Bulky Disease Does Not Adversely Affect Overall Survival in Early Stage Hodgkin Lymphoma: Role of Interim PET and Possible Omission of Radiotherapy in Select Patients
Authors: Pophali Priyanka A , Rybicki Lisa A. , Fenner Kathleen B , Jagadeesh Deepa , Dean Robert M , Pohlman Brad , Smith Mitchell R. , Hill Brian T. 
Published: October 2019

Abstract
Background: Bulky disease is considered a major driver of unfavorable prognosis in early stage Hodgkin Lymphoma (HL). Treatment guidelines for bulky early stage HL call for more aggressive initial therapy compared to non-bulky disease. There are limited data on outcomes in bulky disease, particularly in patients treated with chemotherapy alone, or on the utility of interim PET scans. We retrospectively analyzed data on patients with early stage HL to assess the impact of disease bulk, interim PET and treatment modality on outcomes.
Methods: We reviewed charts of 151 consecutive patients diagnosed with previously untreated early stage (I & II) HL at the Cleveland Clinic from 1995-2011. Bulky disease was defined as a mediastinal mass >1/3 intra-thoracic diameter on PA chest x-ray or any mass ≥ 10 cm on CT scan at diagnosis. Patients were grouped by intent to treat strategy as chemotherapy alone (C) or combined modality treatment (CMT) with chemo-radiation. Baseline characteristics were compared: categorical variables by the Chi-square or Fisher's exact test; continuous variables by the Wilcoxon rank sum test. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method and compared by the log-rank test. Cox proportional hazards analysis was used to test univariable prognostic factors for OS and PFS.
Results: 121 patients (mean age 40±16) with early stage HL had adequate clinical data for inclusion. At the time of review, 106 (87.6%) patients were alive with median follow-up of 47.4 (0-328) months. Characteristics at diagnosis were: 54% female; 80% Caucasian; 77% nodular sclerosis HL; 78% stage II; 31% with B-symptoms; 12% with extranodal disease; 30% (N =36) with bulky disease of whom 89% had bulky mediastinal disease. 96% patients received standard ABVD chemotherapy.
The only significant differences in the baseline characteristics of patients with bulky vs. non-bulky disease were age (mean 35 vs. 42 years, P=0.03), hemoglobin (mean 12.4 vs. 13.4 g/dL, P=0.01) and absolute lymphocyte count (mean 1.29 vs. 1.71 k/µL, P=0.02). Although there was no statistically significant difference in the initial treatment strategy chosen, patients with bulky disease tended to receive CMT more often than patients with non-bulky disease (66% vs. 51%, P=0.16). More females were treated with C compared to CMT (70% vs. 43%, P=0.004). Patients with bulky disease received a greater number of chemotherapy cycles (mean 5.6 vs. 4.6, P=0.01).
Five years after diagnosis, patients with non-bulky HL had Kaplan-Meier estimates of 83% OS and 69% PFS while patients with bulky HL had 88% OS and 81% PFS. There was no statistical difference in OS [Figure 1] or PFS based on disease bulk.
Analysis of the available PET status (65 interim scans) revealed that both the bulky and non-bulky patients had comparable responses on interim PET (negative 82.6% vs. 95.2%, P=0.17). Interim PET scan was highly prognostic for all early stage HL patients for both OS (P < 0.01) and PFS (P < 0.001) as well as specifically for patients with bulky disease (negative vs. positive PET: 5 year OS 90% vs. 75%, P=0.012; 5 year PFS 95% vs. 25%, P<0.01 [Figure 2]).
Among the 23 patients with bulky disease managed with initial CMT, 4 required 2nd line treatment including 3 who underwent autologous stem cell transplant (Auto-SCT). Among the 12 patients managed initially with C, 5 required 2nd line treatment and all 5 underwent Auto-SCT. In total, among those with bulky disease, the OS and PFS were similar irrespective of initial treatment strategy chosen.
In univariate analysis, extra-nodal disease was the only baseline variable that impacted PFS (HR=2.7, CI 1.01-7.20, P=0.048) but did not affect OS (HR=2.46, CI 0.66-9.19, P=0.18).
Conclusions: Patients with bulky early stage HL have comparable survival to patients with non-bulky disease. Among patients with bulky disease, treatment with initial C or CMT resulted in comparable OS and PFS, although a higher proportion of patients treated with C alone required 2nd line treatment. These data support the observation that radiation therapy is not essential to achieve cure in bulky HL. Specifically, omitting radiation in female patients who achieve a negative interim PET scan is a viable treatment strategy which may mitigate the long-term risks of radiation.
Figure 1: OS in Early Stage HL Based on Disease Bulk Figure 1:. OS in Early Stage HL Based on Disease Bulk
Figure 2: PFS in Bulky Early Stage HL Based on Interim PET Figure 2:. PFS in Bulky Early Stage HL Based on Interim PET

Disclosures
No relevant conflicts of interest to declare.