Treatment Approach for Children and Adolescents with Hodgkin Lymphoma

Chemotherapy for Childhood/Adolescent Hodgkin Lymphoma
Radiation Therapy for Children and Adolescents with Hodgkin Lymphoma
        Volume considerations
        Radiation dose
        Technical considerations
        Role of LD-IFRT in childhood and adolescent Hodgkin lymphoma
Accepted Treatment Strategies for Newly Diagnosed Children and Adolescent Patients with Hodgkin Lymphoma
        Nodular lymphocyte-predominant Hodgkin lymphoma
Current Clinical Trials

In general, the use of combined chemotherapy and low-dose involved-field radiation therapy (LD-IFRT) broadens the spectrum of potential toxicities, while reducing the severity of individual drug-related or radiation-related toxicities. Current approaches use chemotherapy with or without LD-IFRT.[1] The volume of radiation and the intensity/duration of chemotherapy are determined by prognostic factors at presentation, including presence of constitutional symptoms, disease stage, and bulk.

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

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

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

Chemotherapy for Childhood/Adolescent Hodgkin Lymphoma

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

Alkylating Agents

• cyclophosphamide
• mechlorethamine
• procarbazine

Vinca Alkaloids

• vincristine
• vinblastine

Steroids

• prednisone
• dexamethasone

Antimetabolites

• methotrexate
• cytosine arabinoside

Other Agents

• doxorubicin
• bleomycin
• dacarbazine
• etoposide

When regimens containing alkylating agents were shown to be associated with an increased risk for therapy-related leukemia,[7] nonalkylator-containing regimens such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) were developed. Doxorubicin, however, is associated with cardiac damage and bleomycin can produce pulmonary fibrosis.[8] Hybrid regimens that utilized lower total cumulative doses of alkylators, doxorubicin, and bleomycin were then developed. The COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, and vinblastine) hybrid is an example of this type of regimen.[9] In an effort to decrease risk for male infertility, etoposide has been substituted for procarbazine in the initial courses of therapy in studies of the German pediatric Hodgkin lymphoma group and dacarbazine for procarbazine in subsequent courses.[10]; [11][Level of evidence: 2A] In the GPOH-HD-2002 ¹ study, the 5-year overall survival (OS) was 97% and event-free survival (EFS) was 89%, with no difference in outcome between boys and girls.[11] ABVE (doxorubicin [Adriamycin], bleomycin, vincristine, and etoposide) and ABVE-PC (prednisone and cyclophosphamide) have been used in Pediatric Oncology Group (POG) trials.[12]; [13][Level of evidence: 1iiDi] Although etoposide is associated with an increased risk for therapy-related acute myeloid leukemia (AML) with 11q23 abnormalities,[14] the risk is very low in those treated with ABVE or ABVE-PC without dexrazoxane.[15] Procarbazine is no longer used in frontline Hodgkin lymphoma trials by the Children's Oncology Group (COG) due to its long-term gonadal toxicity in males.

Investigators have evaluated a regimen of vincristine, doxorubicin, methotrexate, and prednisone (VAMP) to treat children and adolescents with Hodgkin lymphoma.[16] Results were good for patients with low-stage disease without B symptoms or bulky disease. VAMP combined with COP (cyclophosphamide, vincristine, and procarbazine) was inadequate for the treatment of patients with advanced disease.[17]

Certain protocols have used dexrazoxane with doxorubicin in an effort to lower cardiopulmonary toxicity.[18]; [13][Level of evidence: 1iiDi] There remains controversy about the risk of treatment-related AML (tAML) in Hodgkin lymphoma patients receiving dexrazoxane concurrent with etoposide.[12,19] Listed below (Table 1) are the combination chemotherapy regimens that have been utilized for children and young adults with Hodgkin lymphoma.

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

Chemotherapy Regimen	Corresponding Agents
ABVD [20]	doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine
ABVE [15]	doxorubicin (Adriamycin), bleomycin, vincristine, etoposide
VAMP [16]	vincristine, doxorubicin (Adriamycin), methotrexate, prednisone
OPPA +/- COPP (females) [11,21]	vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine
OEPA +/- COPP (males) [21]; OEPA +/- COPDAC (males)[11]	vincristine (Oncovin), etoposide, prednisone, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine, dacarbazine
COPP/ABV [9]	cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin), bleomycin, vinblastine
BEACOPP (advanced stage) [22]	bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine
COP(P) (with or without prednisone)	cyclophosphamide, vincristine (Oncovin), ± prednisone, procarbazine
CHOP	cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin), prednisone
ABVE-PC [13]	doxorubicin (Adriamycin), bleomycin, vincristine, etoposide, prednisone, cyclophosphamide
MOPP/ABV [23]	mechlorethamine, vincristine (Oncovin), procarbazine, prednisone, doxorubicin (Adriamycin), bleomycin, vinblastine

Radiation Therapy for Children and Adolescents with Hodgkin Lymphoma

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

Volume considerations

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

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

Field definition for radiation therapy in unfavorable and advanced Hodgkin lymphoma is variable and protocol dependent. Although IFRT remains the standard when patients are treated with combined modality therapy, restricting radiation therapy to areas of initial bulk disease (generally defined as ≥5 cm at the time of disease presentation) or postchemotherapy residual disease (generally defined as ≥2 cm or more, or residual positron emission tomography [PET] avidity), is under investigation. The rationale for this is to limit radiation exposure to large portions of the body in patients who often have multifocal disease, including organ invasion. Large-volume radiation therapy can compromise organ function and may limit the intensity of retrieval therapy if relapse occurs. However, as previously stated, the current standard of therapy does include postchemotherapy IFRT for patients with intermediate or advanced disease based on data from the Children's Cancer Study Group [9] and the German-Austrian Childhood Hodgkin studies.[21]

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

Table 2. Sample Definitions of Sites and Corresponding Radiation Treatment Fields^a

Involved Node(s)	Radiation Field
Cervical	Neck and infraclavicular/supraclavicularb
Supraclavicular	Neck and infraclavicular/supraclavicular ± axilla
Axilla	Axilla ± infraclavicular/supraclavicular
Mediastinum	Mediastinum, hila, infraclavicular/supraclavicularb,c
Hila	Hila, mediastinum
Spleen	Spleen ± para-aortics
Para-aortics	Para-aortics ± spleen
Iliac	Ipsilateral iliac ± inguinal + femoral
Inguinal	Inguinal + femoral ± iliac
Femoral	Inguinal + femoral ± iliac

aAdapted from Hudson.[24]

bUpper cervical region not treated if supraclavicular involvement is extension of the mediastinal disease.

cPrechemotherapy volume is treated except for lateral borders of the mediastinal field, which is postchemotherapy.

Radiation dose

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

Technical considerations

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

Role of LD-IFRT in childhood and adolescent Hodgkin lymphoma

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

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

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

In the last decade, two major pediatric trials [9,21] have evaluated the utility of LD-IFRT in the treatment of Hodgkin lymphoma. A trial of the former Children’s Cancer Group (CCG) for children and adolescents with Hodgkin lymphoma compared outcome in patients who achieved an initial CR with chemotherapy followed by LD-IFRT or no further therapy. CR was defined as an absence of residual tumor or residual tumor that showed a reduction in size of 70% or more since diagnosis and a change from gallium positivity to gallium negativity for initial gallium-positive lesions.[9] Patients received risk-adapted chemotherapy (stages I–III, COPP/ABV; stage IV, more intensive therapy). The EFS for the 829 eligible patients was 85% at 5 years. CR was obtained in 83% of patients. Five hundred-one patients were randomized to receive LD-IFRT or no further therapy. In an as-treated analysis, 3-year EFS was 93% ± 1.7% for patients receiving LD-IFRT, and 85% ± 2.3% for patients receiving no further therapy. Three-year survival for patients treated with and without LD-IFRT was 98% and 99%, respectively.[9]

In 1995, the GPOH initiated a study to assess the effect on EFS and OS of eliminating radiation for all patients achieving complete resolution of disease following chemotherapy.[21] Radiation dose was determined by extent of disease reduction following completion of chemotherapy. Twenty-three percent of patients achieved a CR, defined as complete resolution of all disease. Sixty-two percent of patients achieved a PR (>75% but <95% disease reduction) and received 20 Gy of radiation (30 Gy if <75% disease reduction). More relapses occurred in patients who achieved a CR and received no radiation (21/222, 9.5%) than in patients who achieved a PR and received radiation (43/758, 5.7%). Overall EFS was 92% for patients receiving radiation and 88% for those receiving no radiation (P = .05). For patients with stage IA, IB, and IIA Hodgkin lymphoma who achieved a CR after chemotherapy, EFS was 97%, which is similar to the EFS of 94% in patients achieving a PR who then received radiation therapy. For all other patients, however, EFS after CR to chemotherapy was 79%, compared with 91% for patients who achieved a PR and then received radiation therapy (P = .01). For both groups, survival was 97%.[21,26] In both the German GPOH-95 and CCG-5942 ⁴ studies, the benefit of radiation therapy on EFS was greater in patients with advanced-stage disease at presentation.

In an attempt to decrease long-term toxicity, the POG used a dose-dense, early response–based treatment approach with ABVE-PC and 21 Gy of radiation to involved regions for intermediate- and high-risk Hodgkin lymphoma patients.[13][Level of evidence: 1iiDi] Those with a rapid early response ([RER] 50% or more reduction of sum of the products of perpendicular diameters of lesions) had three cycles of chemotherapy, then received radiation therapy. Slow early responders (SER) had two additional cycles of chemotherapy before radiation therapy. The 5-year EFS was 84% for intermediate-risk and 85% for high-risk Hodgkin lymphoma patients with no difference in outcomes for RER versus SER patients. Patients with large mediastinal masses had a lower EFS (80%) versus those without (91%). Stage IV patients had a 77.8% EFS versus 92% for all others. These patients were also randomly assigned to receive or to not receive dexrazoxane. Patients who received dexrazoxane had more hematologic and pulmonary toxicity. The dose-dense application of ABVE-PC allowed 63% of patients (RER) to have less chemotherapy exposure. Further follow-up will be needed to determine if long-term toxicities differ between those receiving three versus five cycles of ABVE-PC.

OS of patients who receive chemotherapy alone may be similar to that for patients who receive both chemotherapy and LD-IFRT, despite a difference in EFS. This results from the ability to effectively salvage patients who relapse after initial therapy.[9,21,25] If this potential can be accomplished with relatively nontoxic salvage therapy, then initial treatment with less-intense therapy may be appropriate. If, however, salvage therapy results in a substantial risk for late events such as cardiac failure or secondary malignancies, less-intense initial therapy would be unwise. Thus, it will be important to evaluate prognostic factors that may influence the magnitude of the EFS benefit that derives from the use of LD-IFRT in patients achieving a CR to initial chemotherapy. In the German study, the benefit of radiation therapy was greater in patients with advanced-stage disease at presentation. Other potential prognostic factors may include histology, erythrocyte sedimentation rate, bulk disease, and presence of symptoms.

Accepted Treatment Strategies for Newly Diagnosed Children and Adolescent Patients with Hodgkin Lymphoma

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

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

• VAMP × 4 plus LD-IFRT.[16]
• COPP/ABV hybrid × 4 plus LD-IFRT.[9]
• ABVE × 2 to 4 and LD-IFRT (2 vs. 4 cycles based on early response).[15]
• OEPA (males) or OPPA (females) × 2 and LD-IFRT (German studies suggest that these patients may not require radiation therapy if a CR is obtained).[21,26]

Event-free survival (EFS) rate: Approximately 92%.[9,15,16,21,26]

Overall survival (OS) rate: Approximately 98%.[9,15,16,21,26]

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

• COPP/ABV × 6 plus LD-IFRT.[9]
• ABVE-PC × 3 or 5 plus LD-IFRT (3 vs. 5 cycles based on early response).[13][Level of evidence: 1iiDi]
• OPPA/OEPA × 2; COPP × 2 (girls) or COPDAC x 2 (boys), plus LD-IFRT.[11,21,26]

EFS rate: Approximately 85%.[9,13,21,26]

OS rate: Approximately 93%.[9,13,21,26]

High-Risk Disease (stages IIIB, IVB)

• ABVE-PC × 3 or 5 plus LD-IFRT (3 vs. 5 cycles based on early response).[13][Level of evidence: 1iiDi]
• Intensive chemotherapy with cytarabine/etoposide, COPP/ABV or CHOP (2 cycles of each) plus LD-IFRT.[9]
• OPPA/OEPA × 2; COPP × 4 (girls) or COPDAC x 4 (boys), plus LD-IFRT.[11,21,26]

EFS rate: Approximately 83%.[9,13,21,26]

OS rate: Approximately 94%.[9,13,21,26]

Nodular lymphocyte-predominant Hodgkin lymphoma

Both children and adults treated for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) have a favorable outcome, particularly when the disease is localized (stage I), as it is for most patients.[27-32] A retrospective study that included 210 adults with NLPHL found that only 8 of 32 deaths in these patients could be attributed directly to Hodgkin lymphoma, with most of the remaining deaths being the result of treatment-related toxicity (both acute and long-term).[28] Thus, for both adults and children, treatment for NLPHL focuses on reducing initial therapy to reduce long-term treatment-related morbidity and mortality.

Although standard therapy for children with NLPHL is chemotherapy plus LD-IFRT, there are reports in which patients have been treated with chemotherapy alone or with complete resection of isolated nodal disease without chemotherapy. In a series of 31 adult patients treated with surgery alone, there were seven deaths (median follow-up 7 years), but only one death resulted from Hodgkin lymphoma.[33] In another series, 15 of 24 patients with surgery alone relapsed, but all achieved a subsequent remission with radiation and/or chemotherapy. Only two patients died (one from NLPHL).[34] In a single-institution pediatric experience, six patients with stage I NLPHL treated with surgery alone remained disease free.[30] The largest experience in children with NLPHL treated with resection alone was reported by the European Network Group on Pediatric Hodgkin Lymphoma. In this report of 58 children, survival was 100% with a median follow-up of 43 months. The overall progression-free survival rate in children who achieved CR with surgery was 67% (however, the follow-up is relatively short), while all seven patients with residual disease after initial surgery developed recurrences. Importantly, significant upstaging at recurrence and histologic transformation to a more aggressive B-cell lymphoma were not observed among patients with stage IA disease treated initially with only resection.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I childhood Hodgkin lymphoma ⁵, stage II childhood Hodgkin lymphoma ⁶, stage III childhood Hodgkin lymphoma ⁷ and stage IV childhood Hodgkin lymphoma ⁸. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁹.

References

1. Schwartz CL: The management of Hodgkin disease in the young child. Curr Opin Pediatr 15 (1): 10-6, 2003.  [PUBMED Abstract]
   
   
2. Bhatia S, Robison LL, Oberlin O, et al.: Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 334 (12): 745-51, 1996.  [PUBMED Abstract]
   
   
3. Hancock SL, Donaldson SS, Hoppe RT: Cardiac disease following treatment of Hodgkin's disease in children and adolescents. J Clin Oncol 11 (7): 1208-15, 1993.  [PUBMED Abstract]
   
   
4. Thomson AB, Wallace WH: Treatment of paediatric Hodgkin's disease. a balance of risks. Eur J Cancer 38 (4): 468-77, 2002.  [PUBMED Abstract]
   
   
5. Hudson MM, Donaldson SS: Treatment of pediatric Hodgkin's lymphoma. Semin Hematol 36 (3): 313-23, 1999.  [PUBMED Abstract]
   
   
6. Oberlin O: Present and future strategies of treatment in childhood Hodgkin's lymphomas. Ann Oncol 7 (Suppl 4): 73-8, 1996.  [PUBMED Abstract]
   
   
7. Kaldor JM, Day NE, Clarke EA, et al.: Leukemia following Hodgkin's disease. N Engl J Med 322 (1): 7-13, 1990.  [PUBMED Abstract]
   
   
8. Mefferd JM, Donaldson SS, Link MP: Pediatric Hodgkin's disease: pulmonary, cardiac, and thyroid function following combined modality therapy. Int J Radiat Oncol Biol Phys 16 (3): 679-85, 1989.  [PUBMED Abstract]
   
   
9. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002.  [PUBMED Abstract]
   
   
10. Gerres L, Brämswig JH, Schlegel W, et al.: The effects of etoposide on testicular function in boys treated for Hodgkin's disease. Cancer 83 (10): 2217-22, 1998.  [PUBMED Abstract]
    
    
11. Mauz-Körholz C, Hasenclever D, Dörffel W, et al.: Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. J Clin Oncol 28 (23): 3680-6, 2010.  [PUBMED Abstract]
    
    
12. Tebbi CK, London WB, Friedman D, et al.: Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol 25 (5): 493-500, 2007.  [PUBMED Abstract]
    
    
13. Schwartz CL, Constine LS, Villaluna D, et al.: A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 114 (10): 2051-9, 2009.  [PUBMED Abstract]
    
    
14. Smith MA, Rubinstein L, Anderson JR, et al.: Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17 (2): 569-77, 1999.  [PUBMED Abstract]
    
    
15. Tebbi CK, Mendenhall N, London WB, et al.: Treatment of stage I, IIA, IIIA1 pediatric Hodgkin disease with doxorubicin, bleomycin, vincristine and etoposide (DBVE) and radiation: a Pediatric Oncology Group (POG) study. Pediatr Blood Cancer 46 (2): 198-202, 2006.  [PUBMED Abstract]
    
    
16. Donaldson SS, Link MP, Weinstein HJ, et al.: Final results of a prospective clinical trial with VAMP and low-dose involved-field radiation for children with low-risk Hodgkin's disease. J Clin Oncol 25 (3): 332-7, 2007.  [PUBMED Abstract]
    
    
17. Hudson MM, Krasin M, Link MP, et al.: Risk-adapted, combined-modality therapy with VAMP/COP and response-based, involved-field radiation for unfavorable pediatric Hodgkin's disease. J Clin Oncol 22 (22): 4541-50, 2004.  [PUBMED Abstract]
    
    
18. Tebbi C, Schwartz C, London W, et al.: Hematologic effects of dexrazoxane used with DBVE regimen for treatment of early-stage Hodgkin's disease in children. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-083, 49, 2001. 
    
    
19. Cvetković RS, Scott LJ: Dexrazoxane : a review of its use for cardioprotection during anthracycline chemotherapy. Drugs 65 (7): 1005-24, 2005.  [PUBMED Abstract]
    
    
20. Behrendt H, Brinkhuis M, Van Leeuwen EF: Treatment of childhood Hodgkin's disease with ABVD without radiotherapy. Med Pediatr Oncol 26 (4): 244-8, 1996.  [PUBMED Abstract]
    
    
21. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.  [PUBMED Abstract]
    
    
22. Kelly KM, Hutchinson RJ, Sposto R, et al.: Feasibility of upfront dose-intensive chemotherapy in children with advanced-stage Hodgkin's lymphoma: preliminary results from the Children's Cancer Group Study CCG-59704. Ann Oncol 13 (Suppl 1): 107-11, 2002.  [PUBMED Abstract]
    
    
23. Chow LM, Nathan PC, Hodgson DC, et al.: Survival and late effects in children with Hodgkin's lymphoma treated with MOPP/ABV and low-dose, extended-field irradiation. J Clin Oncol 24 (36): 5735-41, 2006.  [PUBMED Abstract]
    
    
24. Hudson M, Constine LS: Hodgkin's disease. In: Halperin EC, Constine LS, Tarbell NJ, et al.: Pediatric Radiation Oncology. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2004, pp 223-60. 
    
    
25. Loeffler M, Brosteanu O, Hasenclever D, et al.: Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group. J Clin Oncol 16 (3): 818-29, 1998.  [PUBMED Abstract]
    
    
26. Dörffel W, Lüders H, Rühl U, et al.: Preliminary results of the multicenter trial GPOH-HD 95 for the treatment of Hodgkin's disease in children and adolescents: analysis and outlook. Klin Padiatr 215 (3): 139-45, 2003 May-Jun.  [PUBMED Abstract]
    
    
27. Nogová L, Reineke T, Brillant C, et al.: Lymphocyte-predominant and classical Hodgkin's lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol 26 (3): 434-9, 2008.  [PUBMED Abstract]
    
    
28. Diehl V, Sextro M, Franklin J, et al.: Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease. J Clin Oncol 17 (3): 776-83, 1999.  [PUBMED Abstract]
    
    
29. Mauz-Körholz C, Gorde-Grosjean S, Hasenclever D, et al.: Resection alone in 58 children with limited stage, lymphocyte-predominant Hodgkin lymphoma-experience from the European network group on pediatric Hodgkin lymphoma. Cancer 110 (1): 179-85, 2007.  [PUBMED Abstract]
    
    
30. Murphy SB, Morgan ER, Katzenstein HM, et al.: Results of little or no treatment for lymphocyte-predominant Hodgkin disease in children and adolescents. J Pediatr Hematol Oncol 25 (9): 684-7, 2003.  [PUBMED Abstract]
    
    
31. Sandoval C, Venkateswaran L, Billups C, et al.: Lymphocyte-predominant Hodgkin disease in children. J Pediatr Hematol Oncol 24 (4): 269-73, 2002.  [PUBMED Abstract]
    
    
32. Hall GW, Katzilakis N, Pinkerton CR, et al.: Outcome of children with nodular lymphocyte predominant Hodgkin lymphoma - a Children's Cancer and Leukaemia Group report. Br J Haematol 138 (6): 761-8, 2007.  [PUBMED Abstract]
    
    
33. Miettinen M, Franssila KO, Saxén E: Hodgkin's disease, lymphocytic predominance nodular. Increased risk for subsequent non-Hodgkin's lymphomas. Cancer 51 (12): 2293-300, 1983.  [PUBMED Abstract]
    
    
34. Hansmann ML, Zwingers T, Böske A, et al.: Clinical features of nodular paragranuloma (Hodgkin's disease, lymphocyte predominance type, nodular). J Cancer Res Clin Oncol 108 (3): 321-30, 1984.  [PUBMED Abstract]