Should a Bulky Mediastinal Mass ≥7cm in the Longest Dimension be Considered an Adverse Prognostic Factor in Patients with Advanced Hodgkin Lymphoma and Negative Interim PET/CT?
Authors: Dann Eldad J , Lopez-Alonso Rebeca , Qi Shunan , Mashiach Tania , Weiler-Sagie Michal , Yahalom Joachim 
Published: November 2019

Introduction: Nowadays, treatment decision making in advanced Hodgkin lymphoma (ad-HL) is based on pre-therapy risk factors and interim PET/CT (PET-2) results, used as a platform for therapy modification. In the past, a bulky mediastinal mass (BMM) was not found to be a significant risk factor and was not included in the final version of the International Prognostic Score (IPS) system (Hasenclever, NEJM 1998). The current study aimed to assess the effect of BMM presence on relapse-free survival (RFS) in patients (pts) with ad-HL and to determine the optimal cutoff of the mass size for outcome prediction in the PET/CT era.
Methods: The Israeli Hodgkin Lymphoma Study Group selected to initiate therapy with standard BEACOPP (SB: bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) or ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) in HL pts with IPS 0-2 and with intensified therapy using escalated BEACOPP (EB: bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) in pts with IPS ≥3. Treatment was modified according to PET-2 results. To pts with negative PET-2 another 4 cycles of SB/ABVD were administered. PET-2 positive pts received 4 EB cycles followed by radiation therapy (Dann, Blood 2007). In the present study, disease bulkiness, assessed using baseline PET/CT, was retrospectively evaluated in a cohort of HL pts. The data included measurements of the longest diameter of either the biggest single mass or a conglomerate of lymph node masses in the transverse or coronal plane in the PET/CT image. Prognostic values of mediastinal mass cutoffs of ≥5 cm, ≥7 cm, >10 cm for RFS and progression-free survival (PFS) were compared.
Results: One hundred and ninety six pts (female/male: 46/54%) with ad-HL [stage IIB - 28, stage III - 74, stage IV - 94; IPS 0-2 - 104; IPS 3-7 - 92; median age 31 years (16-85)] treated at the Rambam Health Care Campus (n=121) and Memorial Sloan Kettering Cancer Center (n=75) between 2000-2016 were included in the analysis. Mediastinal masses ≥5 cm, ≥7 cm and >10 cm were observed in 125 (63%), 82 (42%), 36 (18%) pts, respectively. PET-2 was negative in 79% of pts.
At a median follow-up of 66.5 (1-222) months [80 (4-222) for pts without disease progression and 12 (1-62) for those with relapse or progression], estimated 5-year RFS and PFS for the entire group were 82% and 79%, respectively. A mass of up to 7 cm was found in 62 % of pts (n=123); 22% (n=44) had a mass measuring between 7 and 9.9 cm and 15% (n=29) had a mass ≥10 cm. Mediastinal masses were prevalent in 126/196 (64%) pts; in 58 (30%) of them the mediastinal mass, while being biggest, did not exceed 7 cm, and 68 (34%) had BMM of ≥7 cm. We found no effect of bulky disease, either mediastinal or non-mediastinal, on the outcome of the PET-2 positive group. Univariate analysis showed that in pts with negative PET-2, BMM ≥7 cm was a significant adverse prognostic factor for both 5-year RFS and PFS (HR 2.85; 95% CI 1.09-7.41; p=0.032 and HR 2.86; 95% CI 1.1-7.45; p=0.032, respectively).
Outcome comparison of PET-2 negative pts with BMM (≥7 cm) to pts with negative PET-2 and either non-mediastinal or mediastinal non-bulky (<7cm) masses (reference group) revealed an inferior 5-year RFS of 73% versus 89% (HR 2.97; 95% CI 1.37-6.42; p=0.006) in the former group. Of note, both groups received an ABVD/SB regimen. HR for RFS was insignificant when a mass size cutoff of ≥5 cm or >10 cm was used. The HR for RFS was particularly high in the comparison between the subgroup of PET-2 negative pts with IPS 0-2 and BMM (≥7 cm) and those with IPS 0-2 in the reference group, demonstrating a 5-year RFS of 59% versus 89% with HR of 4.20 (95% CI 1.59-11.05; p=0.004). PET-2 negative pts with IPS 3-7 and BMM (≥7 cm) did not have an inferior outcome compared to pts with IPS 3-7 from the reference group (5-year RFS of 82% versus 89%). Notably, the two groups were treated with an EB-containing regimen. Our results indicate that BMM is an important adverse prognostic factor predominantly for pts with IPS 0-2. Multivariate Cox regression analysis identified BMM ≥7 cm as the most significant adverse prognostic factor for RFS (Table 1; Fig. 1).
Conclusions: In PET-2 negative pts with ad-HL, mediastinal masses ≥7 cm in any plane are associated with the highest risk for HL progression. These findings should be incorporated in a new prognostic scoring system upon more extensive evaluation in a larger cohort.

Disclosures
No relevant conflicts of interest to declare.