Radiotherapy Use in Refractory and Relapsed Adolescent and Young Adult Hodgkin Lymphoma: A Report from the Children’s Oncology Group

Abstract

Purpose:

Clear indications do not exist for consolidative radiotherapy (CRT) in relapsed and refractory pediatric Hodgkin lymphoma (rrpHL). Increasing numbers of rrpHL patients are radiation naïve, as response-adapted front-line therapies omit CRT for favorable responses. We evaluated practice patterns among treating oncologists for rrpHL.

Methods and Materials:

A survey developed by pediatric and radiation oncologists was distributed to Children’s Oncology Group (COG) Hodgkin Lymphoma Committee members during the Fall 2021 COG meeting. Questions ascertained respondent specialty and annual rrpHL patient volumes. Respondents provided treatment recommendations for two cases. Case 1: 21-year-old female with stage IIB bulky mediastinal HL treated with ABVDx6 without initial radiotherapy with neck and mediastinal relapse and Deauville 4 (D4) response after 2 second-line chemotherapies. Case 1 was modified (modCase1) to a D2 response after second-line therapy. Case 2: 21-year-old female with non-bulky stage IIB disease treated with ABVDx6 without initial radiotherapy with splenic, mediastinal, and neck relapse and D4 activity in those sites after 2 second-line therapies. Descriptive statistics are presented.

Results:

20 (83%) pediatric hematologist/oncologists and 4 (17%) radiation oncologists completed the survey. After autologous stem cell transplant (ASCT) for Case 1, 58% recommended CRT followed by brentuximab vedotin (Bv) maintenance and 33% recommended involved-site radiotherapy (ISRT) alone. For modCase1, 63% would consider CRT instead of ASCT. With ASCT, 21% would recommend CRT to bulk and 38% to all sites at initial relapse. After ASCT for Case 2, 75% recommended ISRT followed by Bv and 17% ISRT alone.

Conclusions:

In a sample of predominantly pediatric-oncologist COG members, most respondents considered that CRT has a role for patients with radiation-naive rrpHL both for groups with D4 disease as well as D2 disease pre-ASCT.

Introduction

Approximately 800 patients are diagnosed with pediatric Hodgkin lymphoma (HL) annually in the US and approximately 15–20% will relapse or be refractory to first line therapy. The management of relapsed or refractory HL (rrpHL) is complex (1). Standard indications do not exist for consolidative radiotherapy (CRT) (1,2). An increasing number of patients with rrpHL treated at North American and European institutions are radiation-naïve due to response-adapted front-line therapies omitting radiotherapy for favorable responses (3,4). Concomitantly, systemic treatment options for rrpHL have expanded with the addition of brentuximab vedotin, immune checkpoint inhibitors (ICI), and CAR T cell therapy alongside high-dose chemotherapy with autologous stem cell transplant (ASCT) (5) leading to a further decline in the utilization of radiation.

While systemic salvage options have evolved, so too has radiation in rrpHL to include smaller treatment volumes and more conformal treatments that reduce the dose to normal tissue, thereby reducing expected late toxicities (3,4,6–8). We sought to evaluate the practice patterns of radiotherapy use for rrpHL among pediatric oncologists and radiation oncologists.

Methods and Materials

An institutional review board–approved survey (University of Florida IRB202200542)was developed by both pediatric oncologists and radiation oncologist members of the Children’s Oncology Group (COG) Hodgkin Lymphoma Steering Committee and was made available to members of the COG Hodgkin Lymphoma Committee from September 30, 2021 to October 8, 2021 via the cloud-based platform Qualtrics (Qualtrics, Provo, Utah, and Seattle, Washington) during the 2021 virtual annual fall COG meeting. Questions ascertained the respondent’s specialty (pediatric oncology or radiation oncology), volume of patients seen annually with rrpHL, and decision factors used in recommending consolidative brentuximab vedotin. Respondents were also presented with two sample patient cases and asked for treatment recommendations as seen in the Survey Appendix (Supplemental Material and Figure 1.

Figure 1.

The image and case description used in Case 1 of the distributed survey. Indicated in red is the pretransplant fluorodeoxyglucose-avid region.

Management of a case with a single persistent site of positron emission tompgrahy (PET) avidity following salvage therapy was presented in Case 1: a 21-year-old female with stage IIB bulky mediastinal HL treated with ABVD (adriamycin, bleomycin sulfate, vinblastine sulfate, and dacarbazine) for 6 cycles and no initial radiotherapy who then had a relapse in the neck and mediastinum two years after initial treatment, followed by a Deauville 4 response to a limited area of the mediastinum after two different second-line chemotherapies. A sample image with description for Case 1 was provided (Figure 1). Respondents were asked what they would recommend after high-dose chemotherapy and ASCT with four choices provided: (1) no consolidative post-transplant therapy; (2) involved-site radiotherapy (ISRT) to the pretransplant PET-avid site; (3) brentuximab consolidation; or (4) ISRT followed by brentuximab consolidation.

Case 1 was modified (modCase1) such that the patient now had a D2 response after second-line therapy. Respondents were asked two questions with responses limited to (a) yes, (b) maybe, and (c) no. Respondents were asked if they would (1) consider consolidative ISRT instead of high-dose chemotherapy and ASCT and (2) consider consolidative ICI therapy instead of high-dose chemotherapy and ASCT. Finally, respondents were asked, if the patient moved forward with high-dose chemotherapy and ASCT, would they recommend post-ASCT radiotherapy. Responses included (1) Yes to the site of bulky mediastinal disease; (2) Yes to all sites of disease at initial relapse; or (3) No.

Management of a case with multiple sites of persistent PET avidity following salvage therapy was presented in Case 2: a 21-year-old female patient with non-bulky stage IIB HL involving the bilateral neck and mediastinum treated with 6 cycles of ABVD and no CRT with relapse at 6 months in the spleen, mediastinum, and neck with Deauville 4 activity in those sites after two different second-line therapies. Respondents were asked for consolidative treatment recommendations following high-dose chemotherapy and ASCT, with the same four responses as Case 1. Descriptive statistics were performed.

Results

Overall, 20 (83%) pediatric oncologists and 4 (17%) radiation oncologist members of the COG Hodgkin Lymphoma committee completed the survey. Median case number of rrpHL reported was 2 to 5 cases per year. The responses to Cases 1 and 2 are presented in Table 1. For both Case 1 and 2, most responded that they would proceed with ISRT followed by brentuximab consolidation. No respondent said they would forego post-ASCT consolidation.

Table 1.

COG Member Responses to Case 1 and Case 2

	Case 1: D4 pre-ASCT single site, n (%)	Case 2: D4 pre-ASCT multisite, n (%)
No consolidative post-ASCT therapy	0	0
ISRT to pre-ASCT PET-avid site	8 (33%)	4 (17%)
Bv consolidation	2 (8%)	2 (8%)
ISRT followed by Bv consolidation	14 (58%)	18 (75%)

Abbreviations: COG, Children’s Oncology Group; n, number of respondents; PET, positron emission tomography; ASCT, autologous stem cell transplant; Bv, brentuximab vedotin; D4, Deauville 4; ISRT, involved site radiotherapy

For modCase1 in which the PET pre-ASCT was Deauville 2 rather than Deauville 4 after two lines of salvage chemotherapy, 63% would possibly consider CRT instead of ASCT, while 38% would possibly consider ICI instead of ASCT. Complete responses are listed in Table 2.

Table 2.

COG Member Responses to modCase 1: D2 PET After Two Lines of Salvage Systemic Therapy

	Consider RT instead of ASCT n (%)	Consider ICI instead of ASCT (%)
Yes	5 (21%)	3 (13%)
Maybe	10 (42%)	6 (25%)
No	9 (38%)	15 (63%)

Abbreviations: COG, Children’s Oncology Group; modCase, modified case; D2, Deauville 2; PET, positron emission tomography; RT, radiotherapy, N, number; ASCT, autologous stem cell transplant; ICI, immune checkpoint inhibitor

For modCase1, when asked if respondents would recommend post-ASCT radiotherapy, 21% would recommend CRT to bulky disease and 38% to all sites at initial relapse. Additionally, 42% would not recommend radiotherapy in this scenario.

Discussion

Multiple options for the management of rrpHL exist, although evidence is lacking to guide practice (9). Overall survival for patients with rrpHL is substantially lower than rates reported in the upfront setting (10,11), underscoring the rationale to provide effective therapy for these patients. In a sample of predominantly pediatric oncologist COG members, most respondents considered that CRT has a role in the treatment of patients with rrpHL, especially cases with Deauville 4 disease prior to ASCT. For cases of Deauville 2 activity after two lines of salvage systemic therapy, the majority would still recommend CRT. Level I data for radiotherapy indications in the relapsed and refractory settings of pediatric HL are lacking. Recently, the National Comprehensive Cancer Network (NCCN) developed guidance for the management of pediatric HL (2) and stated that for refractory and relapsed patients, providers should, “Strongly consider radiation therapy for selected sites that have not been previously irradiated.” A single-institution retrospective review of 46 patients with rrpHL treated at St. Jude Children’s Hospital evaluated differences in the cumulative incidence of local failure after salvage treatment. The 5-year cumulative incidence of local failure after salvage radiotherapy was 12.4% (95% CI, 4.5%-25.1%) among those with an adequate response to salvage chemotherapy compared to 35% (95% CI, 10.0%-64.3%) among those with an inadequate response, emphasizing the importance of radiographic disease assessment on outcome (12). Experts from the EURONET trialist group published their own recommendations on the incorporation of radiotherapy in the rrpHL setting (13). Based on data in adults, indications for peri-transplant radiation included: (1) primary refractory disease; (2) persistent fluorodeoxyglucose (FDG)-avid disease after salvage chemotherapy or after ASCT; (3) specific situations where radiotherapy would be critical for disease control such as compression of a vital structure; and (4) bulky disease (> 5 cm) especially in a site not previously irradiated (13). Radiotherapy was associated with improved disease-free survival (HR 0.357, p=0.032) on Cox regression analysis of a cohort of 92 patients treated at Emory University (14). In a more recent cohort of patients treated uniformly at the University of Minnesota, consolidative radiotherapy was found to significantly improve 2-year progression-free survival (67% vs 42%, p<0.01), with particular benefits in patients with bulky disease, B symptoms, primary refractory disease, and partial response on pre-transplant imaging (15). Among the latter subgroup, radiotherapy for partial remission on pretransplant imaging was associated with an improvement in 2-year progression-free survival of 47% versus 32% without radiotherapy (p=0.02). The findings from our survey of COG experts fall in line with the evidence noting a radiotherapy benefit, particularly among the subgroup of patients with partial remission on pretransplant imaging. In a different study, patients with complete remission to pre-ASCT chemotherapy also demonstrated improved 2-year progression-free survival (64% vs 41%, p = 0.03) (12). For our case scenario in which a patient had Deauville 2 on PET before ASCT, a majority still recommended consolidative radiotherapy – with more respondents recommending consolidating all sites of prior disease compared to bulk alone. The survey also queried pediatric and radiation oncologists on which patients would the respondents consider forgoing ASCT. Data from prior trials including the COG low-risk trial AHOD0431 for patients with newly diagnosed stage I/II classic pediatric HL demonstrated that low-risk relapses (RT naive) managed with additional systemic treatment and consolidative radiotherapy (16) had excellent outcomes The NCCN guidance suggests obviating ASCT only in patients considered highly favorable, that is, those with an initial stage other than IIIB or IVB, naïve to radiotherapy treatment, a disease-free interval exceeding 1 year, and absence of extranodal disease or B symptoms at relapse (2). The EURONET recommendation for patients who may obviate ASCT includes “low-risk” patients meeting the following criteria (13): early relapse after a maximum 4 cycles of first-line chemotherapy or late relapse after a maximum of 6 cycles of first-line chemotherapy meeting all of the following: stage I-III at relapse, no prior radiotherapy or relapse outside prior radiotherapy field, and no excessive radiotherapy fields required in salvage treatment. Additionally, if a patient deemed as “low-risk” does not achieve a complete metabolic response on interim PET, the recommendation is for ASCT.

A particular nuance of the cases provided was the selection of patient sex and age. The association between mediastinal radiotherapy in adolescents and young adults is established, and both cases presented involved young female patients with mediastinal directed ISRT. Aside from the established concerns of cardiopulmonary toxicity, female patients face an added risk of secondary malignancy to breast cancer for which radiotherapy omission may be favored more often compared to male patients. It is notable to consider the high response favoring ISRT in the context of a young female patient. One may conjecture response rates may be even higher if the case patient were male.

While great strides have been made in HL treatment with a goal of maximizing quality of life among survivors, the role of radiotherapy in rrpHL is not clearly defined. In our contemporary era of upfront treatment resulting in the sparing of radiotherapy for many children and adolescents with HL, a majority of COG respondents favored incorporating radiotherapy in the treatment of rrpHL patients with both Deauville 2 and Deauville 4 disease before ASCT. It is noteworthy that there is considerable variation in approaches among pediatric and radiation oncologists, which is further compounded with integration of newer targeted agents, leading to a great opportunity to define a standard approach towards the use of RT in rrpHL through clinical trials.

Data Sharing Statement:

The authors agree to share anonymized data upon reasonable request by researchers.