Chemotherapy for Childhood/Adolescent Hodgkin Lymphoma
Radiation Therapy for Children and Adolescents with Hodgkin Lymphoma
        Volume considerations
        Radiation dose
        Technical considerations
        Current 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
Treatment Strategies Under Clinical Investigation for Childhood/Adolescent Hodgkin Lymphoma
        Low-risk classical Hodgkin lymphoma
        Intermediate-risk classical Hodgkin lymphoma
        High-risk classical Hodgkin lymphoma
        Early stage 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.

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

Alkylating Agents

• cyclophosphamide
• mechlorethamine
• procarbazine

Vinca Alkyloids

• 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] non-alkylator-containing regimens such as ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, and dacarbazine) were developed. Doxorubicin, however, is associated with cardiac damage and bleomycin can produce pulmonary fibrosis.[8] Hybrid regimens that utilized lower total cumulative doses of alkylators, doxorubicin, and bleomycin were then developed. The COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone/doxorubicin, bleomycin, and vinblastine) hybrid is an example of this type of regimen.[9] In an effort to decrease risk for male infertility, etoposide has been substituted for procarbazine in the initial courses of therapy in studies of the German pediatric Hodgkin lymphoma group.[10] DBVE (doxorubicin, bleomycin, vincristine, etoposide) and DBVE-PC (prednisone, cyclophosphamide) have been used in Pediatric Oncology Group (POG) trials.[11,12] Although etoposide is associated with an increased risk for therapy-related acute myeloid leukemia (AML) with 11q23 abnormalities,[13] the risk is very low in those treated with DBVE or DBVE-PC without dexrazoxane.[14] Procarbazine is no longer used in frontline Hodgkin lymphoma 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.[15] Results were good for patients with low-stage disease without B symptoms or bulky disease. VAMP combined with COP was inadequate for the treatment of patients with advanced disease.[16]

Certain protocols have used dexrazoxane with doxorubicin in an effort to lower cardiopulmonary toxicity.[12,17] There remains controversy about the risk of treatment-related AML (tAML) in Hodgkin lymphoma patients receiving dexrazoxane concurrent with etoposide.[11,18] Listed below (Table 1) are the combination chemotherapy regimens that have been utilized for children and young adults 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.

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. Multi-leaf 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 5 years of age), 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 post-chemotherapy 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.[20]

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

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.

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 German Pediatric Hematology Oncology (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.

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 event-free survival (EFS) was higher for patients who received initial chemotherapy and radiation therapy. Overall survival (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 [9,20] 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 German Pediatric Oncology and Hematology Group (GPOH) initiated a study to assess the effect on EFS and OS of eliminating radiation for all patients achieving complete resolution of disease following chemotherapy.[20] 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%.[20,26] In both the German GPOH-95 and CCG-5942 studies, the benefit of radiation therapy on EFS was greater in patients with advanced-stage disease at presentation.

Overall survival of patients who receive chemotherapy alone may be similar to that for patients who receive both chemotherapy and LD-IFRT, despite a difference in EFS. This results from the ability to effectively salvage patients who relapse after initial therapy.[9,20,25] 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.

 [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.[15]
• COPP/ABV hybrid × 4 plus LD-IFRT.[9]
• DBVE × 2 to 4 and LD-IFRT (2 vs. 4 cycles based on early response).[14]
• OEPA (males) or OPPA (females) × 2 and LD-IFRT (German studies suggest that these patients may not require radiation therapy if a CR is obtained).[20,26]

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]
• DBVE-PC × 3 or 5 plus LD-IFRT (3 vs. 5 cycles based on early response).[27]
• OPPA/OEPA × 2; COPP × 2 plus LD-IFRT.[20,26]

High-Risk Disease (stages IIIB, IVB)

• DBVE-PC × 3 or 5 plus LD-IFRT (3 vs. 5 cycles based on early response).[12]
• Intensive chemotherapy with cytarabine/etoposide, COPP/ABV or CHOP (2 cycles of each) plus LD-IFRT.[9]
• Escalated dose BEACOPP × 8 plus LD-IFRT.[21]
• OPPA/OEPA × 2; COPP × 4 plus LD-IFRT.[20,26]

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.[28-33] 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).[29] Thus, for both adults and children, treatment for NLPHL focuses on reducing initial therapy to reduce long-term treatment-related morbidity and mortality.

Although current 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.[34] 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).[35] In a single institution pediatric experience, six patients with stage I NLPHL treated with surgery alone remained disease free.[31] 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.

The following are examples of national/international and/or institutional clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

• COG-AHOD0431 : Patients with stage I or IIA and no bulk disease (mediastinal mass <1/3 maximum chest diameter; extramediastinal mass <6 cm) receive three cycles of doxorubicin (Adriamycin), vincristine, prednisone and cyclophosphamide (AVPC). These patients do not receive etoposide or bleomycin. Patients who attain a CR following three cycles of chemotherapy receive no further therapy. Patients with a PR receive LD-IFRT. Patients who relapse after chemotherapy alone and who, at the time of relapse are stage I or IIA without bulk, continue on the study and receive a salvage regimen consisting of alternating courses of ifosfamide / vinorelbine, and dexamethasone, etoposide, cisplatin, and cytosine arabinoside followed by LD-IFRT.



• In the German Pediatric Oncology Group (GPOH) 2003 trial, patients with stage I or IIA disease (regardless of bulk) receive two cycles of either vincristine, etoposide, prednisone, doxorubicin (OEPA- males) or vincristine, procarbazine, prednisone, doxorubicin (OPPA- females). Patients who have a negative PET scan receive no further therapy, while those that are PET scan-positive receive LD-IFRT.

The following are examples of national clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

The COG Intermediate Risk Trial (COG-AHOD0031) (stages I and II with either B symptoms or bulk, stage II AE, stage IIIA and stage IVA) is evaluating early response after two cycles of ABVE-PC to determine subsequent treatment. Response assessment is based solely on anatomic imaging:

• Patients who achieve a rapid response to two cycles of ABVE-PC receive an additional two cycles of the same chemotherapy. Complete responders then are randomized to receive or not receive LD-IFRT. Partial responders receive LD-IFRT. The hypothesis is that rapid response delineates a subgroup of patients who will not require LD-IFRT.



• Patients who show a slow response to two cycles of ABVE-PC are randomized to receive two further cycles of ABVE-PC or two cycles of ABVE-PC and two additional cycles of a noncross-resistant combination (dexamethasone, etoposide, cisplatin, cytarabine [ARA-C] - {DECA}) prior to LD-IFRT. The hypothesis is that additional noncross-resistant chemotherapy prior to LD-IFRT improves EFS for patients with slow initial disease resolution.



• In the GPOH 2003 trial, following OPPA or OEPA, patients in treatment group 2 are randomized to two additional cycles of COPP or COPDIC, in which dacarbazine replaces procarbazine in an effort to reduce gonadal toxicity while maintaining efficacy.[36]



• A consortium of institutions in the United States are evaluating the Stanford V regimen.

The following are examples of national clinical trials that are currently being conducted. For more information about clinical trials, please see the NCI Web site.

• In the GPOH 2003 trial, following OPPA or OEPA, patients in treatment group 3 are randomized to four additional cycles of COPP or COPDIC, in which dacarbazine replaces procarbazine in an effort to reduce gonadal toxicity while maintaining efficacy.[36]



• A consortium of institutions in the United States are evaluating the Stanford V regimen.

The following is an example of a national clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.

• COG-AHOD03P1 : In this ongoing COG study, patients with stage I, completely resected disease are observed without further treatment. Patients with stage I or IIA disease with no bulk disease and residual disease following initial biopsy, receive three cycles of vincristine, doxorubicin and cyclophosphamide chemotherapy. Patients showing a complete response receive no further therapy; patients with a partial response receive LD-IFRT.



• Other patients with NLPHL are treated on stage appropriate intermediate or high risk classical Hodgkin lymphoma protocols.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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.

References

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