Prognostic Values of Baseline 18F-FDG PET/CT in Patients with Peripheral T-Cell Lymphoma

Purpose In the present study, we aimed to investigate whether the metabolic parameters on baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) could be used to predict prognosis in peripheral T-cell lymphomas (PTCL). Methods A total of 51 nodal PTCL patients who underwent baseline 18F-FDG PET/CT were retrospectively evaluated in the present study. Total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), and maximum standardized uptake value (SUVmax) were also assessed. Besides, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) was also included. Log-rank test and Cox regression analysis were used to evaluate progression-free survival (PFS) and overall survival (OS). Results The median follow-up was 18 months. Patients with low TLG, TMTV, and SUVmax levels had a significantly better clinical outcome than those with high TLG, TMTV, and SUVmax levels. The 2-year PFS rates of the high- and low-TMTV groups were 34.62% and 80%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (p < 0.001), whereas the corresponding 2-year OS rates were 46.15% and 84.00%, respectively (n = 10), intermediate-risk group with TMTV > 62.405 or NCCN-IPI score of 4-8 (2-year PFS and OS were 52.4% and 66.7%, respectively, n = 10), intermediate-risk group with TMTV > 62.405 or NCCN-IPI score of 4-8 (2-year PFS and OS were 52.4% and 66.7%, respectively, n = 10), intermediate-risk group with TMTV > 62.405 or NCCN-IPI score of 4-8 (2-year PFS and OS were 52.4% and 66.7%, respectively, Conclusions Baseline TMTV and TLG were independent predictors of PFS and OS in PTCL patients, and SUVmax and NCCN-IPI scores were also independent predictors of OS. Moreover, the combination of TMTV and NCCN-IPI scores improved patient risk-stratification at the initial stage and might contribute to the adjustment of the therapeutic regime. This trial is registered with ChiCTR1900025526.


Patients.
A total of 51 PTCL patients who underwent pre-treatment 18 F-FDG PET/CT from March 2013 to May 2019 were enrolled in the present study. Inclusion criteria were set as follows: (1) histopathologically confirmed as PTCL (PTCL-NOS, AITL, or ALCL ALK-) and (2) availability of digital image data for analysis. ALCL ALK+ patients who had superior outcome after CHOP or CHOP-like regimens were excluded.
Characteristics of patients included age, gender, B symptoms, LDH (lactate dehydrogenase) level, IPI score, NCCN-IPI score, prognostic index for T-cell lymphoma (PIT) score, Eastern Cooperative Oncology Group (ECOG) performance status, Ann Arbor stage, bone marrow biopsy, and PET/CT data.
2.2. PET/CT Acquisition. All patients underwent 18 F-FDG PET/CT images (Discovery STE; General Electric Medical Systems, Milwaukee, WI, USA). Patients were fasted for at least 6 h before the 18 F-FDG PET/CT, and the blood glucose level was lower than 11 mmol/L. PET and CT images were obtained at 60 ± 10 min after the tracer injection (4.07-5.55 MBq/kg). CT images were acquired at 120 mA, 140 kV, transaxial FOV of 70 cm, pitch of 1.75, rotation time of 0.8 s, and slice thickness of 3.75 mm. PET emission images were acquired from the top of the skull to the upper thigh, 2 min per bed position. PET images were reconstructed with iterative algorithms, with CT data for attenuation correction.
2.3. Image Analysis. All images were retrospectively analyzed using Advantage Workstation 4.3_05 by two experienced nuclear medicine physicians. Maximal standardized uptake value (SUV max ) was determined as the highest SUV of the pixel in the region of interest (ROI). Baseline TMTV, summing the volumes of all hyper-metabolic lesions, was computed using the SUV max threshold of 41% [18]. Bone marrow involvement was considered in volume measurement only if there was focal uptake. Spleen was considered as involved if there was focal uptake or diffuse uptake higher than 150% of the liver background [19]. The TLG was calculated using the following equation: TLG = MTV * SUV mean .

Statistical Analysis.
Statistical analyses were performed using GraphPad Prism 5.0 software (San Diego, CA, USA) and SPSS 22.0 software (IBM, Chicago, IL, USA). Differences in clinical variables between TMTV and TLG groups were analyzed by Pearson chi-squared test and Fisher's exact test. Correlation between TMTV or TLG and clinical prognostic factors was assessed using the Spearman's rank correlation test. Receiver-operating characteristic (ROC) analysis was used to determine the optimal cutoff values for SUV max ,    Table 1 summarizes the patient's characteristics.

Role of 18 F-FDG PET/CT in Outcome Prediction.
Kaplan-Meier analysis revealed that patients with low TLG, TMTV, and SUV max levels had a better clinical outcome than those with high TLG, TMTV, and SUV max levels (Figures 1-3). The 2-year PFS rate of the high-and low-TMTV groups was 34.62% and 80%, respectively (p < 0:001). The 2-year OS rate of the high-and low-TMTV groups was 46.15% and 84.00%, respectively (p < 0:001). The median OS was 13 months in patients with higher TMTV (>62.405). The 2-year PFS rate of the high-and low-TLG groups was 29.63% and 87.50%, respectively (p < 0:001). The 2-year OS rate of the high-and low-TLG groups was 40.74% and 91.67%, respectively (p < 0:001). The median OS was 18 months in patients with higher TLG (>270.725).
In univariate analysis (Table 3), ECOG status, IPI scores, TLG, TMTV, and SUV max were all correlated with both PFS and OS whereas age, NCCN-IPI, and PIT scores were correlated with only OS but not PFS. By Spearman's rank correlation test, there was a strong correlation between TMTV and TLG (r = 0:929, p < 0:001, Table 4). Therefore, TMTV or TLG was, respectively, incorporated into a multivariate analysis with other clinical features. In multivariate analysis (Table 5), TLG and TMTV were independent prognostic factors of both PFS (HR 11.562, 95% CI 3.218-41.542, p < 0:001

Discussion
The International Conference on Malignant Lymphoma (ICML) recommends investigating the quantitative parameters of 18 F-FDG PET/CT for prognostic analysis [21]. Several studies have demonstrated that tumor burden is a poor prognostic factor for different subtypes of lymphoma [13][14][15][16][17]22]. This has led to an increased interest in assessing prognosis using baseline TMTV and TLG, occasionally in combination with clinical scores [23,24].
In this retrospective study, we investigated the prognostic value of TMTV and TLG at baseline PET/CT and found that patients with high TMTV or TLG values showed shorter PFS and OS than those with low TMTV and TLG values. Mehta-Shah et al. [19] has reported that baseline TMTV is an independent predictor of PFS and OS in PTCL patients. Cottereau et al. [25] have conducted a multicenter retrospective analysis on 140 nodal PTCL patients and confirmed a poor prognostic value for the high TMTV in baseline PET/CT images for the prediction of PFS and OS. These results are similar to ours. However, we also confirmed that both baseline TMTV and TLG, which were not included in other reports, were also independent prognostic factors of PFS and OS in nodal PTCL in our study. Nevertheless, some studies have different results [23,26]. Cottereau et al. [23]    BioMed Research International have found that the TMTV rather than TLG remains the only independent predictor for both PFS and OS in PTCL patients and high values of TMTV predict a worse prognosis. In a multicenter retrospective study, Pak et al. [26] have found that baseline TLG is the only independent prognostic factor for PFS in patients with extranodal nasal-type NK/T cell lymphoma. We speculated that such discrepancy could be attributed to the strong correlation between TMTV and TLG, leading to a wrong assessment when they are all included in the multivariate analysis. Furthermore, NCCN-IPI score was also an independent prognostic factor for OS. Patients with an NCCN-IPI score of 0-3 had better clinical outcome than the group with an NCCN-IPI score of 4-8. Some studies have shown that combination of baseline PET/CT parameters and clinical prognostic indices allows us to stratify the progression risk of lymphoma patients [23,24,27,28]. In our present study, we combined TMTV > 62:405 cm 3 and NCCN-IPI score to stratify patients into three risk categories. Patients with both TMTV > 62:405 cm 3 and an NCCN-IPI score of 4-8 had a very poor outcome, with a median OS of 10 months.
SUV max is the most widely used indicator in clinical practice. In a retrospective study consisting of 86 patients, Hwang et al. [29] have shown that patients with a higher SUV max      [26] and Chang et al. [30] have shown similar results that a higher SUV max value is significantly associated with tumor aggressiveness in patients with T-cell lymphoma. However, there are also controversial results. Some studies have suggested that there is no significant correlation between SUV max and prognosis in patients with aggressive NHL [31][32][33]. In our present study, we demonstrated that SUV max was an independent predictor of OS but not PFS. Such difference could be attributed to the heterogeneity of different lymphomas. In addition, the SUV max only represents the glucose metabolism of the most aggressive tumor tissue, which might be another reason for the different outcomes, especially in aggressive NHL.
In some studies, the absolute threshold of SUV ≥2.5 is used to calculate MTV [15,34]. However, SUV values are likely to be affected by partial volume effect, time after injection, and blood glucose level [35,36]. In our present study, MTV was measured using a SUV max threshold of 41% [18]. This potentially overestimated the lesion volume of small tumors. However, only one patient had the volume of tumor < 4 cm 3 in our study. In addition, this also potentially underestimated the lesion volume of high SUV max . However, in our study, only four patients had SUV max > 15 and there was no significant difference in SUV max between patients with higher or lower TMTV. The 41% SUV max threshold method shows an excellent interobserver agreement, and it has been used in different subtypes of lymphoma [14,27,[37][38][39]. To the best of our knowledge, there is no consensus on the MTV calculation method. Recent studies have shown that baseline TMTV values are significantly affected by the choice of the marginal threshold methods [40]. Therefore, it is necessary to define the metabolic volume using an accurate and standardized method.
This study has some limitations. First, this was a singlecenter retrospective analysis with a relatively short followup. In particular, four patients were followed for no more than 6 months because they died of progressive PTCL. Additionally, the number of patients who underwent 18 F-FDG PET/CT after 3-4 cycles of chemotherapy (n = 18) and after all planned first-line therapy (n = 25) was quite small. Therefore, the prognostic role of interim and end-of-treatment PET/CT should be further validated in future trials consisting of larger patient samples.

Conclusions
Baseline TMTV and TLG were independent predictors of PFS and OS in PTCL patients, and SUV max and NCCN-IPI scores were also independent predictors of OS. Moreover, the combination of TMTV and NCCN-IPI scores improved patient risk-stratification at the initial stage, which might contribute to the adjustment of the therapeutic regime.

Data Availability
The data used to support the findings of this study are available from the corresponding author upon request.

Ethical Approval
This study was conducted in accordance with the Declaration of Helsinki. The experimental protocols involving human subjects were approved by the institutional review board of the First Affiliated Hospital of Soochow University with a waiver of informed consent.

Consent
Informed consent is not required for this type of study.

Conflicts of Interest
The authors report no conflicts of interest.