman 2002) CHOP + Ara-C/VP- 16 Australia/New Zealand (Ekert 53 I-IV 5–6 VEEP None 78 92 5 1999) U.S. Children’s Cancer Group 57 PS III/IV 6 MOPP/ 6 ABVD None 77 84 4 (Hutchinson 1998) Nicaragua (Baez 1997) 23 IIIB, IV 8–10 COPP-ABV None 75 3 The Netherlands (van den Berg 21 I-IV (< 4 cm 6 MOPP None 91 100 5 1997) 17 node) 6 ABVD 70 94 21 I-IV 3 MOPP/ 3 ABVD 91 91

Pediatric Oncology Group 81 IIB, III2A, IIIB, IV 4 MOPP/ 4 ABVD None 79 96 5 (Weiner 1997) Costa Rica (Lobo-Sanahuja 1994) 24 IIIB, IV 6 CVPP/ 6 EBO None 60 81 5 Madras, India (Sripada 1995) 43 IIB-IVB 6 COPP/ABV None 90 5 56 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Abbreviations: FS, disease-free survival; EF, extended Oncovin, etoposide, prednisone, Adriamycin; OPA, fi eld; EFS, event-free survival; IF, involved fi eld; PS, Oncovin, prednisone, Adriamcyin; OPPA, Oncovin, pathologic stage; RFS, relapse-free survival; procarbazine, prednisolone, and Adriamycin; VBVP, ABVD, Adriamycin, bleomycin, vinblastine, and dacarba- vinblastine, bleomycin, etoposide, and prednisone; VEEP, zine; COPP, CCNU, vincristine, procarbazine, prednisone; vincristine, etoposide, epirubicin, prednisolone; VEPA, ChlVPP, chlorambucil, vinblastine, procarbazine, and vinblastine, etoposide, prednisone, Adriamycin. prednisolone; CHOP, cyclophosphamide, Adriamycin, a With tumor bulk defi ned as mediastinal mass to Oncovin, prednisone; COP(P), cyclophosphamide, thoracic cavity ratio of > 33% or node or nodal Oncovin, prednisone, and procarbazine; COPP/ABV, aggregate > 6 cm. cyclophosphamide, Oncovin, procarbazine, prednisone/ b With adverse features defi ned as hilar adenopathy, Adriamycin, bleomycin, vinblastine; CVPP, cyclophospha- involvement of more than 4 nodal regions, mediastinal mide, vinblastine, procarbazine, prednisone; EBO, tumor > 33% of chest diameter, node or nodal epirubicin, bleomycin, vincristine; MOPP, nitrogen aggregate > 10 cm. mustard, Oncovin, procarbazine and prednisone; OEPA,

the DAL-HD-90 trial (German-Austrian pediatric mul- involved node(s). For example, the cervical and supra- ticenter trial) showed that up-front centralized review clavicular lymph nodes are generally treated when ab- of patients entered into the study altered the treatment normal nodes are located anywhere within this area; approach in a large number of children (Dieckmann et this is consistent with the anatomic defi nition of lymph al. 2002). Unpublished data from the POG also support node regions used for staging purposes (Kaplan and the superior outcome of children treated with appropri- Rosenberg 1966). However, confi ning the volume to ate radiation fi elds and doses, in contrast to those in include either the cervical or the supraclavicular re- whom protocol violations occurred. gion with an appropriate margin (e. g. 2 cm) may be equally eff ective with less normal tissue exposure. A 3.8.1 Volume Considerations conservative approach adopts the former strategy, but some protocols specify the latter. Th e traditional defi - Th e tandem development of eloquent diagnostic im- nitions of lymph node regions can be helpful, but are aging and eff ective combination chemotherapy has not necessarily suffi cient. Th at is, confi ning the radia- provoked redefi nition of the treatment volume appro- tion volume to the involved region may not fulfi ll the priate for children treated with multimodality therapy. criteria of a judgmental approach. For example, the Future studies on patterns of disease recurrence in this hila are generally irradiated when the mediastinum is setting will augment our understanding of the neces- involved, despite the fact that the hila and mediasti- sary radiation volumes. Nevertheless, knowledge, num are separate lymph node regions. Similarly, the judgment, and skill are required to irradiate children SCV is oft en treated when the axilla or the mediasti- appropriately. Table 3.10 provides an example of in- num is involved, and the ipsilateral external iliac nodes volved-fi eld defi nitions for children. Th ese defi nitions are oft en treated when the inguinal nodes are involved. depend on the anatomy of the region in terms of lymph However, in both these situations care must be taken node distribution, patterns of disease extension into to shield relevant normal tissues to the degree possible, adjacent areas, and consideration for match line prob- such as the breast in the former situation, and ovaries lems should disease recur. In fact, these defi nitions are in the latter. Moreover, the decision to treat the axilla not static, since the uncertainty regarding the presence or mediastinum without the SCV, and the inguinal of subclinical disease has diminished with advanced nodes without the iliacs, might be appropriate depend- imaging techniques, including PET. However, a con- ing on the size and distribution of involved nodes at servative approach remains appropriate for patients presentation. In a very young child, consideration may not treated on protocols. Th us, involved fi elds typically be given to treating bilateral areas (e. g., both sides of still include not just the identifi ably abnormal lymph the neck) to avoid growth asymmetry. However, this is nodes, but the entire lymph node chain containing the less of a concern with low radiation doses, and thus Treatment of Pediatric Hodgkin Lymphoma Chapter 3 57 unilateral fi elds are usually appropriate if the disease is shielded. Depending on the response of the disease to unilateral. Maneuvers to exclude vulnerable normal chemotherapy and the dose administered, fi eld reduc- tissues (e. g. breast, ovaries, heart) are always a compo- tions may be possible. Because 10- to 15-Gy doses can nent of the planning process. cytoreduce HL, increasing the size of the lung or car- From the above discussion, it is clear that treating diac blocks is oft en possible during the course of ther- an involved supradiaphragmatic or mantle fi eld re- apy; however, it is uncommon to use RT in a setting quires precision because of the distribution of lymph where large disease bulk has not already been cytore- nodes and the critical adjacent normal tissues. Th ese duced by chemotherapy. Th e entire heart or lungs are fi elds can be simulated with the arms up over the head, rarely treated above doses of 10 to 16 Gy, depending or down with hands on the hips. Th e former pulls the on the distribution of disease and chemotherapy used. axillary lymph nodes away from the lungs, allowing More specifi cally, the indications for whole-heart ir- greater lung shielding. However, the axillary lymph radiation include pericardial involvement as suggested nodes then move into the vicinity of the humeral by a large pericardial eff usion or frank pericardial in- heads, which should be blocked in growing children. vasion with tumor; such patients will generally receive Th us, the position chosen involves weighing concerns combined modality therapy and 10 to 15 Gy to the en- regarding lymph nodes, lung, and humeral heads. Ef- tire heart. Whole-lung irradiation with partial trans- forts should be made to exclude breast tissue altogeth- mission blocks is a consideration in the setting of overt er or to position it under the lung/axillary blocking. pulmonary nodules. Again, this is protocol-dependent Equally weighted anterior and posterior fi elds are since some children treated for advanced stage HL will treated daily. Anteriorly weighted mediastinal fi elds receive RT only to areas of initial bulk disease or post- excessively irradiate the anterior heart with associated chemotherapy residual disease. However, this ap- cardiac morbidity (Gottdiener et al. 1983). Dose calcu- proach remains investigational, and involved fi eld ra- lations should be based on the patient separation at the diation therapy is usually the appropriate treatment central axis. Nodes in the neck and axilla may receive a approach, as demonstrated by recent reports (Ruhl et higher dose because of the decreased patient thickness al. 2001; Nachman et al. 2002). Th us, for children with compared with the midthorax. Th erefore, separate ax- pulmonary nodules at diagnosis, whole-lung irradia- illary, neck, and low mediastinal dosimetry should be tion to 10 to 15 Gy is a consideration. A gap should be performed, and compensating fi lters or other modifi - calculated when matching the paraaortic fi eld. cations should be used to minimize inhomogeneity. Radiation therapy to a subdiaphragmatic region re- Extended source-to-skin distances decrease dose in- quires the same types of considerations and, of course, homogeneity in these diff erent areas. An anterior la- is dependent on the distribution of involved sites. Th e ryngeal and a posterior occipital block is oft en used spleen or pedicle is included in patients who have throughout treatment if the disease is not thereby splenic involvement, while minimizing the radiation shielded. A posterior cervical spine block might also dose to the kidneys. Whether the spleen (or pedicle) be appropriate to limit this structure to a chosen dose, should be routinely treated in the setting of paraaortic depending on disease location (e. g., involved cervical but not overt splenic involvement is controversial. In nodes are usually not midline) and the total dose used. the absence of a study, elective splenic irradiation is Blocking the thoracic cord is not recommended be- generally advised. Usually the upper pole of the left cause it risks underdosing the mediastinal nodes kidney is within the irradiated volume. A treatment (Prosnitz et al. 1997). Lung blocks should allow ade- planning CT or diagnostic information obtained from quate (1 to 2 cm) margins around the mediastinal dis- the CT or MRI is helpful in determining the blocks. ease. Th e width of the mediastinal/hilar fi eld is gener- When treating the pelvis, special attention must be ally based on the postchemotherapy residual disease, given to the ovaries and testes. Th e ovaries should be whereas the cephalad-caudad dimension respects the relocated, and marked with surgical clips, laterally original disease extent. Humeral head blocks are used along the iliac wings, or centrally behind the uterus. In unless bulky axillary adenopathy would thereby be this manner appropriate shielding may be used in or- 58 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Table 3.10 Involved fi eld radiation guidelines 3.8.2 Dose Considerations Involved node(s) Radiation fi eld In the setting of combined modality therapy, the radia- Cervical Neck and infraclavicular/ tion dose will depend on the overall treatment regimen supraclaviculara and the specifi c chemotherapy utilized. Most data de- Supraclavicular Neck and infraclavicular/ scribing the radiation dose response of HL are based supraclavicular +/– axilla on studies in adults, including the Patterns of Care reports (Coia and Hanks 1988; Schewe et al. 1988; Sears Axilla Axilla +/– infraclavicular/ supraclavicular et al. 1997; Nadali et al. 1998). In the absence of chemotherapy, subclinical disease is reliably (95%) control- Mediastinum Mediastinum, hila, infraclavicular/ led with 25 to 30 Gy, small bulk disease (variously de- a,b supraclavicular fi ned but less than 5 cm in most reports) requires 30 to Hila Hila, mediastinum 35 Gy, and large bulk disease requires an additional 5 to 10 Gy. Th e doses per fraction should be 1.5 to 1.8 Gy Spleen Spleen +/– para-aortics daily, fi ve times a week. Patients treated with large vol- Para-aortics Para-aortics +/– spleen umes may only tolerate 1.5 Gy fractions. Studies ran- domizing children to diff erent radiation doses, in or- Iliac Iliacs, inguinal, femoral der to determine the “correct” dose, are lacking. In the Inguinal External iliac, inguinal, femoral setting of combined therapy, the intensity of the chemotherapy must be understood in order to determine Femoral External iliac, inguinal, femoral the radiation dose and volume. In general, doses of 15 to 25 Gy are used with shrinking fi elds and individual- a Upper cervical region not treated if supraclavicular ized boosts. When the decision is made to include involvement is extension of the mediastinal disease. b Prechemotherapy volume is treated except for lateral some or all of a critical organ (liver, kidney, or heart) in borders of the mediastinal fi eld, which is postchemo- the radiation fi eld, then normal tissue constraints will therapy. relate to the chemotherapy used and patient’s age. In the tables summarizing recent clinical trials for early der to administer as little irradiation as possible, and and advanced stage HL, the radiation doses selected to certainly less than 6 Gy. Th e testes receive 5−10% of complement the chemotherapy regimen are provided. the administered pelvic dose, which is suffi cient to In general, doses of greater than 25 Gy are uncommon cause transient or permanent azoospermia, depending in the pediatric setting. Caution must be used in apply- on the total pelvic dose. Th e greatest shielding can be ing the results from published reports. For example, in aff orded to the testes if the patient is placed in a frog- the recently analyzed DAL-HD-90 trial, doses of 20–25 legged position with an individually constructed testes Gy were administered in combination with OEPA or shield. If multileaf collimation is available, the multi- OPPA, with or without COPP (Dieckmann et al. 2002). leaf can be placed over the testes, additionally decreas- However, a local boost of 5–10 Gy was delivered for ing the transmitted dose. As previously stated, radia- insuffi cient remission following chemotherapy. Tumor tion therapy for unfavorable and advanced HL is burden, indicated by bulky disease or number of in- variable and protocol-dependent. Although IFRT re- volved nodes, proved not to be prognostically signifi - mains the standard when patients are treated with cant in this report, perhaps due to the boost doses. combined modality therapy, restricting RT to areas of Despite the excellent tumor control in this study, radi- initial bulk disease (generally defi ned as 5 cm or more ation doses of 25–35 Gy are rarely recommended in at the time of disease presentation) or postchemother- most current investigations. Also of interest are recent apy residual disease (generally defi ned as 2 cm or more, data from a randomized trial by the German Hodgkin or residual PET avidity) is under investigation. Lymphoma Group in which patients (adults) with stage I to IIIA disease received 20, 30, or 40 Gy to non- Treatment of Pediatric Hodgkin Lymphoma Chapter 3 59 bulky or uninvolved sites following 4 months of che- tions derived from both ABVD and MOPP still pro- motherapy. Bulk (greater than 7.5 cm) disease always vide the most eff ective chemotherapy strategies for received 40 Gy. With this constraint, no diff erence was children and adolescents with intermediate- or high- observed for the various doses (Loeffl er et al. 1997). risk disease presentations. Etoposide is oft en added to these regimens to increase the antitumor activity and 3.8.3 Energy reduce the gonadal toxicity associated with alkylating agent chemotherapy. Attempts to restrict or completely Megavoltage energies are necessary. A 4- to 6-MV lin- omit alkylating agents in these high-risk groups have ear accelerator should be used for supradiaphragmatic resulted in unsatisfactory outcomes, as have protocols fi elds, thereby ensuring adequate doses to the superfi - prescribing ABVD or derivative chemotherapy alone cial nodes in the build-up region as well as to deep (Shankar et al. 1998; Ekert et al. 1999; Friedmann et al. nodal areas such as the mediastinum. Higher energy 2002; Hudson et al. 2004). Regimens reporting the best machines (8 to 15 MV) may be appropriate for treating long-term outcomes prescribe low-dose radiation paraaortic nodes. If high-energy machines must be therapy to nodal regions involved at diagnosis or a ra- used for treatment of the mantle fi eld, some therapists diation boost to areas with suboptimal response to introduce a beam spoiler or bolus on the neck and su- chemotherapy (Nachman et al. 2002; Dorff el et al. praclavicular regions. Cobalt 60 units can underdose 2003). A summary of recommended treatment ap- the fi eld edge, and orthovoltage units are absolutely in- proaches for low-, intermediate-, and high-risk disease appropriate. Distances of less than 80 cm are also con- presentations is outlined in Table 3.11. traindicated because of suboptimal depth-dose characteristics. 3.10 Acute Eff ects of Therapy

3.9 Summary Recommendations for 3.10.1 Chemotherapy Side-Eﬀ ects Primary Disease/Selection of Therapy Th e nausea and vomiting associated with chemothera- Multidisciplinary collaboration facilitates optimal py administration for pediatric HL is generally respon- treatment planning. Ideally, the pediatric and radia- sive to serotonin receptor antagonist antiemetics, such tion oncologist should meet at diagnosis and response as ondansetron. Premedication with benzodiazepines evaluations to review diagnostic imaging studies fol- is usually eff ective in controlling anticipatory nausea lowing examination of the patient. Th e treatment ap- that may develop later as therapy progresses. Most proach should consider host factors that may enhance treatment regimens will cause some degree of revers- the risk for specifi c treatment toxicities, as well as dis- ible alopecia. Myelosuppression remains the most ease factors that may permit therapy reduction or re- common dose-limiting acute toxicity of contemporary quire dose intensifi cation. Since patients with low-risk multiagent chemotherapy. Administration of granulo- disease presentations can achieve long-term DFS us- cyte colony stimulating factor support prevents treating regimens that do not contain alkylators, ABVD or ment delays and facilitates maintenance of chemother- derivative chemotherapy is preferred for this group. apy dose intensity. Hospitalization for antimicrobial An alternative strategy is to add alkylating agents or therapy for febrile neutropenia and blood product etoposide to the regimen, which may preserve cardiac transfusion is occasionally required. Varicella zoster function by reducing anthracycline cumulative dosage infections are quite common during and aft er therapy without compromising disease control. Combined for HL, with a frequency that has been directly related modality treatment regimens using limited cycles of to the intensity of treatment (Reboul et al. 1978). combination chemotherapy and low-dose, involved- Several agents, including nitrogen mustard, vincris- fi eld radiation therapy have produced excellent results tine, vinblastine, and doxorubicin, may result in local in pediatric patients with low-risk disease. Combina- tissue damage if subcutaneous tissue extravasation oc- 60 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

Table 3.11 Recommended treatment approaches in pediatric Hodgkin lymphoma

Clinical presentation Recommended treatment approach

Low risk: Recommended therapy: Localized disease (stage I or II) 2−4 cycles non-cross-resistant chemotherapy without < 3–4 involved nodal regions without B symptoms, alkylators plus low-dose, involved-ﬁ eld radiation lymph node bulka or extranodal extension of disease (15–25 Gy) from contiguous lymph node structures Other considerations: 6 cycles non-cross-resistant chemotherapy alone In clinical trial setting only: 4 cycles of chemotherapy alone

Intermediate risk: Recommended therapy: Localized disease (stage I or II) with 4–6 cycles non-cross-resistant chemotherapy plus low- > 3–4 involved nodal regions, lymph node bulka, dose, involved-ﬁ eld radiation (15–25 Gy) extranodal extension of disease from contiguous lymph Other considerations: node structures 6–8 cycles non-cross-resistant chemotherapy alone Some stage IIBb disease (e. g., sweats only) Stage IIIA disease

High risk: Recommended therapy: Some stage IIBb disease (e. g., fever or weight loss) 6–8 cycles of non-cross-resistant chemotherapy plus Stage IIIB low-dose, involved-ﬁ eld radiation (15–25 Gy) Stage IVA/B Other considerations: 8 cycles non-cross-resistant chemotherapy alone

a Mediastinal bulk defi ned as ratio of measurement of diameter of mediastinal mass to maximum intrathoracic cavity at the dome of the diaphragm of > 33%; other lymph node defi ned as lymph node mass > 6–10 cm. b Stage IIB patients have been variably treated as intermediate or unfavorable risk. Some studies use associated factors, e. g., weight loss, bulk disease, extranodal extension, for further risk stratifi cation.

curs during administration. Vinca alkaloids (vincris- Bleomycin administration causes acute, largely a tine, vinblastine) comprise an important component symptomatic, pulmonary toxicity that can be detected of contemporary, dose-intensive, multiagent chemo- on formal pulmonary function testing. Bleomycin can therapy programs. Peripheral neuropathy commonly be withheld following acute declines of 20% or more in develops when these agents are given on a weekly spirometry or diff usion without compromising out- schedule for an extended period of time. Gabapentin come (Hudson et al. 1993). A substantial proportion of may be helpful in managing severe or refractory pain these abnormalities will improve or resolve during fol- or paresthesias associated with sensory neuropathy. low-up aft er completion of therapy (Marina et al. Motor neuropathy universally results in temporary 1995). Acute cardiac toxicity associated with anthracy- loss of deep tendon refl exes. In cases with progressive cline agents like doxorubicin rarely occurs with the motor dysfunction, e. g., foot drop or hoarseness as- restricted doses of these agents prescribed in contem- sociated with vocal cord paralysis, vinca alkaloid ther- porary regimens. Periodic screening of cardiac func- apy should be withheld until there is an improvement tion is recommended aft er completion of therapy be- in the neurologic function, at which time administra- cause subclinical cardiac injury may become more tion of a reduced dose should be considered. Auto- clinically signifi cant in aging survivors (see Chapter nomic neuropathy associated with vinca alkaloid ther- 12). apy may cause severe constipation/obstipation; aggressive supportive care is essential to prevent this complication. Treatment of Pediatric Hodgkin Lymphoma Chapter 3 61

3.10.2 Radiation Side-Eﬀ ects response to EBV (Rooney et al. 1995) or to the tumor are also being considered. With such approaches, it Th e radiation doses used in contemporary combined may be possible to achieve the goal of optimal response modality treatment protocols are generally well toler- without enhanced toxicity. ated. Premedication with antiemetics controls nausea and vomiting and permits the patient an excellent quality of life during treatment. Transient skin eff ects References may include mild erythema or hyperpigmentation. Adams J (2001) Proteasome inhibition in cancer: develop- Depending on the extent of the cervical treatment ment of PS-341. Semin Oncol 28(6): 613–9 fi elds, patients may experience a transient occipital al- Adams MJ, Lipshultz SE et al (2003) Radiation-associated opecia, mild dysphagia, xerostomia, and taste altera- cardiovascular disease: manifestations and management. tions. Because treatment fi elds are limited to involved Semin Radiat Oncol 13(3): 346–56 Adams MJ, Lipsitz SR et al (2004) Cardiovascular status in nodal regions, declines in blood counts are relatively long-term survivors of Hodgkin’s disease treated with uncommon unless the disease extent requires total chest radiotherapy. J Clin Oncol 22(15): 3139–48 nodal irradiation. Even in those cases, anemia, granu- Atra A, Higgs E et al (2002) ChlVPP chemotherapy in chil- locytopenia, and thrombocytopenia most oft en refl ect dren with stage IV Hodgkin’s disease: results of the bone marrow suppression from prior chemotherapy UKCCSG HD 8201 and HD 9201 studies. Br J Haematol 119(3): 647–51 and uncommonly require interventions like transfu- Bader SB, Weinstein H et al (1993) Pediatric stage IV Hodg- sion or colony-stimulating growth factor support. A kin disease. Long-term survival. Cancer 72(1): 249–55 rare subacute eff ect of mantle radiation is a transient Baez F, Ocampo E et al (1997) Treatment of childhood myelopathy (Lhermitte’s syndrome) that may produce Hodgkin’s disease with COPP or COPP-ABV (hybrid) a sensation of an electric shock radiating down the without radiotherapy in Nicaragua. Ann Oncol 8(3): 247–50 back and into the extremities on fl exion of the neck. Baker LL, Parker BR et al (1990) Staging of Hodgkin disease Th is condition, which is uncommon following radia- in children: comparison of CT and lymphography with tion doses below 30 to 35 Gy, is self-limited and re- laparotomy. AJR Am J Roentgenol 154(6): 1251–5 solves without neurologic sequelae. In general, acute Bar-Shalom R, Yefremov N et al (2003) Camera-based FDG radiation eff ects are mild and reversible. PET and 67Ga SPECT in evaluation of lymphoma: com- parative study. Radiology 227(2): 353–60 Bargou RC, Leng C et al (1996) High-level nuclear NF-kappa B and Oct-2 is a common feature of cultured Hodgkin/ 3.11 Future Directions Reed-Sternberg cells. Blood 87(10): 4340–7 Behrendt H, Brinkhuis M et al (1996) Treatment of child- HL has been curable for many decades. Th e long his- hood Hodgkin’s disease with ABVD without radiotherapy. Med Pediatr Oncol 26(4): 244–8 tory of successful treatments have led to many survi- Behrendt H, Van Bunningen BN et al (1987) Treatment of vors. From them we have learned the toxicity of our Hodgkin’s disease in children with or without radiothera- therapies. In this next millennium, we hope to learn to py. Cancer 59(11): 1870–3 cure with minimal toxicity. Better paradigms of care Bhatia S, Yasui Y et al (2003) High risk of subsequent neo- will be our initial steps toward this goal, but ultimately plasms continues with extended follow-up of childhood Hodgkin’s disease: report from the Late Eff ects Study it will be the biologic understanding of HL that will Group. J Clin Oncol 21(23): 4386–94 allow for the development of more effi cacious and less Bierman PJ, Lynch JC et al (2002) Th e International Prog- toxic therapies. Understanding aberrant pathways of nostic Factors Project score for advanced Hodgkin’s dis- cell death, particularly abnormal apoptotic pathways ease is useful for predicting outcome of autologous hema- attributable to constitutive activation of NF-κB, may topoietic stem cell transplantation. Ann Oncol 13(9): 1370–7 allow targeted therapies that may enhance the response Bohlen H, Kessler M et al (2000) Poor clinical outcome of pa- (Bargou et al. 1996). Early trials using proteasome in- tients with Hodgkin’s disease and elevated interleukin-10 hibitors have been initiated (Adams 2001). Immuno- serum levels. Clinical signifi cance of interleukin-10 serum modulatory approaches designed to enhance the T-cell levels for Hodgkin’s disease. Ann Hematol 79(3): 110–3 62 Chapter 3 Melissa M. Hudson • Cindy Schwartz • Louis S. Constine

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