Study Identifies Two Measures of Tumor Burden for Risk Stratification of Patients With Hodgkin Lymphoma

The presence of bulky disease is commonly used as one factor in categorizing patients with early-stage Hodgkin lymphoma (HL) as having either favorable or unfavorable risk, as well as to determine whether patients can safely de-escalate therapy without compromising disease control. However, because definitions of bulky disease vary, researchers have hypothesized that other, three-dimensional measurements could improve risk stratification and the quantification of disease burden.

Mani Akhtari, MD, of the Department of Radiation Oncology at the University of Texas Medical Branch Hospitals, and co-authors assessed whether two measures of tumor volume on F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) – specifically metabolic tumor volume (MTV; total volumetric sum of all areas of disease) and total lesion glycolysis (TLG; volumetric sum adjusted for standardized uptake value) – could reliably stratify risk among patients with early-stage HL.

According to results published in Blood, MTV and TLG predicted which patients with early-stage HL would have worse outcomes. “Most importantly, we have shown that not all patients with early-stage, unfavorable HL are the same,” the authors noted. “In fact, two distinct categories can be discerned by the MTV or TLG, into low and high disease burdens.”

The investigators retrospectively reviewed the records of all adult patients diagnosed with HL who were treated at the University of Texas MD Anderson Cancer Center in Houston between January 2003 and December 2013. Disease was delineated on pre-chemotherapy PET/CT scans by two methods: manual contouring and sub-thresholding of these contours. Sub-thresholding determined tumor volume with standard uptake volume ≥2.5. MTV; TLG measures were extracted from the threshold volumes (MTVt, TLGt), as well as from the manually contoured soft-tissue volumes (MTVst, TLGst).

They identified 267 patients (median age = 32 years; range = 18-95 years) with Ann Arbor stage I or II disease and a combined initial PET/CT scan (separate PET and CT images merged into a single image). Patients with all histologic HL subtypes were included, except those with nodular lymphocyte-predominant HL. Patients were excluded if they had a follow-up of six months or less, unless they experienced disease progression or death.

For this study, the researchers defined bulky disease as any nodal mass or conglomerate greater than 10 cm in the axial, sagittal, or coronal dimensions. Patients were classified with either unfavorable (n=178; 16%), favorable (n=74; 28%), or stage IIB-advanced (n=15; 6%) disease. Most (n=224; 84%) had stage II disease.

The most common treatment regimen patients received was ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine; n=239; 89%), and 250 patients experienced a complete response following chemotherapy. Three-quarters of patients (n=187) went on to receive consolidative radiation therapy at a median dose of 30.6 Gy (range = 20-42 Gy).

After a median follow-up of 4.96 years (range = 1.03-12.15 years), the five-year rate of freedom from progression (FFP; primary endpoint) was 90 percent (95% CI 86.1-93.5), and the five-year overall survival (OS) was 95.5 percent (95% CI 91.9-98.0). Twenty-seven patients were diagnosed with relapsed or refractory disease, and 12 patients died during follow up.

“There was a high degree of correlation between the two MTV and TLG contouring methods and, given the greater objectivity as well as more prevalent use of the threshold method, we used the MTVt and TLGt for the analysis,” the authors wrote. Univariate analysis determined that the following factors were associated with worse FFP:

  • German Hodgkin Study Group (GHSG) classification, defined as bulky disease, >2 involved sites, and extranodal extension (hazard ratio [HR] = 7.56 for IIB-advanced vs. favorable [p=0.008] and HR=2.89 for unfavorable vs. favorable [p=0.086])
  • not receiving consolidation radiotherapy (HR=4.71; p=0.016)
  • total MTV (for every 100-unit increase in MTVt, HR=1.72; p<0.0005)
  • total TLG (for every 500-unit increase in TLGt, HR=1.13; p<0.005)
  • axial (HR=1.17; p=0.032), sagittal (HR=1.11; p=0.047), or coronal (HR=1.16; p<0.005) diameter of the longest node or nodal conglomerate

When the researchers adjusted for GHSG classification, total MTVt (HR=1.14; 95% CI 1.02-1.26; p=0.016) and total TLGt (HR=1.096; 95% CI 1.00-1.20; p=0.047) were strongly associated with FFP.

Because GHSG classification has been used to assess the risk of treatment failure in patients with HL, the authors also questioned whether adding MTV and TLG improved the predictive accuracy for FFP; results were not statistically different in either model, compared with GHSG alone, suggesting that “both functional parameters add a similar level of predictive ability for FFP.”

They further noted that GHSG groupings had better predictive value when MTVt and TLGt were incorporated into a model. “GHSG grouping [alone] was not significantly associated with outcome, but total MTVt categorization of high (>268) versus low (HR=2.20; 95% CI 0.92-5.25; p=0.076) and TLGt categorization of high (>1,703) versus low (HR=2.822; 95% CI 1.23-6.48; p=0.014) correlated with worse FFP,” they reported. Higher values of both MTVt and TLGt had “worse FFP rates, [had] shorter FFP times, and were more likely to have bulky disease and IIB-advanced stage disease.”

In addition, FFP was significantly worse for patients with unfavorable disease and high MTV or TLG, compared with those with low MTV or TLG (p<0.001); a significant difference was not observed in patients with favorable HL. “This finding allows us to sub-stratify patients with unfavorable [disease] into two distinct categories: early-stage, low-risk unfavorable and early-stage, high-risk unfavorable,” the authors concluded, which could better identify which patients would benefit from treatment escalation.

The study is limited by its retrospective design and small number of events. Most patients were considered to have early-stage unfavorable disease, so the results may not be generalizable to patients with favorable and IIb-advanced disease. The authors noted that future studies will need to confirm these findings and validate the MTV and TLG cutoff thresholds used in the present study.

The authors report no relevant conflicts of interest.


Reference

Akhtari M, Milgrom SA, Pinnix CC, et al. Re-classifying patients with early-stage Hodgkin lymphoma based on functional radiographic markers at presentation. Blood. 2017 October 16. [Epub ahead of print]

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