jueves, 6 de junio de 2019

Childhood Hodgkin Lymphoma Treatment (PDQ®) 4/6 —Health Professional Version - National Cancer Institute

Childhood Hodgkin Lymphoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute
National Cancer Institute

Childhood Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version


Treatment of 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) and reduced treatment volumes (involved-fields). It also led to the abandonment of the use of radiation as a single modality in skeletally immature children.[1-3]
    • Radiation therapy alone may rarely be considered for adolescents and young adults with nodular lymphocyte-predominant Hodgkin lymphoma.
    • Recognition of the excess risk of cardiovascular disease and subsequent neoplasm in adult survivors who were treated for Hodgkin lymphoma during childhood led to the restriction of radiation therapy 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 subsequent 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.[10-12] The cumulative dose of these agents is proactively restricted in pediatric patients to reduce this risk.
    • 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 subsequent 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. Contemporary trials have utilized procarbazine-free standard backbone regimens, such as ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide) in North America [17,18] and OEPA (vincristine, etoposide, prednisone, doxorubicin)-COPDAC (cyclophosphamide, vincristine, prednisone, dacarbazine) in Europe.[19] Both of these regimens represent dose-dense regimens that use six drugs to maximize intensity without exceeding thresholds of toxicity.
  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 in developing countries 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 subsequent leukemia. However, more recent trials are designed to significantly reduce these risks, especially in those with chemotherapy-responsive disease.[17]
    • In general, the use of combined chemotherapy and low-dose involved-site radiation therapy (LD-ISRT) 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.[20,21]

Contemporary Approaches to Treatment of Hodgkin Lymphoma

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 and anatomic imaging. Age, sex, and histological subtype may also be considered in treatment planning.
Treatment options for childhood Hodgkin lymphoma include the following:
  1. Radiation therapy.
  2. Chemotherapy.

Risk designation

Risk designation depends on favorable and unfavorable clinical features, as follows:
  • Favorable clinical features. These 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.[22]
  • Unfavorable clinical features. These features include the presence of B symptoms, bulky mediastinal or peripheral lymphadenopathy, extranodal extension of disease, and advanced (stages IIIB–IV) disease.[22] In most clinical trials, 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%.
    Pleural effusions have been shown to be an adverse prognostic finding in patients treated for low-stage Hodgkin lymphoma.[23][Level of evidence: 2A] The risk of relapse was 25% in patients with an effusion, as opposed to less than 15% in patients without an effusion. Patients with effusions were more often older (15 years vs. 14 years) and had nodular-sclerosing histology.
    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.[22]
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 sex-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. The primary exception to this strategy is in patients with nodular lymphocyte-predominant Hodgkin lymphoma when surgical resection has been advocated for stage I disease with a single resectable node in the United States [24] and for any resectable disease in Europe.[25]
    • Sex-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 irradiation. However, the cardiovascular risk to males after chest irradiation suggests that limiting radiation exposure is also desirable in males.[26]
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, alkylating agents, and radiation therapy. Contemporary trials for patients with intermediate/unfavorable disease presentations are testing whether chemotherapy and radiation therapy can be limited in patients who achieve a rapid early response to dose-intensive chemotherapy regimens; trials are also testing the efficacy of regimens integrating novel, potentially less-toxic agents such as brentuximab vedotin.

Histology-based therapy

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.[24]
Evidence (surgery alone for localized nodular lymphocyte-predominant Hodgkin lymphoma):
  1. Although standard therapy for children with nodular lymphocyte-predominant Hodgkin lymphoma is chemotherapy plus LD-ISRT, there are reports in which patients have been treated with chemotherapy alone or with complete resection of isolated nodal disease without chemotherapy. Surgical resection of localized disease produces a prolonged disease-free survival in a substantial proportion of patients obviating the need for immediate cytotoxic therapy.[24,25,27,28]
  2. Results from a single-arm Children's Oncology Group (COG) trial provide data to support the strategy of observation after surgical resection and treatment with limited chemotherapy for children with favorable stage IA or IIA Hodgkin lymphoma.[24][Level of evidence: 1iiDi]
    • Among 178 patients treated with surgical resection alone for single-node disease (n = 52), chemotherapy alone after complete response (CR) to three cycles of AV-PC (doxorubicin, vincristine, prednisone, and cyclophosphamide) chemotherapy (n = 115), or chemotherapy with low-dose involved-field radiation therapy (LD-IFRT) (21 Gy) after incomplete response to AV-PC chemotherapy (n = 11), the 5-year EFS was 85.5%, and the OS was 100%.
    • Five-year EFS was 77% for patients observed after total resection and 88.8% for patients treated with AV-PC chemotherapy.
Advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma is very rare, and there is no consensus regarding the optimal treatment, although outcomes for patients are excellent.
Evidence (chemotherapy for nodular lymphocyte-predominant Hodgkin lymphoma with unfavorable characteristics):
  1. In a retrospective review of 41 cases of advanced-stage nodular lymphocyte-predominant Hodgkin lymphoma, many different chemotherapy regimens were used, some included rituximab.[29][Level of evidence: 3iiiA]
    • OS was 98%, with the only death resulting from a subsequent neoplasm.
  2. In a retrospective analysis, 97 intermediate-risk patients with lymphocyte-predominant Hodgkin lymphoma were treated on COG study AHOD0031 (NCT00025259).[30]
    • These patients demonstrated a higher CR rate than did patients with classical histology; the 5-year EFS was marginally superior in patients with lymphocyte-predominant Hodgkin lymphoma (91.2%) than in patients with classical Hodgkin lymphoma (83.2%).
    • Most patients treated with four cycles of the ABVE-PC regimen achieved a rapid early response with a CR status and demonstrated excellent EFS and OS without IFRT. This finding suggests that the dose-dense, response-based protocol therapy designed for patients with classical Hodgkin lymphoma may have been more intensive than necessary for patients with lymphocyte-predominant Hodgkin lymphoma.
A summary of treatment approaches for nodular lymphocyte-predominant Hodgkin lymphoma can be found in Table 9. 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.[24,25,27,31] Among long-term survivors of nodular lymphocyte-predominant Hodgkin lymphoma, death is more likely to result from treatment-related toxicity (both acute and long-term) than from lymphoma.[32,33]
Mixed-cellularity Hodgkin lymphoma
In addition to variable responses by histology for lymphocyte-predominant Hodgkin lymphoma, differences by mixed-cellularity histology have also been observed. COG investigators reported a 4-year EFS rate of 95.2% for children with stage I or stage II mixed-cellularity histology treated with minimal AV-PC therapy (and only rarely requiring radiation therapy), which was significantly better than the 75.8% EFS rate for patients who had nodular-sclerosing histology (P = .008).[34]

Radiation Therapy

As previously discussed, most newly diagnosed children will be treated with risk-adapted chemotherapy alone or in combination with consolidative radiation therapy. Radiation therapy 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. Radiation therapy field reductions are made to account for tumor regression with chemotherapy.[35]

Radiation volume

With advancements in systemic therapy, radiation therapy field definitions have evolved and become increasingly restricted. Radiation therapy is no longer needed to sterilize all disease. Advances in radiologic imaging allow more precise radiation target definition. With the use of effective chemotherapy and contemporary treatments using lower radiation doses (<21 and="" are="" contralateral="" gy="" involved-site="" irradiated.="" not="" p="" radiation="" reduced="" sites="" therapy="" uninvolved="" volumes="">
General trends in radiation treatment volume are summarized as follows:
  • Historical regional radiation therapy fields (e.g., mantle, subtotal, or total nodal) have been replaced by involved-nodal radiation therapy (INRT) or ISRT, or rarely, IFRT in select situations such as adolescents and young adults treated with radiation alone for nodular lymphocyte-predominant Hodgkin lymphoma.
  • INRT defines the treatment volume using the prechemotherapy positron emission tomography (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 radiation therapy. 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.[36-38]
  • ISRT, used in contemporary COG trials, is an 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 radiation therapy) 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 than for INRT, typically at least 2 cm around the nodes or region where the lymphoma was located before chemotherapy was given. The exact size of this volume will depend on the individual case scenario.[35]
  • Modified involved-field radiation therapy (mIFRT) is the term used in the EuroNet-PHL-C1 trial to describe treatment volumes that contain the involved lymph node(s) as seen before chemotherapy plus radiation planning margins of 1 cm to 2 cm, depending on the area of involvement. These volumes are comparable to ISRT fields, although the development preceded the widespread availability of CT-based planning. The subsequent EuroNet-PHL-C2 trial employs INRT.
Breast-sparing radiation therapy plans using proton therapy are under evaluation to determine whether there is a statistically significant reduction in dose.[39] Ongoing studies seek to determine whether doses to other critical organs, such as the heart and lungs, can be reduced with proton therapy. Long-term results are awaited.
ISRT or INRT treatment planning
Radiation therapy planning that uses CT scans obtained during the simulation procedure is a requirement for contemporary INRT or ISRT. Fusion of staging imaging (CT or PET-CT) with the planning CT dataset can facilitate delineation of the treatment volume. Radiation therapy planning scans that encompass the full extent of organs at risk (e.g., lungs) are important so that normal tissue exposures can be calculated accurately.
Definitions that are important in planning radiation therapy include the following:
  1. Prechemotherapy or presurgery gross tumor volume (GTV): Imaging abnormalities of nodal or non-nodal tissues at initially involved sites.
  2. Postchemotherapy GTV: Imaging abnormalities at initially involved sites that remain abnormal after chemotherapy.
  3. Postchemotherapy clinical target volume (CTV): Abnormal tissues originally involved with lymphoma, but taking into account the reduction in the axial (transverse) diameter that has occurred with chemotherapy. This delineation requires consideration of the expected routes of disease spread and the quality of pretreatment imaging.
  4. Internal target volume (ITV): ITV encompasses the CTV, with an added margin to account for variation in shape and motion within the patient (e.g., breathing).
  5. Planning target volume (PTV): This encompasses the ITV or CTV and accounts for variation in daily setup for radiation; generally 0.5 cm to 1 cm.
  6. Boost radiation therapy: Some protocols, such as the EuroNet-PHL-C1 protocol, give additional radiation therapy (a boost) to sites with a poor response and/or bulky residual disease after initial chemotherapy. These volumes were determined after completion of all chemotherapy. This approach is sometimes used for patients with residual areas of PET avidity after chemotherapy.
  7. Organ at risk (OAR) determination and dose constraints: Because of the importance of long-term tissue injury after radiation, the dose to normal tissues is kept as low as reasonably achievable while adequately treating the PTV. Some specific organ radiation dose tolerances exist to guide these decisions, and these organs are considered organs at risk.
The treatment volume for unfavorable or advanced disease is somewhat variable and often protocol-specific. Large-volume radiation therapy 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 ISRT that limits radiation exposure to large portions of the body.[14,40]

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 Gy 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 to 10 Gy in regions with suboptimal response to chemotherapy.[40] This approach has not been formally evaluated to quantitate the risk-benefit relationship.

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.
  • Three-dimensional conformal radiation therapy (3-D CRT) or intensity-modulated radiation therapy (IMRT) are standard techniques in the treatment of lymphoma. Appropriate CT-based image guided treatment planning and delivery is standard, preferably with fusion of staging CT and PET imaging with radiation therapy planning CT datasets to delineate the target volumes.[35]
  • 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 subsequent neoplasms, 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.[41]
  • 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 shielding.
  • 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 the chemotherapy used and patient age.
  • Whole-lung irradiation (~10 Gy), with partial transmission blocks or intensity modulation, was historically a consideration in the setting of overt pulmonary nodules that had not achieved a CR.[17,18,40] However, it may be used in exceptional situations.

Role of LD-ISRT 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 radiation therapy. Conversely, the judicious use of LD-ISRT 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.
The treatment approach for pediatric Hodgkin lymphoma should focus on maximizing disease control and minimizing risks of late toxicity associated with both radiation therapy and chemotherapy. Key points to consider in regard to the role of radiation in pediatric Hodgkin lymphoma include the following:
  • The use of LD-IFRT or ISRT 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 subsequent leukemia.
  • Radiation has been used as an adjunct to multiagent chemotherapy in clinical trials for low-, intermediate-, and 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 has, in most studies, produced a superior EFS for children with intermediate-risk and high-risk Hodgkin lymphoma who achieve a CR to multiagent chemotherapy, but it does not clearly improve OS because of the success of second-line therapy.[21]
    However, the intermediate-risk Hodgkin lymphoma study (AHOD0031 [NCT00025259]) did not show a benefit for IFRT in patients who achieved a rapid CR to chemotherapy (defined as >60% reduction in 2-dimensional tumor burden after two cycles and metabolic remission and >80% reduction after four cycles). Four-year EFS was 87.9% for rapid responders who were randomly assigned to IFRT versus 84.3% (P = .11) for rapid responders who were not assigned to IFRT. OS was 98.8% in both groups.[17] In a subset analysis from this study of patients with anemia and bulky limited-stage disease, the EFS was 89.3% for rapid early responder or complete remission patients who received IFRT, compared with 77.9% for patients who did not receive IFRT (P = .019).[42][Level of evidence: 1iiDi]
    Adjuvant radiation therapy may be associated with an increased risk of late effects or mortality.[43]
  • Radiation consolidation may facilitate local disease control in individuals with refractory or 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.[44]
  • The radiation dose to the breast, heart, thyroid, and lung tissue received by patients in contemporary COG trials is 55% to 85% lower than the dose received by survivors analyzed in the Childhood Cancer Survivors Study (CCSS). This should be taken into consideration when estimating the risk of late toxicity associated with modern radiation therapy.[45]
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 trials are summarized in Table 5.
Table 5. Chemotherapy Regimens for Children and Adolescents with Hodgkin Lymphoma
NameDrugsDosageRouteDays
IV = intravenous; PO = oral.
aABVE-PC modifications included reductions of doxorubicin to 25 mg/m2 in all trials and for high-risk Hodgkin lymphoma, use of cyclophosphamide at 600 mg/m2 on days 1 and 2.
COPP [19]Cyclophosphamide600 mg/m2IV1, 8
Vincristine (Oncovin)1.4 mg/m2IV1, 8
Procarbazine100 mg/m2PO1–15
Prednisone40 mg/m2PO1–15
COPDAC [19]Dacarbazine substituted for procarbazine in COPP250 mg/m2IV1–3
OPPA [19]Vincristine (Oncovin)1.5 mg/m2IV1, 8, 15
Procarbazine100 mg/m2PO1–15
Prednisone60 mg/m2PO1–15
Doxorubicin (Adriamycin)40 mg/m2IV1, 15
OEPA [19]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 [46]Vinblastine6 mg/m2IV1, 15
Doxorubicin (Adriamycin)25 mg/m2IV1, 15
Methotrexate20 mg/m2IV1, 15
Prednisone40 mg/m2PO1–14
DBVE [47,48]Doxorubicin25 mg/m2IV1, 15
Bleomycin10 U/m2IV1, 15
Vincristine (Oncovin)1.5 mg/m2IV1, 15
Etoposide100 mg/m2IV1–5
ABVE-PC a[18]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[49]Bleomycin10 U/m2IV7
Etoposide200 mg/m2IV0–2
Doxorubicin (Adriamycin)35 mg/m2IV0
Cyclophosphamide1,200 mg/m2IV1, 8
Vincristine (Oncovin)2 mg/m2IV7
Prednisone40 mg/m2PO0–13
Procarbazine100 mg/m2PO0–6
CVP [50]Cyclophosphamide500 mg/m2IV1
Vinblastine6 mg/m2IV1, 8
Prednisolone40 mg/m2PO1–8
AV-PC [24,34]Doxorubicin (Adriamycin)25 mg/m2IV1, 2
Vincristine1.4 mg/m2; 2.8 mg/m2max doseIV1, 8
Prednisone20 mg/m2PO1–7
Cyclophosphamide600 mg/m2IV1, 2

North American cooperative and consortium trial results

A series of North American trials have evaluated response-based and risk-adapted therapy.
Evidence (response-based and risk-adapted therapy):
  1. The Pediatric Oncology Group organized two trials featuring response-based, risk-adapted therapy utilizing ABVE (doxorubicin [Adriamycin], bleomycin, vincristine, and etoposide) [48] for favorable low-stage patients and dose-dense ABVE-PC (prednisone and cyclophosphamide) for unfavorable advanced-stage patients in combination with 21 Gy IFRT.[18]
    • Children and adolescents with low-risk Hodgkin lymphoma (stages I, IIA, IIIA1) treated with IFRT (25.5 Gy) after CR 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.[48]
    • 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.[18][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.[18]
    • Although etoposide is associated with an increased risk of therapy-related acute myeloid leukemia with 11q23 abnormalities, the risk is very low in those treated with ABVE or ABVE-PC without dexrazoxane.[16,51]
  2. A large COG study (COG-59704) evaluated response-adapted therapy featuring four cycles of the dose-intensive BEACOPP regimen followed by a sex-tailored consolidation for pediatric patients with stages IIB, IIIB with bulky disease, and IV Hodgkin lymphoma.[49][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 girls' therapy was intended to reduce the risk of breast cancer. Key findings from this trial include the following:[49]
    • 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.
    • 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.
    However, infectious complications during therapy and the long-term risks of infertility and subsequent neoplasms undermine this approach as an optimal treatment, particularly in light of new and safe strategies.
  3. 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.[52,53]
    • The combination of vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) is an effective regimen (10-year EFS, 89%) for favorable-risk (low-stage nodular lymphocyte-predominant and classical Hodgkin lymphoma without B symptoms or bulky disease) children and adolescents when used in combination with response-based LD-IFRT (15–25.5 Gy).[46]
    • Patients with favorable-risk Hodgkin lymphoma treated with four cycles of VAMP chemotherapy alone who achieved an early CR had a comparable 5-year EFS to those treated with four cycles of VAMP chemotherapy plus 25.5 Gy IFRT (89% vs. 88%).[54]
  4. The COG AHOD0031 (NCT00025259) study enrolled 1,712 patients in a randomized controlled trial to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. Intermediate-risk Hodgkin lymphoma was defined as Ann Arbor stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulky disease, and IA or IIA with bulky disease. All patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation.[17]
    1. Rapid early responders (defined by CT imaging after two cycles) received two additional ABVE-PC cycles, followed by CR evaluation.
      • Rapid early responders with CR at the end of chemotherapy (based on CT imaging and additionally requiring negative PET or gallium scans) were randomly assigned to receive either IFRT or no additional therapy.
      • Rapid early responders with less than a CR were nonrandomly assigned to IFRT.
    2. Slow early responders were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All slow early responders were assigned to receive IFRT.
    Key 4-year OS and EFS outcomes from this trial include the following:
    • Early response was an important prognostic factor. Overall EFS was 85.0% and significantly (P < .001) higher for rapid early responders (86.9%) than was for slow early responders (77.4%). OS was 97.8% and significantly (P < .001) higher for rapid early responders (98.5%) than was for slow early responders (95.3%).
    • Approximately 45% of patients were rapid early responders and achieved CR by the end of chemotherapy. For this population, EFS did not differ significantly (P= .11) among those who were randomly assigned to IFRT (87.9%) versus no IFRT (84.3%). OS for those receiving IFRT was 98.8% (95% confidence interval [CI], 96.8%–99.5%) and OS for those receiving chemotherapy alone was 98.8% (95% CI, 96.9%–99.6%).
    • Despite achieving rapid early response or CR, stage I or stage II patients with bulky mediastinal adenopathy and anemia had significantly better EFS when randomly assigned to IFRT after four cycles of ABVE-PC.[42]
    • Approximately 20% of patients were slow early responders. For this population, EFS did not differ significantly (P = .11) among those who were randomly assigned to DECA (79.3%) versus no DECA (75.2%).
    • Study results confirm the prognostic significance of early chemotherapy response and support the safety of avoidance of IFRT based on rapid early response with CR by the end of chemotherapy.
    An analysis of patterns of failure among patients who relapsed while enrolled in the AHOD0031 (NCT00025259) study demonstrated that first relapses more commonly occurred within the previously irradiated field and within initially involved sites of disease, including both bulky and nonbulky sites.[55]
  5. The COG AHOD0431 (NCT00302003) study utilized a response-directed treatment strategy for children and adolescents with stage I and stage IIA, nonbulky disease. Chemotherapy sensitivity was assessed by 18F-FDG PET response after three cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy. LD-IFRT (21 Gy) was administered only to patients who did not achieve a complete remission after chemotherapy. The protocol also incorporated a standardized salvage regimen (vinorelbine and ifosfamide plus dexamethasone, etoposide, cisplatin, and cytarabine) for low-risk recurrences (defined as stage I/II, nonbulky disease, regardless of time to relapse) after treatment with chemotherapy alone.[34]
    • At 4 years, OS was 99.6%, with 49.0% in remission after treatment with minimal chemotherapy alone and 88.8% in remission without receiving high-dose chemotherapy with stem cell rescue or more than 21 Gy IFRT.
    • Factors predicting favorable EFS after limited chemotherapy response-based approach included mixed-cellularity histology, low erythrocyte sedimentation rate, and negative 18F-FDG PET after one cycle.

German multicenter trial results

In the last 30 years, German investigators have implemented a series of risk-adapted trials evaluating sex-based treatments featuring multiagent chemotherapy with vincristine, prednisone, procarbazine, and doxorubicin (OPPA)/COPP and IFRT.
Key findings from these trials include the following:
  1. Substitution of cyclophosphamide for mechlorethamine in the MOPP combination results in a low risk of subsequent myelodysplasia/leukemia.[9]
  2. 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.[56]
  3. 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.[57]
  4. Omission of radiation for patients completely responding (defined as complete resolution or only minor residuals in all previously involved regions using clinical examination and anatomic imaging) to risk-based and sex-based OEPA or OPPA/COPP chemotherapy results in a significantly lower EFS in intermediate-risk and high-risk patients than in irradiated patients (79% vs. 91%), but no difference among nonirradiated and irradiated patients assigned to the favorable-risk group.[21]
  5. 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-risk and high-risk patients.[19][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 on the basis of 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 sex is also considered in treatment planning.

Classical Hodgkin lymphoma low-risk disease

Table 6 summarizes the results of treatment approaches used for patients with low-risk Hodgkin lymphoma.
Table 6. Treatment Approaches for Patients With Low-Risk Hodgkin Lymphoma
Chemotherapy (No. of Cycles)aRadiation (Gy)StageNo. 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 5 for more information about the chemotherapy regimens.
bIncluded patients with nodular lymphocyte-predominant Hodgkin lymphoma.
cWithout 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.
dWithout 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.
eResults from as-treated analysis.
VAMP (4)b [46]IFRT (15–25.5)CS I/IIc11089% (10)96% (10)
VAMP (4)b [54]IFRT (25.5)CS I/IIc4188% (5)100% (5)
None4789% (5)
COPP/ABV (4) [14,20]IFRT (21)CS IA/B, IIAd94100% (10)e97% (10)e
None11389% (10)e96% (10)e
OEPA/OPPA (2) [21]IFRT (20–35)I, IIA28194% (5)N/A
None11397% (5)
ABVD [58]IFRT (21–35)I–IV20985% (5)97% (5)
ABVE (2-4)b [48]IFRT (25.5)IA, IIA, IIIA1, without bulky disease5191% (6)98% (6)
AV-PC [34]NoneIA, IIA, without bulky disease27879.9% (4)99.6% (4)
Response-based IFRT (21)

Classical Hodgkin lymphoma intermediate-risk disease

Table 7 summarizes the results of treatment approaches used for patients with intermediate-risk Hodgkin lymphoma.
Table 7. Treatment Approaches for Patients With Intermediate-Risk Hodgkin Lymphoma
Chemotherapy (No. of Cycles)aRadiation (Gy)StageNo. of PatientsEvent-Free Survival (No. of Years of Follow-up)Survival (No. of Years of Follow-up)
CR = complete response; CS = clinical stage; E = extralymphatic; IFRT = involved-field radiation therapy; N/A = not applicable; RER = rapid early response; SER = slow early response.
aRefer to Table 5 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) [20]IFRT (21)CS I/IIb, CS IIB, CS III10384% (10)c100% (3)
None12278% (10)c
OEPA/OPPA (2) + COPP (2) [21]IFRT (20–35)IIEA, IIB, IIIA21292% (5)N/A
OEPA/OPPA (2) + COPDAC (2) [19]IFRT (20–35)IE, IIB, IIEA, IIIA13988.3% (5)98.5% (5)
ABVE-PC (3–5) [18]IFRT (21)IIA/IIIA, if bulky disease5384% (5)95% (5)
ABVE-PC: RER/CR [17]IFRT (21)IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease38087.9% (4)98.8% (4)
ABVE-PC: RER/CR [17]NoneIB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease38284.3% (4)98.8% (4)
ABVE-PC: SER: +DECA [17]IFRT (21)IB, IAE, IIB, IIAE, IIA, IVA, IA, IIA + bulky disease15379.3% (4)96.5% (4)
ABVE-PC: SER: -DECA [17]IFRT (21) 15175.2% (4)94.3% (4)

Classical Hodgkin lymphoma high-risk disease

Table 8 summarizes the results of treatment approaches used for patients with high-risk Hodgkin lymphoma.
Table 8. Treatment Approaches for Patients With High-Risk Hodgkin Lymphoma
Chemotherapy (No. of Cycles)aRadiation (Gy)StageNo. 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 5 for more information about the chemotherapy regimens.
bResults include all treatment strata.
OEPA/OPPA (2) + COPP (4) [21]IFRT (20–35)IIEB, IIIEA/B, IIIB, IVA/B26591% (5)N/A
OEPA/OPPA (2) + COPDAC (4) [19]IFRT (20–35)IIEB, IIIEA/B, IIIB, IVA/B23986.9% (5)94.9% (5)
ABVE-PC (3-5) [18]IFRT (21)IIB, IIIB, IV16385% (5)95% (5)
BEACOPP (4); COPP/ABV (4) (RER; girls) [49]NoneIIB, IIIB, IV3894% (5)b97% (5)b
BEACOPP (4); ABVD (2) (RER; boys) [49]IFRT (21)IIB, IIIB, IV34
BEACOPP (8) (SER) [49]IFRT (21)IIB, IIIB, IV25
Treatment options under clinical evaluation
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following are examples of national and/or institutional clinical trials that are currently being conducted:
  • HLHR13 (NCT01920932) (Adcetris [Brentuximab Vedotin], Combination Chemotherapy, and Radiation Therapy in Treating Younger Patients With Stage IIB, IIIB, and IV Hodgkin Lymphoma): A clinical trial at St. Jude Children’s Research Hospital is evaluating the safety of brentuximab vedotin, etoposide, prednisone, and doxorubicin hydrochloride (two cycles of AEPA) and cyclophosphamide, brentuximab vedotin, prednisone, and dacarbazine (two cycles of CAPDAC), and the efficacy (early CR) after the two cycles of AEPA chemotherapy in high-risk patients with Hodgkin lymphoma (stages IIB, IIIB, IVA, and IVB.) The study will compare EFS in patients with high-risk Hodgkin lymphoma treated with AEPA/CAPDAC with the historical control, unfavorable-risk 2 arm of the St. Jude HOD99 study.
  • AHOD1331 (NCT02166463) (A Randomized Phase III Study of Brentuximab Vedotin [SGN-35] for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma in Children and Adolescents): AHOD1331 is a randomized phase III clinical trial comparing brentuximab vedotin and combination chemotherapy to combination chemotherapy alone in treating younger patients (aged 2 to 18 years) with newly diagnosed high-risk Hodgkin lymphoma. The chemotherapy used with brentuximab vedotin is AVE-PC (doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide). The chemotherapy-alone arm uses the same agents and additionally incorporates bleomycin (ABVE-PC). Patients with bulky mediastinal masses and those patients who remain 18F-FDG PET positive after two cycles receive response-based ISRT.
  • EuroNet-PHL-C2 (NCT02684708) (Second International Inter-Group Study for Classical Hodgkin Lymphoma in Children and Adolescents): EuroNet-PHL-C2 is an international randomized multicenter trial for all first-line classical Hodgkin lymphoma patients younger than 18 years (younger than 25 years in the United Kingdom, Italy, and France) to investigate risk-stratified (defining chemotherapy) and response-adapted (defining radiation therapy) approaches to tailor the amount of treatment to the individual patient and decrease long-term complications. Patients with a negative PET scan (Deauville <4 advanced-stage="" after="" all="" and="" assigned="" be="" between="" chemotherapy="" consolidation="" copdac-28="" cycles="" decopdac-21="" four="" intensified="" intermediate-stage="" li="" not="" oepa="" of="" or="" patients="" radiation="" randomly="" receive="" respectively.="" standard="" therapy.="" two="" will="">

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.[24,59,60] Late recurrences have been reported and are typically responsive to re-treatment. Because deaths observed among individuals with this histological subtype are frequently related to complications from cytotoxic therapy, risk-adapted treatment assignment is particularly important for limiting exposure to agents with established dose-related toxicities.[59,60]
Table 9 summarizes the results of 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 LD-IFRT. Because of the relative rarity of this subtype, most trials are limited by small cohort numbers and nonrandom allocation of treatment.
Results from a single-arm COG trial provide data to support the strategy of observation after surgical resection and treatment with limited chemotherapy for children with favorable-stage IA or IIA Hodgkin lymphoma. Among 178 patients treated with surgical resection alone for single-node disease (n = 52), chemotherapy alone after CR to three cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy (n = 115), or chemotherapy with LD-IFRT (21 Gy) after incomplete response to AV-PC chemotherapy (n = 11), the 5-year EFS was 85.5%, and the OS was 100%. Five-year EFS was 77% for patients observed after total resection and 88.8% for patients treated with AV-PC chemotherapy.[24][Level of evidence: 1iiDi] Retrospective case series report on responses with rituximab alone [61] or in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [62] in adults with nodular lymphocyte-predominant Hodgkin lymphoma; however, pediatric data has not been reported.
Table 9. Treatment Approaches for Patients With 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 5 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.
dSingle lymph node surgically resected.
eAll involved lymph nodes surgically resected.
COPP/ABV (4)b[24]None5296% (5)100% (5)
IFRT (21)29100% (5)
CVP (3) [50]None5574% (5)100% (5)
DBVE (2–4)c[48]None2694% (8)100% (8)
IFRT (25.5)
VAMP (4)c [54]None2689.4% (5)N/A
IFRT (25)685.7% (5)N/A
VAMP (4) [46]IFRT (15–25.5)33100% (10)100% (10)
Noned [24]Noned5277% (5)100% (5)
AV-PC [24]None12485.5% (5)100% (5)
IFRT (21)11
Nonee [25]None5167% (2)100% (2)

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, and the optimal approach is debatable.
In patients with intermediate-risk or high-risk disease, the standard of care in adult oncology practices typically involves at least six cycles of ABVD chemotherapy that would deliver a cumulative anthracycline dose of 300 mg/m2.[63,64] (Refer to the PDQ summary on Adult Hodgkin Lymphoma Treatment for more information.) 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.[65,66] Subsequent need for mediastinal radiation can further enhance the risk of a variety of late cardiac events.[65-67] 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 derivative combinations, whereas alkylating agents and etoposide are integrated into anthracycline-containing regimens for those with intermediate-risk and high-risk disease.
No prospective studies of efficacy or toxicity in adolescent or young adults treated with pediatric versus adult regimens have been reported; however, some secondary analyses have been conducted.[68]
  1. A retrospective review documented the outcomes of patients aged 17 to 22 years treated in the Eastern Cooperative Oncology Group (ECOG) trials E2496 (NCT00003389) or Stanford V versus the COG trial AHOD0031 (NCT00025259).[69][Level of evidence: 3iiiDiii]
    • The 5-year failure-free survival was 68% for the ECOG trial and 81% in the COG trial, with an OS of 89% and 97%, respectively.
    • Limitations of this study include differences in the study populations; more adolescents and young adults aged 17 to 22 years in the E2496 study had stage III or IV disease and B symptoms, whereas more adolescents and young adults aged 17 to 22 years in the AHOD0031 study had bulky disease and received radiation (although with smaller doses than those in E2496). Some of these differences were addressed using a propensity score analysis that confirmed inferior failure-free survival for adolescents and young adults in the E2496 trial than those in the AHOD0031 trial. The study was also not a prospective randomized trial.
  2. A comprehensive review of differences in outcomes between adolescent and young adult patients treated on pediatric versus adult trials was published.[70]
The optimal approach for adolescents and young adults with Hodgkin lymphoma is complicated by critical but understudied variables. Factors such as tumor biology, disease control, supportive care needs, and long-term toxicities in adolescents and young adults with Hodgkin lymphoma remain understudied.
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 website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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