Relapse Analysis of Irradiated Patients Within the HD15 Trial of the German Hodgkin Study Group

doi:10.1016/j.ijrobp.2015.01.048

International Journal of Radiation OncologyBiologyPhysics

Volume 92, Issue 1, 1 May 2015, Pages 46-53

Presented at the 55th Annual Meeting of the American Society for Radiation Oncology, September 22-25, 2013, Atlanta, GA.

https://doi.org/10.1016/j.ijrobp.2015.01.048 Get rights and content

Purpose

To determine, in the setting of advanced-stage of Hodgkin lymphoma (HL), whether relapses occur in the irradiated planning target volume and whether the definition of local radiation therapy (RT) used by the German Hodgkin Study Group (GHSG) is adequate, because there is no harmonization of field and volume definitions among the large cooperative groups in the treatment of advanced-stage HL.

Methods and Materials

All patients with residual disease of ≥2.5 cm after multiagent chemotherapy (CTX) were evaluated using additional positron emission tomography (PET), and those with a PET-positive result were irradiated with 30 Gy to the site of residual disease. We re-evaluated all sites of disease before and after CTX, as well as the PET-positive residual tumor that was treated in all relapsed patients. Documentation of radiation therapy (RT), treatment planning procedures, and portal images were carefully analyzed and compared with the centrally recommended RT prescription. The irradiated sites were compared with sites of relapse using follow-up computed tomography scans.

Results

A total of 2126 patients were enrolled, and 225 patients (11%) received RT. Radiation therapy documents of 152 irradiated patients (68%) were analyzed, with 28 irradiated patients (11%) relapsing subsequently. Eleven patients (39%) had an in-field relapse, 7 patients (25%) relapsed outside the irradiated volume, and an additional 10 patients (36%) showed mixed in- and out-field relapses. Of 123 patients, 20 (16%) with adequately performed RT relapsed, compared with 7 of 29 patients (24%) with inadequate RT.

Conclusions

The frequency and pattern of relapses suggest that local RT to PET-positive residual disease is sufficient for patients in advanced-stage HL. Insufficient safety margins of local RT may contribute to in-field relapses.

Introduction

The combination of multiagent chemotherapy (CTX) and radiation therapy (RT) has improved survival rates of patients with Hodgkin lymphoma (HL), and the combined-modality approach has become the standard of care for patients in early favorable and early unfavorable stages 1, 2, 3. Today HL is one of the most favorable cancers in terms of cure. The role of consolidative RT after intense CTX for patients in advanced stages is discussed controversially. Results of randomized trials challenged the benefit of adjuvant RT 4, 5, 6, 7, 8, 9, and therefore the European Organization for Research and Treatment of Cancer (EORTC) conducted a trial to determine the role of consolidative RT after CTX. The data of this analysis showed no improvement in outcome when adding consolidative involved-field RT (IF-RT) for patients in complete remission after CTX (10). However, patients in partial remission treated with IF-RT had the same outcome as patients in complete remission (10).

In addition, the German Hodgkin Study Group (GHSG) HD12 trial for patients in advanced stages also evaluated the value of consolidative local RT to initial bulky regions and/or sites of residual disease after BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) CTX. The final analysis of the HD12 trial demonstrated that patients with residual disease show improved progression-free survival (PFS) due to consolidative RT (11).

The following GHSG HD15 trial for advanced HL investigated the value of fluorodeoxyglucose positron emission tomography (FDG-PET) for treatment stratification in patients with advanced stages. After completion of CTX, all patients with residual disease of ≥2.5 cm underwent PET, and those with PET-positive results were irradiated with 30 Gy local RT to the site of residual disease; for bone lesions RT was also recommended (12).

The aim of the present analysis was to determine whether relapses occur in the irradiated planning target volume (PTV) and whether the definition of local RT used by the GHSG is adequate, because there is no harmonization of field and volume definitions among the large cooperative groups in the treatment of advanced-stage HL. In addition, we analyzed the correlation between quality of RT and risk of relapse.

Section snippets

Study design

The HD15 trial (recruitment 2003-2008) was an open, multicenter, randomized trial. Included were patients with de novo HL in advanced stages (ie, Ann Arbor stage IIB having a large mediastinal mass [one-third or more of the maximal thoracic diameter] or extra nodal lesions, and all patients in stages III and IV). Patients were randomly assigned to receive either 8 cycles BEACOPP escalated (Besc), or 6 cycles Besc, or 8 cycles BEACOPP14 (B14). After completion of CTX patients were restaged, and

HD15 trial

A total of 2126 patients were eligible in the final analysis. Five-year freedom from treatment failure was 84.4% for the 8×Besc group, 89.3% for the 6×Besc group, and 85.4% for the B14 group. Overall survival in the 3 groups was 91.9%, 95.3%, and 94.5%, respectively, and significantly better in the 6×Besc group compared with the 8×Besc group. The 8×Besc group showed a higher mortality.

After CTX, 822 patients with residual disease were evaluated using FDG-PET. Of those, 739 patients were

Discussion

The aim of the present analysis was to evaluate whether relapses occur in the irradiated sites and whether the definition of local RT used by the GHSG is adequate, because the international study groups are using different RT strategies in the treatment of patients with advanced-stage HL. In addition we analysed the correlation between quality of RT and patterns of relapse.

This study produced the following results: (1) Local RT with 30 Gy to PET-positive residuals after 6 cycles BEACOPP

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Radiation Therapy for Advanced-Stage Hodgkin Lymphoma
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Citation Excerpt :
Patterns of relapse studies prove to be informative for designing the optimal RT field for AS-HL patients. For GHSG H15, which gave RT postchemotherapy to residual PET-positive disease ≥2.5 cm and bone lesions, Kriz et al reported the patterns of relapse for 152 irradiated patients for whom RT documents were available (68% of the irradiated patients).28 RT was given locally with a 1.5-cm margin around the gross tumor volume, which was defined as the residual PET-positive tumor as well as any CT correlates in the same area.
The backbone of treatment for patients with advanced-stage Hodgkin lymphoma is systemic therapy. The use of radiation therapy as a component of combined-modality treatment in this setting is controversial. In this review, we describe the data in support of and against the use of radiation therapy for stage III and IV Hodgkin lymphoma. Specifically, we review the data for the use of radiation therapy in the consolidation and partial-response settings, including for patients with initial bulky disease. We also discuss the use of radiation therapy in the era of more modern systemic therapies, including checkpoint inhibitors and brentuximab vedotin.
Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lymphoma Radiation Oncology Group Guidelines
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After esc-BEACOPP, RT is effective for patients with residual FDG-avid masses ≥2.5 cm in largest diameter.138,139 An adequate ISRT volume should include the contiguous non-FDG–avid soft tissue mass.48,138 On occasions when RT is given after ABVD chemotherapy, the CTV includes residual PET-negative masses generally corresponding to initially bulky sites.
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Ten patients with PHL treated with proton therapy to 21 Gy involved-site radiation therapy (ISRT_21Gy) were replanned to deliver 30 Gy by treating the ISRT to 30 Gy (ISRT_30Gy), delivering 21 Gy to the ISRT plus a 9-Gy boost to postchemotherapy residual volume (rISRT_boost), and delivering 30 Gy to the residual ISRT target only (rISRT_30Gy). Radiation doses to the OARs were compared.
The ISRT_30Gy escalated the dose to the target by 42% but also to the OARs. The rISRT_boost escalated the residual target dose by 42%, and the OAR dose by only 17% to 26%. The rISRT_30Gy escalated the residual target dose by 42% but reduced the OAR dose by 25% to 46%.
Boosting the postchemotherapy residual target dose to 30Gy can allow for dose escalation with a slight OAR dose increase. Treating the residual disease for the full 30Gy, however, would reduce the OAR dose significantly compared with ISRT_21Gy. Studies should evaluate these strategies to improve outcomes and minimize the late effects.
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Radiation doses to mediastinal organs at risk in early-stage unfavorable Hodgkin lymphoma– a risk stratified analysis of the GHSG HD17 trial
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High-risk stage IIB Hodgkin lymphoma treated in the H10 and AHL2011 trials: total metabolic tumor volume is a useful risk factor to stratify patients at baseline
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: Conflict of interest: none.

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Clinical InvestigationRelapse Analysis of Irradiated Patients Within the HD15 Trial of the German Hodgkin Study Group

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Study design

HD15 trial

Discussion

Int J Radiat Oncol Biol Phys

Ann Oncol

Blood

Lancet

Int J Radiat Oncol Biol Phys

Blood

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma

N Engl J Med

Clinical Investigation
Relapse Analysis of Irradiated Patients Within the HD15 Trial of the German Hodgkin Study Group