Factors with prognostic significance in early-stage Hodgkin lymphoma (HL) include bulky disease, number of regions involved, advanced age, and the presence of B symptoms. According to research published in Blood, though, baseline total metabolic tumor volume (TMTV) as assessed by positron emission tomography (PET) appears to be a better tool for stratifying early response among patients with early-stage HL. “This study clearly shows the independent prognostic value of baseline TMTV,” wrote lead author Anne Ségolène Cottereau, MD, of Hôpital Cochin in Paris, France, and colleagues of the findings.
The researchers enrolled patients from the randomized H10 Intergroup trial (n=549) that evaluated treatment adaptation based on interim PET response after two treatment cycles (iPET2). Only 258 patients (median age = 31 years; range = 15-71 years) were suitable for TMTV calculation.
All participants received ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), followed by 30 Gray involved-node radiotherapy, regardless of iPET2 result. Eligible patients had supradiaphragmatic stage I and II HL and TMTV that could be computed from baseline PET scan.
Participants were categorized as having favorable or unfavorable disease according to European Organisation for Research and Treatment of Cancer (EORTC)/Lymphoma Study Association criteria. Unfavorable disease was defined as having at least one of the following: ≥50 years of age, ≥4 nodal areas, mediastinal-thoracic-ratio ≥0.35, no B symptoms and erythrocyte sedimentation rate (ESR) ≥50, or B symptoms and ESR ≥30.
Patients in the favorable group (n=101) received three cycles of treatment; patients in the unfavorable group (n=157) received four cycles of treatment.
“If these data are confirmed, [they] may help to design new response-adapted therapeutic strategies.”
—Anne Ségolène Cottereau, MD
After a median follow-up of 55 months (range not reported), 27 progression-free survival (PFS) events (defined as disease progression, relapse, or death) occurred, only three of which occurred in the favorable arm. Twelve overall survival (OS) events were also reported, none of which occurred in the favorable arm.
Five-year PFS was 88 percent, and five-year OS was 95 percent. Rates appeared to be higher among those with favorable disease than unfavorable disease (PFS = 95% and 84%; OS = 100% and 92%, respectively). Survival rates did not significantly differ from those in the original H10 Intergroup cohort who were not included in this study, the authors reported.
At baseline, median TMTV was 67 cm3 (interquartile range = 32-114 cm3), and there was a significant difference between the unfavorable and favorable disease cohorts (median = 87 cm3 vs. 48 cm3, respectively; p<0.0001).
Patients were classified based on tumor burden: 212 low (TMTV ≤147 cm3) and 46 high (TMTV >147 cm3). High TMTV was associated with:
- extension of disease
- significantly bulkier mediastinum
- more nodal involved areas
- stage II disease
- B symptoms
- higher ESR
High TMTV was also associated with significantly worse outcomes, including:
- shorter PFS (hazard ratio [HR] = 5.2; p<0.0001)
- shorter OS (HR=7.2; p=0.0001)
- lower rates of 5-year PFS (71% vs. 92%; p<0.0001)
- lower rates of 5-year OS (83% vs. 98%; p<0.0001)
“The prognostic value of TMTV was not impacted by the stratification on the treatment arm,” the researchers wrote. In a sub-analysis of patients with unfavorable disease, TMTV maintained prognostic significance for both PFS (HR=4.2; p=0.0001) and OS (HR=4.0; p=0.0035). Also, patients with low-volume TMTV (74%) – despite having unfavorable disease – had a five-year PFS of 90 percent and OS of 96 percent, compared with 67 percent and 80 percent, respectively, for patients with high-volume TMTV.
The investigators then compared the prognostic value of TMTV with other baseline clinical and biologic factors, including those used in the EORTC, German Hodgkin Study Group, and National Comprehensive Cancer Network staging systems. Multivariate analysis revealed that, of all these factors, only TMTV and iPET2 retained statistical significance for both PFS and OS (see TABLE).
“Most of the parameters included in the risk-assessment systems currently available for stratifying early-stage HL are variably correlated to disease extent, number, [and] size of the area involved,” the authors wrote. “Indeed, they are indirect and inaccurate surrogates for tumor burden.” The frequency of iPET2 positivity was significantly higher in patients with high TMTV, the authors reported, suggesting that “PET/computed tomography could be more appropriate to estimate tumor burden.”
In patients with a positive iPET2 (n=21), high TMTV was associated with an HR for PFS of 3.4 (p=0.026) and 12.9 for OS (p=0.002). TMTV also identified a group of participants with negative iPET2 (n=237; 92%) who ultimately had a poor prognosis (HR for PFS=4.6; p=0.0009 and HR for OS=0.02; p value not reported). Also, patients with a negative iPET2 and a high baseline TMTV had a five-year PFS of 82 percent, compared with 95 percent for those with low baseline TMTV.
The study demonstrates the “value of TMTV, an imaging biomarker [that is] available at diagnosis, measurable in early-stage HL, and superior to the clinical and biologic parameters already used,” the researchers concluded.
The study is limited by a small number of patients in each risk group. The results of the study should also be validated in another independent data set, and “if these data are confirmed, may help to design new response-adapted therapeutic strategies,” the authors noted.
Chugai Pharmaceutical provided support for the study.
The authors report no financial conflicts.
Cottereau AS, Versari A, Loft A, et al. Prognostic value of baseline metabolic tumor volume in early stage Hodgkin’s lymphoma in the standard arm of H10 trial. Blood. 2018 January 23. [Epub ahead of print]