The Impact of Baseline and Interim PET/CT Parameters on Clinical Outcome in Patients with Diffuse Large B Cell Lymphoma
Taking a step forward from the IPI, attention is focused on the role of 18F-FDG PET/CT as a tool for guidance in risk stratification in patients with aggressive non-Hodgkin's lymphoma (NHL). Here, we analyzed the predictive value of various PET/CT parameters in patients with DLBCL. Particularly, we were interested in patients with an IPI score of 1, 2, or 3, whose prognosis are confusing. Between Jul 2008 and Feb 2010, a total of 100 patients (including 57 patients with an IPI score of 1-3) who were treated with R-CHOP for DLBCL, and had assessable PET/CT parameters were analyzed in this study. Absolute value of SUVmax, SUVsum(sum of SUVmax) and TLGsum(SUVmean x Volumemeta) from baseline and interim PET/CT, and ΔSUVsum, ΔSUVmax, and ΔTLGsum between baseline and interim PET/CT were selected as PET/CT parameters. The median number of R-CHOP cycles was 6, and interim PET/CT was performed after 2 or 3 cycles. None of the parameters which showed percentile change between initial and interim PET/CT were associated with prognosis. Instead, absolute value of SUVsum from baseline PET/CT, and SUVmax and SUVsum from interim PET/CT were significantly relevant to PFS in all patients, and in patients with an IPI score of 1–3.
The international prognostic index (IPI) has been the most powerful predictor of outcome in patients with aggressive non-Hodgkin's lymphoma (NHL) since 1990s . However, with the introduction of novel treatment with superior effectiveness, the significance of this prognostic system had to be re-evaluated. Because of the benefit from addition of rituximab to conventional CHOP chemotherapy in every aspect of long term outcome [2–6], R-CHOP is currently the standard chemotherapy in patients with diffuse large B cell lymphoma (DLBCL). In the era of new immunochemotherapy, Sehn et al. re-evaluated the utility of IPI , which remains predictive, but distinguishes only two risk groups, rather than the four groups. They redistributed IPI factors into the revised-IPI (R-IPI), which identifies three distinct prognostic groups with significantly different outcomes. Considering IPI and R-IPI together, “zero” and “4 or 5” risk factors consistently remained its “excellent” and “worst” prognostic significance; however, prognostic significance of “1 or 2 or 3” risk factors are confusing according to different classifications with an intermediate to poor prognostic prediction. Therefore, development of novel prognostic marker for patients with an IPI score of 1, 2, or 3 might have important clinical implication in risk stratification and in appropriate management of the disease.
18F-FDG PET/CT is now widely used in the staging of most lymphomas, and accepted as a tool for response assessment . Taking a step forward from the IPI, attention is focused on the role of 18F-FDG PET/CT as a tool for guidance in risk stratification. However, there are conflicting opinions on this issue [9–18], and questions remain on the utility of 18F-FDG PET/CT as a prognostic indicator in patients with DLBCL. Among PET parameters, the most frequently studied is standardized uptake value (SUV), which is currently a popular semi-quantitative index of 18F-FDG metabolic rate. However, SUV has limitation, because it cannot reflect tumor dimensions and volume, and only represents metabolic activity per gram of tissue. On the other hand, total lesion glycolysis (TLG) is a parameter in which tumor volume and tumor activity are integrated [19, 20].
Here, we analyzed the predictive value of SUV, TLG from baseline and interim PET/CT, and ΔSUV, ΔTLG between baseline and interim PET/CT, in patients with DLBCL. Particularly, we attempted to validate the clinical implications of PET/CT as a prognostic indicator in patients with an IPI score of 1, 2, or 3.
Patients' characteristics and clinical outcome according to IPI and R-IPI. Clinical variables of the patients are presented in Table I. Forty five patients (45.0%) presented with advanced stage disease, and the distribution of patients according to IPI was 52 (52.0%, low), 23 (23.0%, low-intermediate), 15 (15.0%, high-intermediate), and 10 (10.0%, high), respectively. Based on R-IPI score, 33 (33.0%), 42 (42.0%), and 25 (25.0%) patients fell into very good, good, and poor risk groups. The median follow up period was 21 months (range, 14–39), and 2-year PFS and OS were 86.2 and 90.1%, respectively. When outcome is plotted according to the standard IPI, it seems to be predictive in patients treated with R-CHOP (PFS, P = 0.054; OS, P = 0.047), but low-intermediate and high-intermediate groups exhibit closely overlapping curves (Supporting Information Fig. 1A,B). The survival curve according to the revised IPI distinguishes two separate prognostic group rather than three risk groups; curves were nearly overlapping in very good and good risk groups, and poor risk group was only distinguishable (PFS, P = 0.144, OS, P = 0.058) (Supporting Information Fig.2A,B).
Table I. Patients' Characteristics
|Age, median (range)||55 (20–78)|
|Male/Female||56 (56.0)/44 (44.0)|
| I–II||55 (55.0)|
| III–IV||45 (45.0)|
| Low||52 (52.0)|
| Low intermediate||23 (23.0)|
| High intermediate||15 (15.0)|
| High||10 (10.0)|
| Very good||33 (33.0)|
| Good||42 (42.0)|
| Poor||25 (25.0)|
|No. of R-CHOP, median (range)||6 (3–8)|
|No. of R-CHOP before interim-PET|
| 2||46 (46.0%)|
| 3||54 (54.0%)|
18F-FDG PET/CT has become an essential imaging tool for management of patients with NHL, including DLBCL. Among the PET parameters, SUV is currently the most commonly used semi-quantitative index of 18F-FDG PET/CT. It reflects tumor glucose metabolism, and is represented by mean (SUVmean), or maximum value (SUVmax). Previous studies suggested the association between SUVmax and tumor aggressiveness [21–23]. And recently, the fact that proliferation potential of tumor cells measured by Ki-67 stain positively correlated with SUVmax has been reported [24–28]. However, the measurement of SUVmax has confined to the detection of the most obvious metabolic activity of the tumor at single site, but not the overall tumor activity. To compensate for this defect, SUVsum and TLGsum are used in the present study, as indicators that could potentially reflect overall tumor burden of the whole body.
In this study, we attempted to evaluate the prognostic value of various PET parameters derived from a pretreatment and an interim PET/CT. Among the initial PET parameters, PFS in all patients differed significantly according to initial SUVsum, whereas initial SUVmax and initial TLGsum did not show a statistical difference. As with the results in overall patients, PFS appears to be correlated not with the initial SUVmax or initial TLGsum, but with the initial SUVsum in patients with an IPI score of 1, 2, or 3. Against our expectation, none of the parameters which reflect percentile changes between initial and interim PET/CT were not associated with prognosis. Instead, absolute value of SUVmax and SUVsum from interim PET/CT were consistently significant in prediction of PFS in all patients, and in patients with and IPI score of 1–3 as well.
In contrast to the previous reports that spotlight the prognostic significance of single PET parameter from either the baseline or the interim PET/CT, the various PET parameters obtained from both baseline and interim PET/CT were evaluated and compared in this study. PET parameters in this study can be roughly classified into two classes: SUVmax based (SUVmax, SUVsum, ΔSUVmax, ΔSUVsum) and SUVmean based (TLGsum, ΔTLGsum). And, the interesting thing we found was that the PET/CT parameters which were found to be associated with prognosis were SUVmax based, but not SUVmean based. When comparing SUVmax and SUVsum, SUVsum is more consistently associated with prognosis both in baseline and interim PET/CT, which probably reflects the importance of not only tumor proliferation but also overall tumor burden when predicting patients' prognosis. However, the fact that SUVmax is equally relevant with the prognosis just as SUVsum at interim PET/CT, suggests us that the proliferative potential of the residual tumor despite of chemotherapy is extremely important to predict patients' clinical outcome. In addition, this study definitely demonstrates the importance of absolute value of SUVmax or SUVsum, rather than the percentile change of SUVmax (ΔSUVmax) or SUVsum(ΔSUVsum).
Hence, current treatment strategy based on stage of the disease is not fully satisfactory in DLBCL, and more novel therapeutic approach based on precise risk stratification more than stage is challenging. Recently, attention is focused on the role of 18F-FDG PET/CT as a tool for guidance in risk stratification. Here, we analyzed and compared the various PET/CT parameters, and found that the absolute value of SUVsum from baseline PET/CT, and SUVmax and SUVsum from interim PET/CT were significantly relevant to clinical outcome in all patients. In addition, we were interested in patients of intermediate risk with an IPI score of “1 or 2 or 3”, whose prognosis is not clear as “excellent” or “worst” prognostic group, thus whose therapeutic decision could be potentially guided by the results of the PET/CT. As with the results in all patients, SUVsum from baseline PET/CT, and SUVmax and SUVsum from interim PET/CT were predictive for clinical outcome in this group of patients. These results could serve as a basis for future studies for the use of PET/CT in clinical practice, as an adjunct to IPI.
From July 2008 and February 2010, a total of 222 patients were diagnosed with DLBCL at Samsung Medical Center. After excluding 8 patients with central nervous system involvement at initial diagnosis, and excluding 94 patients without available PET/CT data, 120 DLBCL patients who had available data including standard uptake value (SUV) and total metabolic volume (TMV) of the disease at a baseline and an interim PET/CT were selected. Of these 120 patients, we excluded 10 patients who were treated in clinical trials, six patients who were treated with R-CHOP followed by auto-PBSCT, and four patients whose interim PET/CT was performed after more than three cycles of RCHOP. Finally, 100 patients who were treated with R-CHOP alone as first line treatment, and with interim PET/CT information that was performed after two or three cycles of RCHOP were included and analyzed in this study. Patients were to receive intravenous infusions of R-CHOP given every 21 days. Each RCHOP cycle consisted of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (maximum dose, 2.0 mg/dose) given intravenously on day 1, and oral prednisolone 100 mg on days 1 through 5.
18F-FDG PET/CT imaging and measurements of PET parameters
Baseline 18F-FDG PET/CT was performed within 14 days before initiation of R-CHOP and interim PET/CT was performed between 10 and 21 days after two or three cycles of R-CHOP. Patients fasted for at least 6 h before the PET/CT. Blood glucose levels were measured before the injection of 18F-FDG, and were lower than 200 mg/dL in all patients. PET/CT imaging was performed using dedicated PET/CT scanners (Discovery LS or Discovery STe, GE Healthcare, Milwaukee, WI, USA) without intravenous or oral contrast material. Same kind of PET/CT scanner was used for both baseline and interim evaluation. Whole-body CT was performed 60 min after the injection of 18F-FDG (5.5 MBq/kg). After the CT scan, an emission scan was obtained from the thigh to head. Attenuation-corrected PET images were reconstructed from the CT data.
All PET/CT images were reviewed by two experienced nuclear medicine physicians, who were unaware of the clinical outcomes on a dedicated workstation (GE Advantage Workstation 4.4). A PET positive lesion was defined according to the modified IWG criteria . In brief, focal or diffuse 18F-FDG uptake above background in a location incompatible with normal anatomy or physiology. The number of target lesions for quantitative response analysis was limited up to a maximum of five measurable lesions per organ and 10 measurable lesions in total showing high 18F-FDG uptake. The SUVmax was defined as the maximum SUV of the hypermetabolic lesion showing the highest 18F-FDG uptake. The SUVmean and total lesion glycolysis (TLG) of each hypemetabolic measurable lesion were measured using Volume Viewer software, which provides an automatically delineated volume of interest (VOI) using an isocontour threshold method based on the SUV. The activity of aortic arch was considered as mediastinal blood pool background activity, which was used as a threshold for determining the VOI boundary [29, 30]. Using this threshold, SUVmean and voxel number of the VOI were automatically generated. The TLG was calculated by multiplying the SUVmean by the number of voxels. To evaluate overall hypermetabolic tumor burden, the sum of SUVmax (SUVsum) or TLG (TLGsum) of each hypemetabolic measurable lesion was acquired on both baseline and interim PET images. As quantitative PET parameters for predicting prognosis, the SUVmax, SUVsum, and TLGsum on baseline and interim PET, and percentile changes in the SUVmax (ΔSUVmax), SUVsum (ΔSUVsum), and TLGsum (ΔTLGsum) between baseline and interim PET were evaluated. As a qualitative PET assessment, interim PET/CT was also evaluated as positive or negative for residual viable tumor according to the criteria of the International Harmonization Project (IHP).
The primary end point of this study was progression free survival (PFS), which was defined as the time from initial diagnosis to disease progression, relapse, and death from any cause, or last follow-up. The secondary end point was overall survival, which was defined as the time from initial diagnosis to death from any cause, or last follow-up. Probability of PFS and OS were calculated by the Kaplan-Meier method and compared using the log-rank test. For identification of significant PET/CT parameters on PFS and OS, Cox proportional hazard model was used, and the hazard ratio (HR) and 95% confidence interval (CI) were determined for the covariates that were shown to be statistically significant. Statistical analysis was performed using a commercial software (PASW Statistics 18, IBM Inc., New York, NY).
The authors thank Hwan Joo Lee in the Department of Nuclear Medicine, Samsung Medical Center, for assistance with data analysis.
Silvia Park*, Seung Hwan Moon, Lee Chun Park*, Deok Won Hwang*, Jun Ho Ji*, Chi Hoon Maeng*, Su-Hee Cho*, Hee Kyung Ahn*, Ji Yean Lee*, Seok Jin Kim*, Joon Young Choi, Won Seog Kim*, * Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea, Department of Nuclear Medicine Samsung Medical Center, Sungkyunkwan University School of Medicine Seoul, Korea.