Clinical Manifestations

Pediatric patients most commonly present with painless cervical or supraclavicular lymphadenopathy. Mediastinal lymphadenopathy occurs in up to 66% of patients and may be associated with a nonproductive cough or other symptoms of tracheal or bronchial compression. Axillary or inguinal lymphadenopathy is less frequently seen as the first presenting sign. Primary infradiaphragmatic disease is rare in pediatric patients and occurs in fewer than 5% of cases. Splenic involvement occurs in 30% to 40% of pediatric patients with Hodgkin’s lymphoma, whereas hepatic involvement is exceedingly rare. The pulmonary parenchyma, chest wall, pleura, and pericardium are the most commonly involved extranodal sites of disease. Bone marrow involvement at the time of initial presentation of Hodgkin’s lymphoma is also uncommon in children. Approximately 65% of children have stage I and II disease and 35% have stage III and IV disease (Table 72-1).

TABLE 72-1 Pediatric Hodgkins Lymphoma: Demographic and Clinical Characteristics at Presentation

* Data taken from Ruhl et al⁴⁹ and Nachman et al.⁴⁸

† Data taken from Cleary et al.¹³⁶

‡ Data derived from both pathologically and clinically staged patients.

Nonspecific systemic symptoms are often associated with lymphadenopathy and may include fatigue, anorexia, mild weight loss, and pruritus. The prognostically significant constitutional or B symptoms that are included in the staging assignment are unexplained fever with temperatures taken orally that are higher than 38° C, unexplained weight loss of 10% within 6 months preceding diagnosis, and drenching night sweats. B symptoms occur in approximately 33% of patients (see Table 72-1). Laboratory changes observed at presentation are nonspecific but may provide clues about the extent of disease. Hematologic abnormalities may include anemia, neutrophilic leukocytosis, lymphopenia, eosinophilia, and monocytosis. Anemia may be associated with the presence of advanced disease and may result from impaired mobilization of iron stores or, less commonly, from hemolysis. Several autoimmune disorders have been reported in patients with Hodgkin’s lymphoma, including nephrotic syndrome, autoimmune hemolytic anemia, autoimmune neutropenia, and immune thrombocytopenia.³² These conditions typically remit as the lymphoma is responding to therapy. Several acute phase reactants, including erythrocyte sedimentation rate and serum copper, ferritin, and C-reactive protein levels, may be elevated at diagnosis and useful in follow-up evaluations.

Patient Evaluation

Posteroanterior and lateral thoracic radiographs should be performed as soon as Hodgkin’s lymphoma becomes part of the differential diagnosis to assess mediastinal involvement, airway patency, and other intrathoracic structures. This is particularly important if sedation is planned for diagnostic procedures. An excisional lymph node biopsy is the preferred diagnostic procedure because it permits evaluation of the malignant Hodgkin’s Reed-Sternberg cells within the background of characteristic architectural changes of the specific histologic subtypes. All nodal regions, including Waldeyer’s ring, should be assessed by careful physical examination. An upright chest radiograph should be obtained to assess mediastinal bulk that is defined by mediastinal lymphadenopathy measuring 33% or more of the maximum intrathoracic cavity. CT is most frequently used to evaluate the nodal regions in the neck, axilla, thoracic and abdominal cavities, and pelvis. Administration of both oral and intravenous contrast agents is required for CT to accurately distinguish lymphadenopathy from other infradiaphragmatic structures. Organ size is an unreliable indicator of lymphomatous involvement in the liver or spleen, because tumor deposits may be less than 1 cm in diameter and not visualized by diagnostic imaging modalities. Increased size of either organ can, of course, be caused by nonmalignant causes. The presence of hypodense lesions by CT and/or abnormal functional avidity by PET scanning provides stronger evidence of tumor infiltration in these organs.

Functional nuclear imaging studies are appropriately used in patients with Hodgkin’s lymphoma as a diagnostic and monitoring modality. PET scanning uses uptake of the radioactive glucose analog ¹⁸fluoro-2-deoxyglucose (FDG) as a correlate of tumor activity. PET scanning is now widely available and is a standard part of the staging workup and assessment of response to therapy. Fused PET/CT offers the advantage of integrating functional and anatomic tumor characteristics. Residual or persistent gallium or FDG avidity is useful in predicting prognosis and the need for additional therapy in post-treatment evaluation.33,34,35,36,37 Moreover, PET may be useful in evaluating abnormalities that become clinically manifest or appear on imaging in order to assess recurrence.³⁸ The utility of PET for follow-up is being studied because reports suggest low rates of diagnosing relapsed disease and problems with a high degree of false-positive findings.^39,40,41

Because extranodal disease involving the bones and bone marrow is relatively uncommon in children, these staging evaluations can be omitted in patients presenting with localized and asymptomatic disease. Bone pain should be evaluated with plain radiographs. PET scanning is supplanting technetium-99 (⁹⁹Tc) bone scans, which historically have been performed for an elevated serum alkaline-phosphatase concentration beyond that expected for age, or extranodal disease identified by other staging evaluations. A bone marrow biopsy should be performed in any patient with clinical stage III or IV disease or B symptoms. Because the pattern of infiltration in the bone marrow may be diffuse or focal and is often accompanied by reversible marrow fibrosis, a bone marrow aspirate alone is inadequate to assess the marrow for disease.

Staging

Physical examination and diagnostic imaging evaluations are used to designate a clinical stage according to the Ann Arbor staging system.⁴² In the past, pathologic staging, based on the findings of a staging laparotomy, including splenectomy, was routinely used to assess infradiaphragmatic disease. The increasing use of systemic therapy in children and the development of more accurate diagnostic imaging modalities led to the routine use of clinical staging and abandonment of surgical staging except to assess equivocal findings. Currently, surgical staging—most typically, nodal sampling without splenectomy—is pursued only if the anticipated findings will significantly alter the treatment plan.

Risk-Adapted Treatment Approach

Contemporary treatment for children and adolescents with Hodgkin’s lymphoma involves a risk-adapted approach based on the patient’s presenting features at diagnosis.* Factors included in the risk assessment vary across studies, but they most often include the presence of B symptoms, mediastinal and peripheral lymph node bulk, extranodal extension of disease to contiguous structures, number of involved nodal regions, Ann Arbor stage, and gender. A favorable clinical presentation is typically characterized as localized (stage I/II) nodal involvement in the absence of B symptoms and bulky disease. Although the historical definition of mediastinal bulk was based on a ratio greater than one-third between the transverse dimension of the mediastinal mass to the intrathoracic cavity on an upright chest radiograph, some trials have moved to use a simple size criteria on cross-sectional imaging as used for peripheral lymph node bulk. That definition, however, is highly variable across studies, ranging from 4 to 10 cm as a minimal threshold. Moreover, there is additional subjectivity in the definition of bulk when there are multiple matted or adjacent nodes, contributing to confusion on such risk stratification in practice. Fewer than three or four involved nodal regions are considered favorable.

In some risk-adapted treatment protocols, patients with localized disease presenting with unfavorable features are designated intermediate in risk and treated similarly to those with advanced-stage disease, whereas in others a therapy intermediate in intensity is prescribed. The criteria for unfavorable clinical presentations have also differed among studies, but the criteria most often used are B symptoms, bulky lymphadenopathy, hilar lymphadenopathy, more than three to four involved nodal regions, extranodal extension to contiguous structures, and advanced-stage (IIIB to IV) disease. The results of contemporary trials indicate that children and adolescents with early-stage or favorable presentations of Hodgkin’s lymphoma are excellent candidates for reduced therapy.44,47,48,49 Ongoing trials are evaluating whether intensification of therapy improves outcomes in patients with intermediate-risk and high-risk presentations.

Although not widely used to guide therapy assignment in pediatric trials, other factors such as gender, age at diagnosis, and histologic findings are considered in individual patients. The trials organized by the German-Austrian Pediatric Oncology Group (GPOH) and one trial by the Children’s Cancer Group (now integrated in the Children’s Oncology Group—COG) have been unique in their aims to prospectively evaluate gender-based therapy.^49,51 Long-term follow-up of the GPOH 90 and 95 studies demonstrate that the substitution of etoposide for procarbazine in the vincristine, prednisone, procarbazine, and doxorubicin (OPPA) regimen does not compromise disease-free survival rates and provides less potential risk for gonadal toxicity.^45,49 Although age at presentation has not been used as a criterion to assign therapy in prospective trials, reports describing outcomes after treatment with chemotherapy alone stress the benefits of this approach in younger children at higher risk of radiation-related toxicity.^46,48

Lastly, retrospective reports of excellent outcome in patients with completely resected nodular lymphocyte-predominant disease have motivated prospective studies prescribing observation alone.^52,53 At the same time, early-stage nodular lymphocyte-predominant Hodgkin’s lymphoma responds well to chemotherapy alone, IFRT alone, or combined-modality therapy. As an example of the later, VAMP (vinblastine, Adriamycin [doxorubicin], methotrexate, and prednisone) plus low-dose IFRT (LDRT) in a series of 33 patients had a 100% 10-year survival rate and EFS rate.⁵⁴ Because data supporting the effectiveness of IFRT alone are based on full-dose RT (e.g., ≥30 Gy), it is not considered appropriate for children who are not fully grown.

A summary of trials in children with early-stage and advanced-stage Hodgkin’s lymphoma is provided in Tables 72-2 and 72-3 (a more complete tabulation is available in the Expert Consult online version of this chapter).

Response-Based Therapy

The response to chemotherapy, either early in its course or at its completion, is known to be an important prognostic factor in Hodgkin’s lymphoma.¹³ This knowledge has led to a hypothesis that modifications in therapy may be based on the initial response to chemotherapy in a similar fashion to the management of acute lymphoblastic leukemia. Based on rapidity of a complete response to chemotherapy, a reduction or augmentation of therapy may be possible, a concept under cautious investigation in clinical trials. Response-based approaches titrate the overall duration of chemotherapy and/or the need for radiotherapy by assessing the early response to chemotherapy. Two Pediatric Oncology Group trials (POG 8725 and 8625) comparing chemotherapy alone versus chemoradiotherapy supported this idea that a rapid early response (RER) to chemotherapy reflects the chemosensitivity of a patient’s Hodgkin’s lymphoma and is a predictor of good long-term control.^7,14 The implication is that treatment can be reduced in intensity or duration for those with RER in order to mitigate toxicity, or increased for those with a slow early response (SER) in order to improve disease control.

The augmentation in therapy for SER can be an increased radiotherapy dose or additional chemotherapy, or both. The French Society of Pediatric Oncology MDH90 treated 202 children with stage I or II Hodgkin’s lymphoma with four cycles of vinblastine, bleomycin, etoposide, and prednisone (VBVP). Good responders received 20 Gy IFRT alone, while poor responders were given an additional one to two cycles of OPPA and then either 20 Gy IFRT (good responders at second evaluation) or 40 Gy IFRT (poor responders). The 5-year overall survival (OS) and EFS rates were 97.5% and 91.1%, respectively.⁴⁷ In the German trial, GPOH HD-95, early-stage patients who had a complete response to chemotherapy (two cycles of OPPA for girls or two cycles of OEPA for boys) did not receive adjuvant radiotherapy. OPPA/OEPA chemotherapy alone produced a 5-year disease-free survival rate of 88%, which was not significantly different from that observed in patients who received radiotherapy (92%).⁴⁵ In this trial, higher-risk patients who received radiotherapy were prescribed radiation doses of up to 35 Gy if a complete response was not achieved. The use of higher-dose radiotherapy with simple anterior-posterior beams is certainly known to cause undesirable musculoskeletal toxicities and the potential for increased cardiopulmonary injury and secondary cancers, such that augmentation of chemotherapy or more conformal radiotherapy may be better approaches for nonresponders. POG 9425 administered three versus five cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) chemotherapy and 21-Gy regional radiotherapy for rapid and slow responders, respectively.⁵⁵ The 2-year EFS rate was 88.2%, with no statistical difference between early and slow responders. These studies suggest that interim or early response-adapted therapy may be useful in identifying patients with favorable disease, who can be treated with lower radiotherapy doses or abbreviated chemotherapy regimens.

A recently closed COG intermediate-risk Hodgkin’s lymphoma study may provide additional data on response-based strategies, including when it may be safe to eliminate radiotherapy for some patients. Children with stage IA/IIA bulky disease or IB, IIB, IIIA, or IVA disease receive two cycles of ABVE-PC prior to response evaluation with CT imaging. Those with RER, and who go on to a complete response after an additional two cycles of the same chemotherapy, are randomized to 21 Gy of IFRT or no additional treatment. Patients with an SER to two cycles of chemotherapy are randomized to either standard therapy (an additional two cycles of ABVE-PC plus 21-Gy IFRT) or intensified therapy (standard therapy plus two additional cycles of chemotherapy—dexamethasone, etoposide, cytarabine, and cisplatin [DECA]—before IFRT). This trial will provide useful data regarding the selection of patients who may avoid radiotherapy and the value of chemotherapy intensification among those with an SER.

Although most completed trials have used CT, with or without gallium or PET to determine response, it is becoming increasingly clear that PET scanning after the initial (one or two) chemotherapy cycles will better identify good-prognosis patients and facilitate treatment intensification.13,36,56,57 Whether radiotherapy can be omitted among patients with a negative PET scan after chemotherapy is unknown and should be considered investigational at the present. The corollary problem is how to define a response by PET criteria because low levels of residual FDG activity after therapy are common. Another unresolved problem is the interpretation of splenic or hepatic involvement by Hodgkin’s lymphoma given the physiologic uptake of FDG in these organs. A consensus panel has promulgated PET-based response criteria known as the International Harmonization Project.^58,59

Chemotherapy Regimens and Radiation Therapy

Volume

Most children with Hodgkin’s lymphoma are treated with combined chemotherapy and low-dose IFRT. Meticulously and judiciously designed fields are necessary for maximum success in terms of both disease control and minimal tissue damage. The definitions of such fields depend 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. Involved fields typically should include not just the identifiably abnormal lymph nodes but the entire lymph node region containing the involved nodes (Table 72-4).

TABLE 72-4 Involved-Field Radiation Guidelines

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

† Prechemotherapy volume is treated except for lateral borders of the mediastinal field, which is based on postchemotherapy volume.

The traditional definitions of lymph node regions can be helpful but are not sufficient. For example, the 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 hila are usually irradiated when the mediastinum is involved, however, despite the fact that the hila and mediastinum are separate lymph node regions. Similarly, the supraclavicular fossa (SCV) is often treated when the axilla or the mediastinum is involved, and the ipsilateral external iliac nodes are often treated when the inguinal nodes are involved. In both situations, however, care should be taken to shield relevant normal tissues to the degree possible, such as the breast in the former situation and ovaries in the latter. Moreover, the decision to treat the axilla or mediastinum without the SCV, and the inguinal nodes without the iliacs, might be appropriate depending on the size and distribution of involved nodes at presentation. In a very young child (<5 years of age), consideration may be given to treating bilateral areas (e.g., both sides of the neck) to avoid growth asymmetry. This is less of a concern with low radiation doses, however, and unilateral fields are usually appropriate if the disease is unilateral. Efforts to exclude unnecessary normal tissues are always important, such as breast tissue in a child with isolated mediastinal disease and no axillary involvement.

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 down with hands on the hips. The former 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. The position chosen therefore involves weighing concerns regarding lymph nodes, lung, and humeral heads. Attempts should be made to exclude or position breast tissue under the lung and axillary blocking.

When the decision is made to include some or all of a critical organ in the radiation therapy field, such as liver, kidney, or heart, normal tissue constraints, depending on the chemotherapy used and patient age, are critical. The width of a mediastinal field, therefore, is generally based on the postchemotherapy residual disease, whereas the cephalad-caudad dimension respects the original disease extent. Humeral head blocks are appropriate unless bulky axillary adenopathy is thereby shielded. Laryngeal and occipital blocks are used unless disease is located in the vicinity of these structures; these blocks can be placed at the beginning of treatment or after some portion of it. Depending on the response of the disease to chemotherapy and the dose administered, field reductions may be possible. The entire heart or lungs are rarely treated above doses of 10 to 16 Gy, depending on the distribution of disease and chemotherapy used. Specific treatment decisions are protocol dependent because some children treated for advanced-stage Hodgkin’s lymphoma will receive radiation therapy only to areas of initial bulky disease or postchemotherapy residual disease. This approach remains investigational, however, and IFRT may remain the appropriate treatment.

When treating the subdiaphragmatic region, a treatment-planning CT and diagnostic information obtained from a CT or MRI help draw the blocks. When treating the pelvis, special attention must be given to the ovaries and testes. The ovaries should be relocated, and marked with surgical clips, laterally along the iliac wings or centrally behind the uterus. In this manner, appropriate shielding may be used. The testes receive 5% to 10% of the administered pelvic dose, which is sufficient to cause transient or permanent azoospermia, depending on the total pelvic dose. The greatest shielding can be afforded to the testes if the patient is placed in a frog-leg position with an individually constructed testes shield. If multileaf collimation is available, the multileaf can be placed over the testes, additionally decreasing the transmitted dose. Clearly, careful planning and judgment are necessary.

Radiation therapy for unfavorable and advanced Hodgkin’s 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 bulky disease (generally defined as 5 to 6 cm or more at presentation) or postchemotherapy residual disease (generally defined as 2 to 2.5 cm or more, or residual PET avidity) is under investigation. Also under investigation is the use of involved-nodal radiation therapy (INRT) where the initial nodes grossly involved by lymphoma are targeted with a small margin rather than treating an entire anatomic compartment. The rationale for this relates to both the anatomic definitions of lymph node regions and the patterns of recurrence. Clinical definitions of lymph node regions are historic and based on anatomic or bony landmarks without the benefit of CT scanning to identify the location of nodes. The European Organization for Research and Treatment of Cancer–Groupe d’Études des Lymphomes de l’Adulte (EORTC-GELA) has recently introduced the concept of INRT.97,98 This uses all available clinical information, including prechemotherapy and postchemotherapy imaging with CT and FDG/PET scans, to define the treatment field according to the prechemotherapy extent of disease. The concept is based on evidence that disease recurs most often in initially involved lymph nodes, ^99,100 suggesting that chemotherapy is adequate to treat disease contained within radiologically normal lymph nodes, while RT is needed only to treat sites of macroscopic enlargement. In a study of early stage Hodgkin’s lymphoma patients, PET identified 36% of involved lymph nodes that were radiographically normal on CT scanning. Therefore, evaluation with FDG-PET scanning before chemotherapy may help delineate the complete extent of disease.⁹⁷ Initial clinical data with the use of INRT are emerging. Campbell and colleagues¹⁰¹ reviewed clinical outcomes of patients with limited-stage Hodgkin’s lymphoma treated with EFRT, IFRT, and INRT of 5 cm or less. No marginal recurrences or locoregional failures occurred with INRT.¹⁰¹

Dose

In the setting of combined therapy, the intensity of the chemotherapy is important to consider in the choice of the radiation therapy dose and volume. However, doses of 15 to 25 Gy are typical with shrinking fields and boosts individualized (see Tables 72-2 and 72-3). Doses of more than 25 Gy are uncommon in the pediatric setting. Of interest are the results of the GPOH HD-90 trial, in which radiation therapy was administered in combination with vincristine, prednisone, procarbazine, and doxorubicin (OPPA) or OEPA, with or without COPP. The radiation doses were 20 to 25 Gy, with a local boost of 5 to 10 Gy for insufficient remission following chemotherapy. Tumor burden, indicated by bulky disease or number of involved nodes, proved not to be prognostically significant, likely because of the high doses used for bulky disease.¹⁰² Most current treatment approaches for children would not include radiation doses of this magnitude.

Treatment Approaches

Chemotherapy Alone versus Chemotherapy Combined with Radiation Therapy

Non-cross-resistant combination chemotherapy alone is well established as an effective modality for the treatment of pediatric Hodgkin’s lymphoma.* This treatment approach eliminates the risk of radiation-induced complications. However, the higher-cumulative doses of anthracyclines, alkylating agents, and bleomycin chemotherapy increase the risk of cardiopulmonary toxicity, infertility, and leukemogenesis, and may be less effective than combined-modality therapy for treatment of bulky nodal disease. Chemotherapy alone trials have been limited by their small numbers of patients, nonrandom treatment assignments, lack of long-term follow-up related to disease control, and late-treatment sequelae. Despite these deficiencies, identification of clinical factors predicting an optimal outcome following treatment with chemotherapy alone remains an important objective of many ongoing trials because of the desire to avoid late radiation therapy sequelae.

Investigators from North American pediatric cooperative groups have undertaken three longitudinal controlled trials to evaluate chemotherapy alone versus combined-modality therapy.^6,7,48 The first two trials failed to show a statistically significant advantage in EFS or OS rates with the addition of radiation therapy to non-cross-resistant chemotherapy. The CCG compared 12 cycles of alternating MOPP/ABVD with 6 cycles of ABVD plus low-dose (21 Gy) radiation.⁶ Rates of EFS and OS suggested a survival advantage for the combined-modality group (90% for 4-year EFS rate) over the chemotherapy alone group (84% for 4-year EFS rate), but this difference was statistically insignificant. In a POG trial, adding low-dose radiation to four cycles of alternating MOPP and ABVD chemotherapy did not improve disease-free or OS rates.⁷ However, statistical and quality assurance issues produced problems with interpretation of these data. Moreover, the findings of both studies are irrelevant to present-day practice because the treatments included the more leukemogenic MOPP-based therapy and an excessive number of treatment cycles.

Using a more contemporary regimen, the CCG compared chemotherapy alone with the COPP/ABV hybrid to combined-modality therapy including low-dose IFRT.⁴⁸ Clinical risk features, including the presence of B symptoms, hilar lymphadenopathy, mediastinal and peripheral lymph node bulk, and the number of involved nodal regions, determined treatment assignment. Patients who achieved a complete response to chemotherapy were eligible to be randomized to receive low-dose IFRT or no further therapy. The trial was prematurely terminated because patients treated with chemotherapy alone had a significantly higher number of relapses. The difference in outcome was most marked for stage IV patients in whom combined-modality therapy produced a 3-year 90% EFS rate compared with 81% in those randomized to receive chemotherapy alone.

In a nonrandomized trial that omitted radiation for patients achieving a complete remission with chemotherapy, the investigators reported a similar advantage for patients treated with radiation consolidation following combination chemotherapy in the GPOH-HD 95 trial. In this study, patients treated with radiation therapy after a partial response to combination chemotherapy had a superior relapse-free survival rate (93%) compared with those who achieved a complete response with chemotherapy alone (89%). The difference in outcomes for patients treated with combined-modality therapy versus chemotherapy alone was significant for patients treated for advanced-risk and intermediate-risk disease but not early-stage disease.

The current standard of care is to include IFRT across all stages of pediatric Hodgkin’s lymphoma. The results of chemotherapy alone investigations, however, document excellent efficacy of this treatment approach, particularly in children with early-stage favorable Hodgkin’s lymphoma. Circumstances where radiotherapy may have particular toxicity, as in the very young child, may warrant chemotherapy alone. The incremental value of adjuvant radiotherapy is small, but its importance lies in the avoidance of relapse therapy. Balanced against this is the incremental toxicity, which is difficult to quantify because the modern techniques have insufficient long-term follow-up. At the same time, there is an appreciation that radiation volume reductions should be an area of active investigation to reduce side effects, but only to the extent that the risk of relapse is not enhanced.97,98,99,100

By the same token, conformal techniques such as intensity-modulated radiotherapy (IMRT) or proton radiotherapy are also under investigation in Hodgkin’s lymphoma.* Figures 72-1 and 72-2 are illustrative examples of the use of IMRT to ensure coverage of involved regions. In the first case, the mediastinal disease has extensive anterior chest wall extension, whereas the second case depicts splenic IMRT with AP-PA mantle fields. In these examples, radiation exposure to normal tissues (lung, heart, kidney) was minimized to reduce toxicity, not readily accomplished by standard AP-PA beam arrangements.

Figure 72-1 Use of intensity-modulated radiation therapy (IMRT) is not standard in Hodgkin’s lymphoma but may be preferred in special circumstances. In this case, IMRT was used to treat extensive anterior chest wall involvement at diagnosis. This 18-year-old male with stage IVB nodular sclerosing Hodgkin’s lymphoma presented with fevers, sweats, chest pain, pruritus, and right supraclavicular adenopathy. Staging showed neck, bilateral axillary, and bulky mediastinal adenopathy. Extensive anterior chest wall involvement is noted on PET (A) and CT imaging (B). After a complete response to ABVE-PC chemotherapy for four cycles, the patient underwent involved-field radiotherapy (IFRT) to 21 Gy in 14 fractions. Standard AP/PA fields would have included too much lung. Instead, an IMRT plan yielded a better dose distribution with lower risk for pulmonary toxicity while ensuring good coverage of initial sites of involvement. C, The IMRT dose distribution in a color wash superimposed on an axial CT scan taken following chemotherapy at the level of the carina. Two years following therapy, the patient remains free of lymphoma and is a competitive swimmer in college. ABVE-PC, Adriamycin (doxorubicin), bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide.

Figure 72-2 Use of nonstandard intensity-modulated radiation therapy (IMRT) to treat the spleen along with the AP/PA mantle field. A 12-year-old presented with stage IIIAS lymphocyte predominant Hodgkin’s lymphoma with bulky right axillary adenopathy. On staging evaluation, the PET scan (A) showed bilateral neck and axillary adenopathy and bulky mediastinal disease, as well as multiple splenic nodules. After a complete response to ABVE-PC chemotherapy for four cycles, involved-field radiotherapy (IFRT) to 21 Gy in 14 fractions was initiated. The supradiaphragmatic disease was well covered by standard AP/PA fields (B). AP/PA or oblique fields to the spleen would have treated too large a volume of the heart or kidney. Instead, a four-field IMRT plan along with shallow breathing and appropriate margin for respiratory motion was devised. C and D, Superior and inferior aspects of the spleen treatment, with the dose distribution shown with a color wash superimposed on the treatment planning CT scan. IMRT technique successfully minimized the dose to the heart and left kidney. ABVE-PC, Adriamycin (doxorubicin), bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide.

An argument often cited for abandoning radiotherapy in Hodgkin’s lymphoma is the lack of any survival advantage for radiotherapy in the vast majority of studies. A recent meta-analysis of adult and pediatric trials, however, suggests that favorable-risk patients may in fact have a small survival advantage without excessive risk for secondary malignant tumors.¹⁵ Nevertheless, a valid objective of ongoing studies is to identify patient subgroups where radiotherapy may have no value. The response-based paradigm may yield important observations of when chemotherapy alone approaches are preferred. PET imaging is proving particularly useful for response assessment and radiation therapy planning.¹¹⁶ One note of caution was observed in an adult Italian randomized Hodgkin’s lymphoma trial, however: When IFRT was omitted in patients with bulky disease who had had a complete response to chemotherapy based on PET, there was a 10% reduction in the EFS rate.¹¹⁷

Treatment Algorithms

Table 72-5 summarizes recommendations for risk-adapted treatment approaches. Because patients with localized favorable disease presentations can achieve long-term disease-free survival using regimens that do not contain alkylators, ABVD or derivative chemotherapy is preferred for this group.^{44,47,132,133} Alkylating agents or etoposide can be added to the regimen, however, without compromising disease outcome if the investigator prefers to restrict anthracycline chemotherapy exposure to preserve cardiac function.^48,49,134 Combined-modality treatment approaches, including low-dose IFRT, have produced excellent results in children with favorable localized disease and can reduce cumulative chemotherapy doses.

TABLE 72-5 Recommendations for Treatment Approach in Pediatric Hodgkin’s Lymphoma

IFRT, involved-field radiotherapy; INRT, involved-nodal radiotherapy; PET2, PET scan after second cycle of chemotherapy used as indicator of rapid early response.

* Stage IIB patients have been variably treated as intermediate- or unfavorable-risk patients. Some studies use associated factors, such as weight loss, bulky disease, or extranodal extension, for further risk stratification.

Combinations derived from both ABVD and MOPP with the addition of etoposide still provide the most effective chemotherapy strategies for children and adolescents with intermediate-risk or high-risk disease presentations.^48,49 In most regimens reporting good long-term outcomes, low-dose radiation therapy is administered following chemotherapy to areas of bulky disease or nodes (usually, the regions harboring the involved nodes) present at diagnosis. In contrast to treatment regimens used for adults with advanced or unfavorable Hodgkin’s lymphoma that commonly prescribe six cycles of ABVD, an alkylating agent regimen is most often alternated with ABVD or similar hybrid therapy in an effort to reduce potential cardiopulmonary toxicity. Attempts to completely omit alkylating agents in these high-risk groups have resulted in unsatisfactory outcomes, as have protocols prescribing ABVD or derivative chemotherapy alone.^46,135 Abbreviated, dose-dense regimens that induce rapid tumor response may permit reduction of cumulative chemotherapy doses below threshold levels associated with significant long-term toxicity.⁵⁵