Validation of the Semiautomatic Quantification of ¹⁸F-Fluoride PET/CT Whole-Body Skeletal Tumor Burden

DISCUSSION

Semiautomatic quantification of whole-body skeletal tumor burden with ¹⁸F-fluoride PET/CT (TLF₁₀ and FTV₁₀) has been shown to be a strong and independent prognostic biomarker in breast (6) and prostate (7,14) cancers. To the best of our knowledge, semiautomatic quantification of ¹⁸F-fluoride PET/CT had not previously been validated for clinical use. Therefore, we manually quantified whole-body skeletal tumor burden (the method of quantification most often used in clinical practice) and compared it with semiautomatic quantification to validate the latter method.

Like studies comparing manual with semiautomatic quantification for ¹⁸F-FDG PET/CT—studies that revealed a high level of agreement (15)—our study for ¹⁸F-fluoride PET/CT obtained comparable results. In our study, mountain plots were centered over zero for both the manual and the semiautomatic methods, with a small left tail, showing that although the methods had some differences, they correlated strongly overall. These differences were secondary to an underestimation of the manually quantified values in a few cases, when compared with the semiautomatic method. Furthermore, the visual assessment of the Bland–Altman scatterplots showed uniform bias, and we can thus conclude that these metrics are similar, equivalent, and strongly correlated.

Although both methods of quantification are related, the manual method is time-consuming. In addition, the manually drawn VOIs are elliptic; in patients with multiple lesions, the observer might reduce the size of these VOIs to avoid overlap of VOIs, and this reduction might reduce the total volume of lesions. That is why there was such a discrepancy between the median mTLF₁₀ (255 g) and the median saTLF₁₀ (574 g). This issue does not occur in the semiautomatic quantification because the software draws the VOIs according to the exact shape of the lesions, without overlap.

The semiautomatic quantification, therefore, clearly becomes the method of choice for whole-body tumor determination. Furthermore, it was necessary to confirm that saTLF₁₀ and saFTV₁₀ were prognostic factors in breast cancer. Specifically, when quantifying osteoblastic bone metastases on the ¹⁸F-fluoride PET/CT studies, we applied a cutoff SUV_max of 10, which has been shown to separate normal bone from malignant lesions in approximately 98% of patients (8,16). This cutoff is not undisputed, and some authors prefer a cutoff of 15 to minimize nonpathologic and normal-bone uptake (17,18). There are no comparative studies between the 2 cutoffs (10 and 15) to decide which is better. However, we believe that increasing the cutoff reduces the sensitivity (while increasing the specificity), potentially leading to erroneous measurement of skeletal tumor burden. After semiautomatic quantification, a visual inspection is warranted to manually exclude VOIs placed in areas unrelated to bone metastases. Hence, increasing the SUV_max cutoff (to 15, for instance) may render this task more time-consuming because not only will areas unrelated to bone metastases have to be excluded but areas related to bone metastases will have to be included.

One limitation of both quantification methods relates to metastatic lesions whose activity is near the level of physiologic activity. For instance, in a metastasis in the pubic bone, which is near the bladder, a perfect delimitation was sometimes not possible because of the physiologic urinary excretion. Manual quantification also has limitations, in addition to being laborious. First, because it is observer-dependent, the VOI may vary widely, potentially influencing the whole-body quantification results. Second, the number of quantifiable lesions is not perfect. Although manual quantification was attempted in all patients regardless of the number of lesions, in some patients with a very high tumor burden (above 20 VOIs delineated), the software processing began to slow (most likely because of work overload) and the workstation had to be restarted. This problem did not occur with the semiautomatic quantification method; therefore, that method has the additional benefit of being able to include all patients, even those with a high volume of disease. A recent study showed that manual volumetric quantification of ⁶⁸Ga-PSMA PET/CT correlated with serum prostate-specific antigen values in patients with suspected biochemical recurrence of prostate cancer (19), but unfortunately, the authors excluded from the analysis patients with more than 10 lesions, claiming that manual measurement of tumor volumes was time-consuming and labor-intensive. To date, there is only one clear advantage of manual over semiautomatic quantification: the manual method allows drawing of an irregular ROI. In that scenario, semiautomatic quantification software still needs improvement, as there is no freehand drawing tool for VOIs, allowing only spheric VOIs and their variations. Segmentation is a necessary step in semiautomatic quantification and requires human interaction. Totally automatic forms of volumetric quantification will dispense with the segmentation process; such procedures are under study and will require extensive validation before clinical use (20).

One clear strength of this study was the possibility of addressing the clinical relevance of these quantitative findings. In our retrospective analysis of female breast cancer patients, semiquantitative determination of whole-body tumor burden on ¹⁸F-fluoride PET/CT independently correlated with overall survival (6). This finding demonstrates the potential of this approach for prognostication of these patients. Although we have validated this approach for breast cancer patients, our findings need confirmation for other cancer types.

Guidelines recommend that tumor burden be reported when available (9), but such reporting is feasible only for localized solid tumors. In current clinical practice, information on ¹⁸F-fluoride PET/CT skeletal tumor burden cannot be reported for patients with widespread disease such as lymphomas and bone metastases from breast and prostate cancer and must be reserved for research. A quantitative metric widely used in clinical practice because of its ease of measurement is SUV_max. In our analyses, the highest SUV_max on ¹⁸F-fluoride PET/CT examination was not a significant prognostic factor, as also shown by other investigators (6), even though the SUV_max of the primary lesion is a prognostic factor in breast cancer patients on ¹⁸F-FDG PET/CT (21,22). The lack of correlation between the highest SUV_max and outcome justifies calculation of whole-body skeletal tumor burden and not just the highest SUV_max.

In daily clinical practice, quantification of whole-body skeletal tumor burden has to be in at least a semiautomatic form. In this respect, the quantification proposed here is feasible, fast, and reproducible. These advantages open the door to new clinical possibilities in the theranostics setting (7,14) and in evaluating response to therapy (17).