Residency · Residency · Radiation Oncology
Pediatric Hodgkin Lymphoma: Response-Adapted Therapy and Late Effects
Introduction
Hodgkin lymphoma (HL) in children and adolescents is among the most curable pediatric cancers, with overall survival rates exceeding 95%. As a result, the primary therapeutic challenge has evolved from simply achieving cure to minimizing long-term treatment toxicity while maintaining these high cure rates. To address this, response-adapted therapy has been developed, utilizing interim PET/CT scans and rapid early response assessments to guide the intensity of treatment and decisions regarding radiation therapy.
Pediatric vs. Adult Hodgkin Lymphoma
Pediatric HL exhibits a bimodal age distribution, with incidence peaks occurring between ages 5-7 and again at 15-19 years. Younger children tend to have a higher proportion of mixed cellularity and lymphocyte-predominant subtypes compared to adults. Importantly, children are more susceptible to radiation-related late effects because their tissues are still developing. Additionally, their longer life expectancy increases the lifetime risk of secondary malignancies and cardiovascular disease. Consequently, treatment protocols for pediatric HL are specifically designed to minimize cumulative exposure to anthracyclines and alkylating agents, which are known to contribute to these late toxicities.
Risk Stratification in Pediatric HL
Risk stratification in pediatric HL is categorized into low, intermediate, and high risk based on disease stage, bulk, and symptoms. Low-risk patients typically have stage IA or IIA disease without bulky masses and no B symptoms. These patients receive 2-3 cycles of modified chemotherapy regimens such as AV-PC or ABVE, and radiation therapy may be omitted if they demonstrate a rapid early response. Intermediate-risk patients include those with stage IA or IIA disease with bulky masses, stage IIB, or stage IIIA disease. They generally receive four cycles of chemotherapy, with radiation therapy decisions guided by response assessment. High-risk patients present with stage IIIB, IVA, or IVB disease and are treated with 6-8 cycles of dose-intensive regimens like ABVE-PC. Radiation therapy is targeted to initially bulky or slow-responding sites in this group.
Response-Adapted Strategy
The response-adapted strategy relies on early assessment of tumor response to chemotherapy. Rapid early response (RER) is evaluated by CT after the first one to two chemotherapy cycles and is defined as a greater than 60% reduction in tumor volume. Patients who do not meet this threshold, termed slow early responders (SER), receive intensified chemotherapy and/or radiation therapy. Additionally, interim PET/CT after two cycles of chemotherapy plays a crucial role in guiding subsequent management. A Deauville score of 1-2 indicates a complete metabolic response, allowing for potential treatment de-escalation. The Children's Oncology Group (COG) trials AHOD0031 and AHOD1331 incorporate PET-directed decisions to optimize therapy.
Key Cooperative Group Trials
Several key cooperative group trials have shaped current pediatric HL management. The COG AHOD0031 trial focused on intermediate-risk pediatric HL and randomized rapid early responders, identified by CT, to receive involved-field radiation therapy (IFRT) at 21 Gy versus no radiation. The trial demonstrated that omitting radiation in rapid early responders did not significantly affect four-year event-free survival (EFS), which was 86% without radiation versus 88% with radiation. Slow early responders received augmented chemotherapy plus IFRT, confirming the feasibility of safely omitting radiation in select patients.
The COG AHOD0431 trial addressed low-risk pediatric HL (stage IA/IIA non-bulky). Patients received three cycles of AV-PC chemotherapy, and radiation therapy was omitted in those achieving complete response. Event-free survival exceeded 90% without radiation in rapid responders, establishing observation after chemotherapy as a viable strategy in low-risk patients.
The COG AHOD1331 trial targeted high-risk pediatric HL and incorporated brentuximab vedotin into frontline therapy. This trial used PET-adapted therapy, allowing de-escalation for patients with a Deauville score of 1-2 after two cycles. The goal was to reduce cumulative exposure to anthracyclines and bleomycin while maintaining efficacy.
European cooperative group trials EuroNet-PHL-C1 and C2 also employed PET-guided radiation omission after OEPA/COPDAC chemotherapy. Patients with Deauville scores of 1-2 after two cycles did not receive radiation, whereas those with scores of 3 or higher received involved-site radiation therapy (ISRT) at 19.8 Gy to PET-positive residual sites. These results support PET-adapted radiation omission with high event-free survival rates.
Radiation Therapy When Indicated
When radiation therapy is indicated in pediatric HL, the dose is typically lower than in adults to minimize growth and late effects. COG protocols use 21 Gy delivered in 14 fractions, while EuroNet protocols use 19.8 Gy in 11 fractions. The volume of radiation follows involved-site radiation therapy (ISRT) principles as outlined by the International Lymphoma Radiation Oncology Group (ILROG) pediatric guidelines. Pre-chemotherapy PET/CT is essential for defining the radiation volume, with post-chemotherapy anatomy used to determine axial dimensions.
Advanced radiation techniques such as intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), or proton therapy are employed to minimize dose to developing tissues. Deep inspiration breath hold (DIBH) is used for mediastinal disease to reduce cardiac and pulmonary exposure. Proton therapy offers significant dose reduction to critical structures such as the heart, lungs, and breasts. For mediastinal disease, techniques like the butterfly technique or anterior-weighted beams are utilized to optimize dose distribution.
Late Effects of Treatment
Long-term survivors of pediatric HL face several potential late effects related to their treatment. Cardiovascular disease is the leading cause of non-relapse mortality in HL survivors, with risk increasing in proportion to anthracycline dose and mediastinal radiation. The mean heart dose during radiation is the strongest predictor of cardiac toxicity, and no safe threshold has been identified. Echocardiographic surveillance is recommended to begin 5-10 years after treatment.
Secondary malignancies are a significant concern. Breast cancer risk is increased 20-30 fold in women who received chest irradiation before age 30, with risk emerging approximately 8-10 years post-treatment. Screening with MRI should begin at age 25 or 8 years after radiation, whichever comes first. Thyroid cancer risk is elevated following neck irradiation, warranting annual thyroid examinations. Other solid tumors, including lung, colorectal, and sarcomas, also carry increased risk that continues to rise decades after treatment.
Thyroid dysfunction is common, with hypothyroidism occurring in 30-50% of patients who received neck irradiation. Annual thyroid-stimulating hormone (TSH) monitoring is recommended lifelong. Hyperthyroidism and thyroid nodules may also develop.
Pulmonary toxicity is a concern, especially with bleomycin use compounded by mediastinal radiation. Pulmonary function testing should be performed at baseline and during follow-up. Patients are advised against smoking, and caution is warranted with supplemental oxygen during anesthesia due to increased risk of pulmonary complications.
Musculoskeletal and growth effects result from radiation to growth plates, potentially causing growth arrest and asymmetry. Clavicular hypoplasia and soft tissue hypoplasia may also occur. To mitigate these effects, radiation field size should be minimized and age-appropriate dose constraints applied.
Fertility can be compromised by alkylating agents such as those used in MOPP, BEACOPP, and cyclophosphamide-containing regimens. ABVD-based regimens have lower gonadotoxicity. Fertility preservation counseling should be provided before treatment initiation. The risk from pelvic radiation depends on dose and field size, and oophoropexy may be considered in select cases to preserve ovarian function.
Key Clinical Pearls
Cure rates for pediatric Hodgkin lymphoma exceed 95%, shifting the focus of therapy toward minimizing late effects. Response-adapted strategies using PET/CT enable safe omission of radiation therapy in rapid early responders, as demonstrated by the COG AHOD0031 trial. When radiation therapy is necessary, involved-site radiation therapy at doses between 19.8 and 21 Gy is standard, with proton therapy preferred to reduce dose to developing tissues. Breast cancer screening with annual MRI should begin at age 25 or eight years after chest radiation, whichever occurs first. Lifelong survivorship care is essential to monitor and manage risks related to cardiac health, thyroid function, pulmonary status, fertility, and secondary malignancies.
References
- Friedman DL, Chen L, Wolden S, et al. Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk Hodgkin lymphoma: a report from the Children's Oncology Group Study AHOD0031. J Clin Oncol. 2014;32(32):3651-3658.
- Mauz-Korholz C, Metzger ML, Kelly KM, et al. Pediatric Hodgkin lymphoma. J Clin Oncol. 2015;33(27):2975-2985.
- Castellino SM, Geiger AM, Mertens AC, et al. Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood. 2011;117(6):1806-1816.
- Schwartz CL, Constine LS, Villaluna D, et al. A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood. 2009;114(10):2051-2059.