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Childhood Hodgkin Lymphoma Treatment (PDQ®)

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Treatment for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma

Historical Overview of Treatment for Hodgkin Lymphoma

Long-term survival has been achieved in children and adolescents with Hodgkin lymphoma using radiation, multiagent chemotherapy, and combined-modality therapy. In selected cases of localized lymphocyte-predominant Hodgkin lymphoma, complete surgical resection may be curative and obviate the need for cytotoxic therapy.

Treatment options for children and adolescents with Hodgkin lymphoma include the following:

  1. Radiation therapy as a single modality.
    • Recognition of the excess adverse effects of high-dose radiation therapy on musculoskeletal development in children motivated investigations of multiagent chemotherapy alone or with lower radiation doses (15–25.5 Gy) to reduced treatment volumes (involved-fields) and multiagent chemotherapy. It also led to the abandonment of the use of radiation as a single modality and restriction of its use in contemporary trials.[1-3]
    • Recognition of the excess risk of cardiovascular disease and secondary carcinogenesis in adult survivors who were treated for Hodgkin lymphoma during childhood led to the restriction of radiation therapy as a single modality in contemporary trials.[4,5]
  2. Multiagent chemotherapy as a single modality.
    • The establishment of the noncross-resistant combinations of MOPP (mechlorethamine, vincristine [Oncovin], procarbazine, and prednisone) developed in the 1960s and ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine) developed in the 1970s made long-term survival possible for patients with advanced and unfavorable (e.g., bulky, symptomatic) Hodgkin lymphoma.[6,7] MOPP-related sequelae include a dose-related risk of infertility and secondary myelodysplasia and leukemia.[2,8] The use of MOPP-derivative regimens substituting less leukemogenic and gonadotoxic alkylating agents (e.g., cyclophosphamide) for mechlorethamine or restricting cumulative alkylating agent dose exposure reduces this risk.[9] ABVD-related sequelae include a dose-related risk of cardiopulmonary toxicity related to doxorubicin and bleomycin. The cumulative dose of these agents is proactively restricted in pediatric patients to reduce this risk.[10-12]
    • In an effort to reduce chemotherapy-related toxicity, hybrid regimens alternating MOPP and ABVD or derivative therapy were developed that utilized lower total cumulative doses of alkylators, doxorubicin, and bleomycin.[13,14]
    • Etoposide has been incorporated into treatment regimens as an effective alternative to alkylating agents in an effort to reduce gonadal toxicity and enhance antineoplastic activity.[15] Etoposide-related sequelae include an increased risk of secondary myelodysplasia and leukemia that appears to be rare when etoposide is used in restricted doses in pediatric Hodgkin lymphoma regimens.[16]
    • All of the agents in original MOPP and ABVD regimens continue to be used in contemporary pediatric treatment regimens. COPP (substituting cyclophosphamide for mechlorethamine) has almost uniformly replaced MOPP as the preferred alkylator regimen in most frontline trials.
  3. Radiation therapy and multiagent chemotherapy as a combined-modality therapy. Considerations for the use of multiagent chemotherapy alone versus combined-modality therapy include the following:
    • Treatment with noncross-resistant chemotherapy alone offers advantages for children managed in centers lacking radiation facilities and trained personnel, as well as diagnostic imaging modalities needed for clinical staging. This treatment option also avoids the potential long-term growth inhibition, organ dysfunction, and solid tumor induction associated with radiation.
    • Chemotherapy-alone treatment protocols usually prescribe higher cumulative doses of alkylating agent and anthracycline chemotherapy, which may produce acute- and late-treatment morbidity from myelosuppression, cardiac toxic effects, gonadal injury, and secondary leukemia.
    • 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. The results of prospective and controlled randomized trials indicate that combined modality therapy, compared with chemotherapy alone, produces a superior event-free survival (EFS). However, because of effective second-line therapy, overall survival (OS) has not differed among the groups studied.[17,18]

Treatment Approaches

Contemporary treatment for pediatric Hodgkin lymphoma uses a risk-adapted and response-based paradigm that assigns the length and intensity of therapy based on disease-related factors such as stage, number of involved nodal regions, tumor bulk, the presence of B symptoms, and early response to chemotherapy by functional imaging. Age, gender, and histological subtype may also be considered in treatment planning.

Risk designation

  • Favorable clinical features include localized nodal involvement in the absence of B symptoms and bulky disease. Risk factors considered in other studies include the number of involved nodal regions, the presence of hilar adenopathy, the size of peripheral lymphadenopathy, and extranodal extension.[19]
  • Unfavorable clinical features include the presence of B symptoms, bulky mediastinal or peripheral lymphadenopathy, extranodal extension of disease, and advanced (stages IIIB–IV) disease.[19] Bulky mediastinal lymphadenopathy is designated when the ratio of the maximum measurement of mediastinal lymphadenopathy to intrathoracic cavity on an upright chest radiograph equals or exceeds 33%.
  • Localized disease (stages I, II, and IIIA) with unfavorable features may be treated similarly to advanced-stage disease in some treatment protocols or treated with therapy of intermediate intensity.[19]
  • Inconsistency in risk categorization across studies often makes comparison of study outcomes challenging.

Risk-adapted treatment paradigms

  • No single treatment approach is ideal for all pediatric and young adult patients because of the differences in age-related developmental status and gender-related sensitivity to chemotherapy toxicity.
  • The general treatment strategy that is used to treat children and adolescents with Hodgkin lymphoma is chemotherapy for all patients, with or without radiation. 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.
  • Ongoing trials for patients with favorable disease presentations are evaluating the effectiveness of treatment with fewer cycles of combination chemotherapy alone that limit doses of anthracyclines and alkylating agents.
  • Contemporary trials for patients with intermediate/unfavorable disease presentations are testing if chemotherapy and radiation therapy can be limited in patients who achieve a rapid early response to dose-intensive chemotherapy regimens.
  • Gender-based regimens consider that male patients are more vulnerable to gonadal toxicity from alkylating agent chemotherapy and that female patients have a substantial risk of breast cancer after chest radiation.

Histology-based therapy (stage I nodular lymphocyte-predominant Hodgkin lymphoma)

Histological subtype may direct therapy in patients with stage I completely resected, nodular lymphocyte-predominant Hodgkin lymphoma, whose initial treatment may be surgery alone.

This treatment approach is supported by the following findings from the literature:

  • Both children and adults treated for nodular lymphocyte-predominant Hodgkin lymphoma have a favorable outcome, particularly when the disease is localized (stage I), as it is for most patients.[20-23]
  • Death among long-term survivors of nodular lymphocyte-predominant Hodgkin lymphoma is more likely to result from treatment-related toxicity (both acute and long-term) than death from lymphoma.[24,25]
  • Although standard therapy for children with nodular lymphocyte-predominant Hodgkin lymphoma 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 one trial of 52 nodular lymphocyte-predominant Hodgkin lymphoma patients who were treated with chemotherapy alone, the 5-year EFS was 96%.[23][Level of evidence: 1iiDi] Surgical resection of localized disease produces a prolonged disease-free survival in a substantial proportion of patients obviating the need for immediate cytotoxic therapy.[21,22,26] Recurrence after surgical resection has not been associated with significant upstaging or histological transformation to a more aggressive B-cell lymphoma.[21]

A summary of treatment approaches for nodular lymphocyte-predominant Hodgkin lymphoma can be found in Table 8.

Radiation Therapy

As discussed in the previous sections, most newly diagnosed children will be treated with risk-adapted chemotherapy alone or in combination with consolidative radiation therapy (RT). RT volumes can have variable and protocol-specific definitions, but generally encompass lymph node regions initially involved at the time of diagnosis, without extensive inclusion of uninvolved regions. RT field reductions are made to account for tumor regression with chemotherapy.[27]

Volume considerations

With advancements in systemic therapy, RT field definitions have evolved and become increasingly restricted. RT is no longer needed to sterilize all disease. Advancements in radiologic imaging allow more precise radiation target definition. Historically, concerns about the symmetry of growth in young children with unilateral disease involvement often prompted treatment of the contralateral tissues. With contemporary treatments utilizing 15 to 21 Gy, treatment of contralateral uninvolved sites is not necessary in all but perhaps the very young.

General trends in radiation treatment volume are summarized as follows:

  • Total nodal and regional RT fields have largely been replaced by IFRT (see Table 3).
  • Targeted therapy, which involves restricting RT to areas of initial bulky disease (generally defined as ≥5 cm at the time of disease presentation) or postchemotherapy residual disease (generally defined as ≥2.5 cm or residual positron emission tomography [PET] avidity), is under investigation (COG-AHOD0831).
  • Involved-nodal RT, introduced by the European Organization for Research and Treatment of Cancer Lymphoma Group and the Groupe d'Etude des Lymphomes de l'Adulte, remains investigational, although initial clinical data are emerging.[28-30] This approach defines the treatment volume using the prechemotherapy PET–computed tomography (CT) scan that is obtained with the patient positioned in a similar manner to the position that will be used at the time of RT. This volume is later contoured onto the postchemotherapy-planning CT scan. The final treatment volume only includes the initially involved nodes with a margin, typically 2 cm.
  • Involved-site RT is an evolving approach to be used for patients when optimal prechemotherapy imaging (PET-CT in a position similar to what will be used at the time of RT) is not available to the radiation oncologist. Because the delineation of the area of involvement is less precise, a somewhat larger treatment volume is contoured for RT, specifically the whole site where the lymphoma was located before chemotherapy was given. The exact size of this volume will depend on the individual case scenario.
Table 3. Sample Definitions of Sites and Corresponding Involved-Field Radiation Therapy Treatment Fieldsa
Involved Node(s)Radiation Field
aAdapted from Terezakis et al.[31]
bUpper cervical region is not treated if supraclavicular involvement is an extension of the mediastinal disease.
cPrechemotherapy volume is treated except for lateral borders of the mediastinal field.
CervicalNeck and/or supraclavicularb/infraclavicular
SupraclavicularSupraclavicular/infraclavicular and lower neck
AxillaAxilla ± supraclavicular/infraclavicular
MediastinumMediastinum, hila, and infraclavicular/supraclavicularb,c
HilaHila, mediastinum
SpleenSpleen ± para-aortic
Para-aorticPara-aortic ± spleen
IliacIliac, inguinal, femoral
InguinalExternal iliac, inguinal, femoral
FemoralExternal iliac, inguinal, femoral

A breast-sparing radiation-therapy plan using proton therapy is being evaluated to determine if there is a statistically significant reduction in dose.[32] Long-term results are awaited.

Considerations in IFRT Treatment Planning

Traditional definitions of lymph node regions can be helpful for defining IFRT but may not be sufficient. The following issues should be considered in IFRT treatment planning:

  • In early-stage Hodgkin lymphoma, the definition of IFRT depends on the anatomy of the region in terms of lymph node distribution and patterns of disease extension into regional areas; protocol-specific RT fields in early-stage Hodgkin lymphoma may be even more restricted.
  • Because patients with early-stage Hodgkin lymphoma frequently relapse in initially involved lymph nodes, it may be prudent to reduce treatment fields to include only the initially involved lymph node(s).
  • Cervical and supraclavicular 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 supraclavicular 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. The decision to treat the axilla or mediastinum without the supraclavicular lymph nodes and to treat the inguinal nodes without the iliac nodes may be appropriate, depending on the size and distribution of involved nodes at presentation.
  • The hila are sometimes irradiated when the mediastinum is involved, even though the hila and mediastinum are separate lymph node regions.
  • The treatment volume for unfavorable or advanced disease is somewhat variable and often protocol-specific. Large-volume RT may compromise organ function and limit the intensity of second-line therapy if relapse occurs. In patients with intermediate or advanced disease, who often have multifocal/extranodal disease, the current standard of therapy includes postchemotherapy IFRT that limits radiation exposure to large portions of the body.[14,33]
  • A single-institution review of 53 Hodgkin lymphoma patients found that PET-CT information resulted in changing the IFRT design in 17% of patients, with most receiving more radiation.[34]

Radiation dose

The dose of radiation is also variously defined and often protocol specific. General considerations regarding radiation dose include the following:

  • Doses of 15 to 25 Gy are typically used, with modifications based on patient age, the presence of bulky or residual (postchemotherapy) disease, and normal tissue concerns.
  • Some protocols have prescribed a boost of 5 Gy in regions with suboptimal response to chemotherapy.[33]

Technical considerations

Technical considerations for the use of radiation therapy to treat Hodgkin lymphoma include the following:

  • 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.
  • Individualized immobilization devices are preferable for young children to ensure accuracy and reproducibility.
  • 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. Possible indications for whole-heart irradiation (~10 Gy) are pericardial involvement, as suggested by a large pericardial effusion or frank pericardial invasion with tumor.
  • Whole-lung irradiation (~10 Gy), with partial transmission blocks, are a consideration in the setting of overt pulmonary nodules.[33,35,36] For example, the GPOH HD-95 trial administered ipsilateral whole-lung RT to patients who had not achieved a complete response (CR) in the lungs to the first two cycles of chemotherapy.[33] COG-9425 and COG-AHOD0031 used whole-lung RT in patients with pulmonary nodules at diagnosis, with the latter protocol randomly assigning some patients on the basis of response.
  • While CT-based 2-dimensional radiation therapy remains the standard technique for radiation delivery in pediatric Hodgkin lymphoma, 3-dimensional conformal radiation therapy (3-D CRT) or intensity-modulated radiation therapy (IMRT) may be considered in situations where the more conformal techniques would reduce dose to surrounding normal critical structures (e.g., when treating the thorax to spare dose to the heart, lungs, and developing breast tissue, or when treating the abdomen and pelvis to minimize dose to the highly radiosensitive reproductive organs).
  • Data are accumulating in regard to the efficacy of IMRT and the decrease in median dose to normal surrounding tissues. Some uncertainty exists about the potential for increased late effects from IMRT, particularly secondary malignancy, because with IMRT, a larger area of the body receives a low dose compared with conventional techniques (although the mean dose to a volume may be decreased).
  • Proton therapy is currently being investigated and may further decrease the mean dose to the surrounding normal tissue compared with IMRT or 3-D CRT, without increasing the volume of normal tissue receiving lower-dose radiation.

Role of LD-IFRT in childhood and adolescent Hodgkin lymphoma

Because all children and adolescents with Hodgkin lymphoma receive chemotherapy, a question commanding significant attention is whether patients who achieve a rapid early response or a CR to chemotherapy require RT. Conversely, the judicious use of LD-IFRT may permit a reduction in the intensity or duration of chemotherapy below toxicity thresholds that would not be possible if single modality chemotherapy were used, thus decreasing overall acute and late toxicities.

Key points to consider in regard to the role of radiation in pediatric Hodgkin lymphoma include the following:

  • The treatment approach for pediatric Hodgkin lymphoma should focus on maximizing treatment efficacy and minimizing risks for late toxicity associated with both RT and chemotherapy.
  • The use of LD-IFRT in pediatric Hodgkin lymphoma permits reduction in duration or intensity of chemotherapy and thus dose-related toxicity of anthracyclines, alkylating agents, and bleomycin that may preserve cardiopulmonary and gonadal function and reduce the risk of secondary leukemia.
  • Radiation has been used as an adjunct to multiagent chemotherapy in clinical trials for intermediate/high-risk pediatric Hodgkin lymphoma with the goal of reducing risk of relapse in initially involved sites and preventing toxicity associated with second-line therapy.
  • Compared with chemotherapy alone, adjuvant radiation produces a superior EFS for children with intermediate/high-risk Hodgkin lymphoma who achieve a CR to multiagent chemotherapy, but it does not affect OS because of the success of second-line therapy.[17,18] Adjuvant radiation therapy may be associated with excess late effects or mortality.[37]
  • Radiation consolidation may facilitate local disease control in individuals with refractory/recurrent disease, especially in those who have limited or bulky sites of disease progression/recurrence, or persistent disease that does not completely respond to chemotherapy.[38]

Additionally, when considering the role of RT in the initial management of Hodgkin lymphoma, one must carefully consider the endpoint that is being evaluated. Unlike most other pediatric malignancies, Hodgkin lymphoma is often salvageable if initial treatment does not result in a CR or if relapse occurs. For example, studies comparing combination chemotherapy with or without RT in adults with advanced-stage Hodgkin lymphoma showed that EFS was higher for patients who received initial chemotherapy and RT; however, OS was no different for patients whose initial therapy was chemotherapy alone.[39] Among adult Hodgkin lymphoma patients, study results conflict regarding whether adjuvant RT improves OS compared with chemotherapy alone, despite an improvement in EFS, because of the ability to effectively salvage patients who relapse after initial therapy.[40] Thus, it is not clear whether EFS or OS should be the appropriate endpoint for a trial comparing chemotherapy with or without radiation.

Finally, an inherent assumption is 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. However, it is not clear how histology, presence of bulky disease, presence of B symptoms, or other variables affect the efficacy of postchemotherapy radiation.

Chemotherapy

All of the agents in original MOPP and ABVD regimens continue to be used in contemporary pediatric treatment regimens. COPP (substituting cyclophosphamide for mechlorethamine) has almost uniformly replaced MOPP as the preferred alkylator regimen in most frontline trials. Etoposide has been incorporated into treatment regimens as an effective alternative to alkylating agents in an effort to reduce gonadal toxicity and enhance antineoplastic activity.

Combination chemotherapy regimens used in contemporary trials are summarized in Table 4.

Table 4. Contemporary Chemotherapy Regimens for Children and Adolescents with Hodgkin Lymphoma
NameDrugsDosageRouteDays
IV = intravenous; PO = oral.
COPP [41]Cyclophosphamide600 mg/m2IV1, 8
Vincristine (Oncovin)1.4 mg/m2IV1, 8
Procarbazine100 mg/m2PO1–15
Prednisone40 mg/m2PO1–15
COPDAC [41]Dacarbazine substituted for procarbazine in COPP250 mg/m2IV1–3
OPPA [41]Vincristine (Oncovin)1.5 mg/m2IV1, 8, 15
Procarbazine100 mg/m2PO1–15
Prednisone60 mg/m2PO1–15
Doxorubicin (Adriamycin)40 mg/m2IV1, 15
OEPA [41]Vincristine (Oncovin)1.5 mg/m2IV1, 8, 15
Etoposide125 mg/m2IV3–6
Prednisone60 mg/m2PO1–15
Doxorubicin (Adriamycin)40 mg/m2IV1, 15
ABVD [7]Doxorubicin (Adriamycin)25 mg/m2IV1, 15
Bleomycin10 U/m2IV1, 15
Vinblastine6 mg/m2IV1, 15
Dacarbazine375 mg/m2IV1, 15
COPP/ABV [14]Cyclophosphamide600 mg/m2IV0
Vincristine (Oncovin)1.4 mg/m2IV0
Procarbazine100 mg/m2PO0–6
Prednisone40 mg/m2PO0–13
Doxorubicin (Adriamycin)35 mg/m2IV7
Bleomycin10 U/m2IV7
Vinblastine6 mg/m2IV7
VAMP [42]Vinblastine6 mg/m2IV1, 15
Doxorubicin (Adriamycin)25 mg/m2IV1, 15
Methotrexate20 mg/m2IV1, 15
Prednisone40 mg/m2PO1–14
DBVE [43,44]Doxorubicin25 mg/m2IV1, 15
Bleomycin10 U/m2IV1, 15
Vincristine (Oncovin)1.5 mg/m2IV1, 15
Etoposide100 mg/m2IV1–5
ABVE-PC [35]Doxorubicin (Adriamycin)30 mg/m2IV0, 1
Bleomycin10 U/m2IV0, 7
Vincristine (Oncovin)1.4 mg/m2IV0, 7
Etoposide75 mg/m2IV0–4
Prednisone40 mg/m2PO0–9
Cyclophosphamide800 mg/m2IV0
BEACOPP [45]Bleomycin10 U/m2IV7
Etoposide200 mg/m2IV0–2
Doxorubicin (Adriamycin)35 mg/m2IV0
Cyclophosphamide1200 mg/m2IV1, 8
Vincristine (Oncovin)2 mg/m2IV7
Prednisone40 mg/m2PO0–13
Procarbazine100 mg/m2PO0–6
CVP [46]Cyclophosphamide500 mg/m2IV1
Vinblastine6 mg/m2IV1, 8
Prednisolone40 mg/m2PO1–8

Results from selected clinical trials

North American cooperative and consortium trials

The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy utilizing ABVE (doxorubicin [Adriamycin], bleomycin, vincristine, and etoposide) [44] for favorable low-stage patients and dose-dense ABVE-PC (prednisone and cyclophosphamide) for unfavorable advanced-stage patients in combination with 21 Gy IFRT.[35]

Key findings from these trials include the following:

  • Children and adolescents with low-risk Hodgkin lymphoma (stages I, IIA, IIIA1) treated with IFRT (25.5 Gy) after complete response to two cycles of DBVE (doxorubicin, bleomycin, vincristine, and etoposide) had outcomes comparable to those treated with four cycles of DBVE and IFRT (25.5 Gy). This response-dependent approach permitted reduction in chemotherapy exposure in 45% of patients.[44]
  • A dose-dense, early response–based treatment approach with ABVE-PC permitted reduction in chemotherapy exposure in 63% of patients who achieved a rapid early response after three ABVE-PC cycles.[35][Level of evidence: 1iiDi] Five-year EFS was comparable for rapid early responders (86%) and slow early responders (83%) treated with three and five cycles of ABVE-PC, respectively, followed by 21 Gy radiation. Patients who received dexrazoxane had more hematological and pulmonary toxicity.
  • Although etoposide is associated with an increased risk for therapy-related acute myeloid leukemia with 11q23 abnormalities, the risk is very low in those treated with ABVE or ABVE-PC without dexrazoxane.[16,47]

The Children’s Cancer Group (CCG) undertook a randomized controlled trial comparing survival outcomes in children treated with risk-adapted COPP/ABV hybrid chemotherapy alone with those treated with COPP/ABV hybrid chemotherapy plus LD-IFRT.[14] The study was closed early because of a significantly higher number of relapses among patients treated with chemotherapy alone. Long-term results include the following:[14,17]

  • Among patients who achieved a CR to initial therapy, the projected 10-year EFS (in an as-treated analysis) was 91% for those randomly assigned to receive LD-IFRT and 83% for those randomly assigned to receive no further therapy.
  • Estimates for OS did not differ between the randomized groups as a result of successful treatment after relapse (10-year OS rates were 97% for IFRT and 96% for no further therapy in the as-treated analysis).

Another CCG Study (COG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP regimen followed by a gender-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[45][Level of evidence: 2Dii] For rapid early responding girls, an additional four courses of COPP/ABV (without IFRT) were given. Rapid early responding boys received two cycles of ABVD followed by IFRT. Slow early responders received four additional courses of BEACOPP and IFRT. Eliminating IFRT from the girl's therapy was intended to reduce the risk of breast cancer. Key findings from this trial include the following:[45]

  • Rapid early response (defined by resolution of B symptoms and >70% reduction in tumor volume) was achieved by 74% of patients after four cycles of BEACOPP.[45]
  • The 5-year EFS was 94% with a median follow-up time of 6.3 years.
  • Results support that early intensification followed by less intense response-based therapy results in high EFS.

The Stanford, St. Jude Children's Research Hospital, and Boston Consortium administered a series of risk-adapted trials over the last 20 years. Key findings include the following:

  • Substitution of nonalkylating agent chemotherapy (e.g., methotrexate or etoposide) as an alternative to alkylating agent chemotherapy results in an inferior EFS among patients with unfavorable clinical presentations.[48,49]
  • The combination of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) is an effective regimen (10-year EFS, 89%) for favorable-risk (low stage without B symptoms or bulky disease) children and adolescents with Hodgkin lymphoma when used in combination with response-based LD-IFRT (15–25.5 Gy).[42]
  • Patients with favorable-risk Hodgkin lymphoma treated with four cycles of VAMP chemotherapy alone who achieve an early CR have a comparable 5-year EFS to those treated with four cycles of VAMP chemotherapy plus 25.5 Gy IFRT (89% vs. 88%).[50]
German multicenter trials

In the last 30 years, German investigators have implemented a series of risk-adapted trials evaluating gender-based treatments featuring multiagent chemotherapy with OPPA/COPP and IFRT.

Key findings from these trials include the following:

  • Substitution of cyclophosphamide for mechlorethamine in the MOPP combination results in a low risk of secondary myelodysplasia/leukemia.[9]
  • Omission of procarbazine from the OPPA combination and substitution of methotrexate for procarbazine in the COPP combination (OPA/COMP) results in a substantially inferior EFS.[51]
  • Substitution of etoposide for procarbazine in the OPPA combination (OEPA) in boys produces comparable EFS to that of girls treated with OPPA and is associated with hormonal parameters, suggesting lower risk of gonadal toxicity.[52]
  • Omission of radiation for patients completely responding to risk- and gender-based OEPA or OPPA/COPP chemotherapy results in a significantly lower EFS in intermediate- and high-risk patients compared with irradiated patients (79% vs. 91%), but no difference among nonirradiated and irradiated patients assigned to the favorable-risk group.[18]
  • Substitution of dacarbazine for procarbazine (OEPA-COPDAC) in boys produces comparable results to standard OPPA-COPP in girls when used in combination with IFRT for intermediate- and high-risk patients.[41][Level of evidence: 2A]

Accepted Risk-Adapted Treatment Strategies for Newly Diagnosed Children and Adolescents with Hodgkin Lymphoma

Contemporary trials for pediatric Hodgkin lymphoma involve a risk-adapted, response-based treatment approach that titrates the length and intensity of chemotherapy and dose of radiation based on disease-related factors including stage, number of involved nodal regions, tumor bulk, the presence of B symptoms, and early response to chemotherapy as determined by functional imaging. In addition, vulnerability related to age and gender is also considered in treatment planning.

Classical Hodgkin lymphoma low-risk disease

Table 5. Low-Risk Disease (Stages I–IIA; No Bulky Disease; No B Symptoms)
Chemotherapy (No. of Cycles)aRadiation (Gy)Stage No. of PatientsEvent-Free Survival (No. of Years of Follow-up)Survival (No. of Years of Follow-up)
CS = clinical stage; IFRT = involved-field radiation therapy; N/A = not applicable; No. = number.
aRefer to Table 4 for more information about the chemotherapy regimens.
bWithout bulky mediastinal (defined as one-third or more of intrathoracic ratio measured on an upright posteroanterior chest radiograph) or peripheral lymphadenopathy (defined as 6 cm or more) or B symptoms.
cWithout adverse features, defined as one or more of the following: hilar adenopathy, involvement of more than four nodal regions; mediastinal tumor with diameter equal to or larger than one-third of the chest diameter, and node or nodal aggregate with a diameter larger than 10 cm.
dResults from as-treated analysis.
VAMP (4) [42]IFRT (15–25.5)CS I/IIb11089% (10)96% (10)
VAMP (4) [50]IFRT (25.5)CS I/IIb4188% (5)100% (5)
None4789% (5)
COPP/ABV (4) [14,17]IFRT (21)CS IA/B, IIAc94100% (10)d97% (10)d
None11389% (10)d96% (10)d
OEPA/OPPA (2) [18]IFRT (20–35)I, IIA28194% (5)N/A
None11397% (5)
ABVE (2-4) [44]IFRT (25.5)IA, IIA, IIIA15191% (6)98% (6)

Classical Hodgkin lymphoma intermediate-risk disease

Table 6. Intermediate-Risk Disease (All Stage I and Stage II Patients Not Classified as Early Stage; Stage IIIA)
Chemotherapy (No. of Cycles)aRadiation (Gy)Stage No. of PatientsEvent-Free Survival (No. of Years of Follow-up)Survival (No. of Years of Follow-up)
CS = clinical stage; E = extralymphatic; IFRT = involved-field radiation therapy; N/A = not applicable.
aRefer to Table 4 for more information about the chemotherapy regimens.
bWith adverse disease features, defined as one or more of the following: hilar adenopathy, involvement of more than four nodal regions; mediastinal tumor with diameter equal to or larger than one-third of the chest diameter, and node or nodal aggregate with a diameter larger than 10 cm.
cResults from as-treated analysis.
COPP/ABV (6) [17]IFRT (21)CS I/IIb, CS IIB, CS III10384% (10)c100% (3)
None12278% (10)c
OEPA/OPPA (2) + COPP (2) [18]IFRT (20–35)IIEA, IIB, IIIA21292% (5)N/A
OEPA/OPPA (2) + COPDAC (2) [41]IFRT (20–35)IE, IIB, IIEA, IIIA13988.3% (5)98.5% (5)
ABVE-PC (3–5) [35]IFRT (21)IB, IIA, IIIA5384% (5)95% (5)

Classical Hodgkin lymphoma high-risk disease

Table 7. High-Risk Disease (Stages IIIB, IVB)
Chemotherapy (No. of Cycles)aRadiation (Gy)Stage No. of PatientsEvent-Free Survival (No. of Years of Follow-up)Survival (No. of Years of Follow-up)
E = extralymphatic; IFRT = involved-field radiation therapy; N/A = not applicable; No. = number; RER = rapid early response; SER = slow early response.
aRefer to Table 4 for more information about the chemotherapy regimens.
OEPA/OPPA (2) + COPP (4) [18]IFRT (20–35)IIEB, IIIEA/B, IIIB, IVA/B26591% (5)N/A
OEPA/OPPA (2) + COPDAC (4) [41]IFRT (20–35)IIEB, IIIEA/B, IIIB, IVA/B23986.9% (5)94.9% (5)
ABVE-PC (3-5) [35]IFRT (21)IB, IIA, IIIA16385% (5)95% (5)
BEACOPP (4); COPP/ABV (4) (RER; girls) [45]NoneIIB, IIIB, IV3894% (5)97% (5)
BEACOPP (4); ABVD (2) (RER; boys) [45]IFRT (21)IIB, IIIB, IV34
BEACOPP (8) (SER) [45]IFRT (21)IIB, IIIB, IV25

Nodular lymphocyte-predominant Hodgkin lymphoma

The use of combination chemotherapy and/or radiation therapy can achieve excellent long-term progression-free survival and OS in patients with nodular lymphocyte-predominant Hodgkin lymphoma.[23,53,54] Late recurrences have been reported and are typically responsive to re-treatment. Because deaths observed among individuals with this histological subtype are more frequently related to complications from cytotoxic therapy, risk-adapted treatment assignment is particularly important for limiting exposure to agents with established dose-related toxicities.[53,54] Table 8 summarizes the results of contemporary treatment approaches used for nodular lymphocyte-predominant Hodgkin lymphoma, some of which feature surgery alone for completely resected disease and limited cycles of chemotherapy with or without low-dose IFRT. Because of the relative rarity of this subtype, most trials are limited by small cohort numbers and nonrandom allocation of treatment.

Table 8. Nodular Lymphocyte-Predominant Hodgkin Lymphoma
Chemotherapy (No. of Cycles)aRadiation (Gy)No. of PatientsEvent-Free Survival (No. of Years of Follow-up)Survival (No. of Years of Follow-up)
IFRT = involved-field radiation therapy; N/A = not applicable; No. = number.
aRefer to Table 4 for more information about the chemotherapy regimens.
bAllocation to radiation therapy or no radiation therapy based on response to therapy.
cAllocation based on clinical response.
dAll involved lymph nodes surgically resected.
COPP/ABV (4)b [23]None5296% (5)100% (5)
IFRT (21)29100% (5)
CVP (3) [46]None5574% (5)100% (5)
VAMP (4)c [50]None2687.5% (5)N/A
IFRT (25)6
VAMP (4) [42]IFRT (15–25.5)33100% (10)100% (10)
Noned [21]None5167% (2)100% (2)
DBVE (2–4)c [44]None2694% (8)100% (8)
IFRT (25.5)

Treatment of Adolescents and Young Adults with Hodgkin Lymphoma

The treatment approach used for adolescents and young adults with Hodgkin lymphoma may vary based on community referral patterns and age restrictions at pediatric cancer centers. In patients with high-risk disease, the standard of care in medical oncology practices typically involves at least six cycles of ABVD chemotherapy that would deliver a cumulative anthracycline dose of 300 mg/m2.[55,56] In late-health outcomes studies of pediatric cancer survivors, the risk of anthracycline cardiomyopathy has been shown to exponentially increase after exposure to cumulative anthracycline doses of 250 mg/m2 to 300 mg/m2.[57,58] Subsequent need for mediastinal radiation can further enhance the risk of a variety of late cardiac events.[57-59] In an effort to optimize disease control and preserve both cardiac and gonadal function, pediatric regimens for low-risk disease most often feature a restricted number of cycles of ABVD or derivative combinations, whereas alkylating agents and etoposide are integrated into anthracycline-containing regimens for those with intermediate- and high-risk disease.

Participation in a clinical trial should be considered for adolescent and young adult patients with Hodgkin lymphoma. Information about ongoing clinical trials is available from the NCI Web site.

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, stage II childhood Hodgkin lymphoma, stage III childhood Hodgkin lymphoma and stage IV childhood Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

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

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  • Updated: August 22, 2014