In our study, we have demonstrated that the absolute value SUVmax from interim-treatment scans were significantly associated with OS and PFS on univariate analysis. In addition, the calculated PET parameters from interim-treatment/pre-treatment PET-CT scans, MTVmid/pre, SUVmaxmid/pre, and iSUVmid/pre, were predictive for PFS and OS. Calculated SUVmean from interim-treatment/pre-treatment PET-CT scans is also predictive of OS. This is consistent with the hypothesis that the chemosensitivity of the tumor as measured by PET-CT early during treatment is predictive of clinical outcome.
These data suggest that absolute value and calculated PET metrics taken from quantitative analysis of PET imaging may augment the IPS for predicting PFS or OS. IPS is utilized for prognostication of patients with advanced Hodgkin's disease and not early stage disease. The development of prognostic and predictive tools for patients beyond standard clinical staging could be an important advancement for adaptive treatment approaches. Relapses in this study occurred only in patients with advanced stage disease, so we could not determine if quantitative PET parameters were predictive for early stage disease. For the patients in this study, PFS and OS are 100% for early stage, non-bulky disease (n = 9). In a larger group of 101 patients with favorable early stage disease treated with Stanford V chemotherapy followed by radiation therapy (20 or 30 Gy) according to established protocols at Stanford, FFP was 94% and OS was 97% . In our study, four-year PFS for advanced disease (stage III and IV or early stage bulky disease) is 70% and OS is 85% (n = 21). In a larger group of 142 patients with advanced disease treated with Stanford V chemotherapy followed by 36 Gy to involved sites at Stanford, 5-year PFS was 89% and OS was 96%. The small sample size in our study limits our ability to directly compare clinical outcomes between the patients in our study and the larger group of patients with Hodgkin's disease treated at Stanford.
We showed that absolute value interim-treatment SUVmax was predictive for OS using the average SUVmax of 4.0 as the threshold value. This threshold level was chosen for illustrative purposes to demonstrate that differences in clinical outcomes can be separated based upon quantitative PET metrics. This analysis points to the potential utility of a quantitative approach for cases that may be difficult to assess following chemotherapy. However, the optimal cut-off values to be used in Hodgkin's disease still needs to be further evaluated in prospective clinical studies. The optimal technique and threshold values for segmenting hypermetabolic tumor foci also warrants further examination.
We describe several quantitative PET parameters that may be potentially applicable for predicting clinical outcome in patients with Hodgkin's disease. In our study, PET parameters from pre-treatment scans were not significant. This may be due to the small sample size of our study. Alternatively, it may be that the chemosensitivity of the tumor is more important for predicting clinical outcome than the magnitude of metabolically active tumor burden at diagnosis. It is interesting to note that both interim-treatment absolute value and calculated (interim-treatment/pre-treatment) SUVmax were predictive for overall survival and progression free survival. We hypothesize that tumor chemosensitivity may be reflected in interim-treatment PET scan parameters. Absolute value interim-treatment MTV has the advantage of being more directly measured than calculated MTV, although calculated MTV has the advantage of reflecting the change in metabolic activity from baseline. The absolute value PET parameters were used to determine the calculated PET parameters (for instance, absolute value interim-treatment SUVmax/pre-treatment SUVmax). In our dataset, absolute value SUVmax and calculated SUVmax were highly correlated (Spearman R = 0.94 and p = 0.0001). It is also notable that 16 patients had interim-treatment SUVmax of 0, and as a result, calculated SUVmax also shared the same value 0 for 16 of the 30 patients. The best approach for applying quantitative PET data in the treatment of patients with Hodgkin's disease warrants further study in a prospective manner.
Our results although preliminary, are consistent with the joint Italian-Danish study showing that [18F]FDG-PET scan following two cycles of AVBD chemotherapy predicts progression-free survival in Hodgkin's disease patients. The interpretation of the PET-CT scans differs in our study in that we employ quantitative analysis rather than qualitative assessment. The establishment of quantitative methods of assessing PET-CT scans may aid in the interpretation of scans with minimal residual uptake or with "intermediate-positive" disease. It also has the potential for standardizing the interpretation of scans to reduce the variability in technique among clinical trials and across different institutions. Since a PET-CT is generally performed to assess the extent of disease before and during treatment for patients with Hodgkin's disease, quantitative analysis would be a practical and cost-effective strategy for incorporating these data into clinical practice.
The limitations of our study are the relatively small number of patients, relatively small number of clinical events (progression and/or death), and retrospective method. Due to the small number of patients, we were not able to select a more homogenous population of patients receiving identical chemotherapy regimen, e.g. our stage I-II patients. Due to the low numbers of events we were also unable to perform a multivariate analysis to exclude the influence of other clinical and treatment related prognostic factors as compared to our quantitative PET metrics. In spite of these limitations, we present statistically significant data correlating quantitative interim-treatment PET metrics with clinical progression.
In conclusion, quantitative assessment of FDG-PET status after chemotherapy will likely be helpful for identifying patients at high risk of treatment failure at an early time point when treatment intensification could be considered. The preliminary findings of our study supports the quantitative interpretation of FDG-PET images as possibly an important tool guiding the design of prospective clinical trials of functional imaging for Hodgkin's disease.