Radiotherapy is here to stay

In this issue of Blood, Parekh et al¹ report additional results of a frontline pediatric Hodgkin lymphoma (HL) phase 3 trial that demonstrate the impact of an early positron emission tomography (PET) response after 1 cycle of chemotherapy and involved-field radiotherapy (IFRT) on outcomes and patterns of relapse.

The death of Dr. Brian Sorrentino at age 60 of stage IV lung cancer secondary to the HL treatment he received as a teenager is a grave reminder that to cure is not enough. Dr. Sorrentino was a world-renowned physician–scientist at St. Jude Children’s Research Hospital who helped develop a cure for a rare and deadly disease called X-linked severe combined immunodeficiency.² Dr. Sorrentino was diagnosed with HL in the late 1970s when he was 17 years old. Like so many patients in that treatment era, he received chemotherapy and large field, high-dose radiotherapy (RT) to his chest as part of his cure. Secondary to his therapy, he developed lung cancer that ultimately took his life at the early age of 60. These are the realities of our survivors that challenge us to cure better each day. Dr. Sorrentino’s story reminds us of the risks related to RT and drives us to use RT more efficiently but not eliminate it altogether, as seen by the results in the publication by Parekh and colleagues.¹ 

Over the past decades, advances in the treatment of pediatric HL have focused on a reduction in treatment intensity to minimize late effects and maximize the quality of life for survivors of this very curable disease. While there are countless patients like Dr. Sorrentino with significant late effects of their RT, there is still a role for RT in the treatment of HL. As the first cure for HL, RT is incredibly effective. Just as hematologists have evolved their systemic therapy approaches over time, radiation oncologists have refined techniques, limited field sizes and healthy tissue exposures, and applied novel approaches such as proton-beam therapy to maximize the benefit of RT while minimizing harm, which have greatly reduced the risk of late effects in HL survivors.

In alignment with these principles, the overall goal of the trial AHOD0431 was to deliver a low-intensity regimen that would limit cumulative exposure to chemotherapy agents associated with late effects for low-stage patients.³ This article by Parekh and colleagues provides detailed information from the trial demonstrating a slow early response (SER) is a poor prognostic factor, and patients with an SER who received RT had a statistically significant benefit in their progression-free survival (PFS) compared with those with an SER and no RT (10-year PFS of 80.9% vs 64.0%, respectively; P = .03).¹ Additionally, there was an outcome difference for rapid early responders (RERs) vs SER regardless of RT, with a 10-year PFS of 87.1% (96% with IFRT) for RERs and 73.5% for SER patients, further illustrating the prognostic significance of interim PET scans and the need to alter therapy for SERs.

A recent publication by Chohan and colleagues replicated these findings in a retrospective multicenter review comparing combined modality therapy (CMT) to chemotherapy alone. In this cohort, there was a 2-year PFS of 95.1% for CMT vs 75.3% for chemotherapy alone (P = .005).⁴ The main difference in PFS was observed for unfavorable patients and those with a positive PET2. This trend toward worse outcomes for patients with a positive interim PET has been seen in countless trial results, such as the adult European Organisation for Research and Treatment of Cancer H10 trial⁵ and HD16 trial⁶ and in pediatric trial HOD90,⁷ in which patients with a partial response after 2 cycles had a 10-year EFS of 84.5% compared with 95% for those with a complete response.

A remaining question is what the best treatment approach should be for early-stage patients who remain PET⁺ at early response assessment (ERA). The 2 main options are to (1) augment therapy (either through increased cycles or the addition of novel immunotherapy agents) or (2) irradiate poorly responding sites to higher doses. In the current treatment era, we must critically assess the risks and benefits of augmentation of chemotherapy or the application of novel therapies against the tried and true radiotherapy. Several protocols have attempted augmentation of chemotherapy for SER patients, such as AHOD0031, in which all SER (PET and anatomic response criteria) received 2 additional cycles of therapy. While there was no benefit in 4-year EFS for SER who received additional therapy, there was a benefit seen for those who were PET⁺ at early response assessment.⁸ This suggests augmentation of therapy may best be suited for a smaller select population with poor PET response at ERA.

In terms of radiotherapy, as mentioned in the article, 21 Gy of RT may not have been sufficient as 60% (n = 6) of PET⁺ patients receiving upfront IFRT relapsed within an initial site of disease that was irradiated, of which 83% (n = 5) relapsed only in a PET1⁺ site. Therefore, the dose of 21 Gy may not be sufficient for disease control for this cohort of patients. Augmentation of the dose or a boost to PET⁺ sites at ERA as per the European Network for Paediatric Hodgkin Lymphoma C1 trial may be needed.⁹ 

While many diseases have abandoned their first cures, radiation therapy is an incredibly effective therapy to treat HL. The side effect profile is well known, site-specific, and can spare the rest of the body from more intensive therapy. The long-term effects of novel agents are not yet delineated and should be used with caution in the frontline treatment setting until further data emerge.

In conclusion, while survivors of HL have significant morbidity and mortality from their RT like Dr. Sorrentino, RT has evolved greatly since that time. To enhance cures and minimize late effects, there is a role for the use of RT to significantly improve the outcomes, especially for patients with early-stage disease and SER.