Prognostic value of metabolic tumor volume of pretreatment ¹⁸F-FAMT PET/CT in non-small cell lung Cancer

Lung cancer is the leading cause of cancer-related death worldwide for both men and women. Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancers [1]. Despite progress in treatment strategies, overall survival (OS) in NSCLC remains unacceptably short—even for early-stage disease—and progressively worsens with increasing TNM stage [2, 3]. Currently, TNM stage is one of the most important prognostic factors for NSCLC and serves a valuable guide when choosing a treatment strategy [3, 4]. However, TNM staging alone does not always provide satisfactory results because each stage consists of a heterogeneous population with a different risk of relapse. Therefore, improved methods are needed to accurately predict prognosis and guide treatment strategy.

Fluorine-18 (¹⁸F) fluorodeoxyglucose (FDG) positron emission tomography (PET) is widely used for initial staging, restaging at recurrence, estimating radiotherapeutic or chemotherapeutic responses, and delineating radiotherapeutic targets [5–10]. The standardized uptake value (SUV) in the NSCLC primary lesion at the time of diagnosis is known to be an important prognostic factor [11].

Maximum SUV (SUV_max) is a long-established value in clinical practice for quantifying a lesion’s metabolism. However, as it is based on a single voxel value, SUV_max may not represent total tumor metabolism. By contrast, PET metabolic parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), are volumetric indices, and are thus more reliable reflections of tumor burden and aggressiveness [12]. Furthermore, these metabolic parameters are potentially useful prognostic markers for various malignancies examined by ¹⁸F-FDG PET [13–16].

We have developed l-[3-¹⁸F]-α–methyltyrosine (¹⁸F-FAMT), an amino acid PET tracer that specifically accumulates in tumor cells via L-type amino acid transporter 1 (LAT1) [17–20]. In the last two decades, ¹⁸F-FAMT has been investigated in various tumors and shown to offer some additional clinical benefits over ¹⁸F-FDG [21, 22]. ¹⁸F-FAMT uptake within the primary tumor, as depicted by SUV_max, is associated with poor outcomes in NSCLC patients and is a stronger prognostic factor than ¹⁸F-FDG uptake [23], making it useful for diagnosis, staging [19], and assessment of therapeutic response [24]. Therefore, in this study we postulated that the metabolic tumor burden, as indicated by MTV and total lesion retention (TLR) of ¹⁸F-FAMT, is useful as an indicator of prognosis. The purpose of this study was to determine the prognostic value of PET metabolic parameters (namely MTV, TLG, and TLR) on ¹⁸F-FDG and ¹⁸F-FAMT PET/CT in patients with NSCLC.

In the present study, MTV of ¹⁸F-FAMT was found to be highly prognostic of OS in NSCLC cases, regardless of tumor subtype and stage. The clinical stage remained as an independent prognostic factor of OS along with MTV. Previous meta-analysis has shown that ¹⁸F-FDG uptake, as represented by SUV_max, in the primary tumors of NSCLC patients, is an independent prognostic factor for survival [11]. However, in this study, SUVmax of ¹⁸F-FAMT and ¹⁸F-FDG was not an independent prognostic factor of OS. One possibility for this result is that when a tumor reaches an advanced stage, SUVmax, which is a single voxel representation, is no longer prognostic.

Several studies have found that the volumetric parameter is potentially a better predictor of outcome than SUV_max [26–28]. We confirmed that MTV and TLG of ¹⁸F-FDG failed to serve as independent prognostic factors for NSCLC cases, although recent studies [15, 28–30] and a meta-analysis [12] suggest otherwise. The heterogeneity of the patient populations and different methods used to obtain MTV values might account for this discrepancy. Interestingly, we also found that TLR was not an independent prognostic factor, whereas MTV of ¹⁸F-FAMT remained significant. This result may relate to the fact that SUV_mean of ¹⁸F-FAMT is typically low and TLR, defined as MTV multiplied by SUV_mean, might underestimate the tumor volume.

This study mainly examined the prognostic potential of MTV and TLR of ¹⁸F-FAMT, a tumor-specific PET radiotracer. Representative patient images, as shown in Figs. 4 and 5, suggest that ¹⁸F-FAMT uptake represents malignancy more accurately than ¹⁸F-FDG uptake, based on patient OS. Our results suggest that MTV of ¹⁸F-FAMT might have an advantage over MTV of ¹⁸F-FDG, whereas the independent prognostic value of SUV_max for both radiotracers remains questionable. MTV and TLG of ¹⁸F-FDG have been evaluated in various tumors within the last decade and found to have potential for treatment evaluation or as a prognostic tool [31, 32]. However, ¹⁸F-FDG has inherent limitations; for instance, physiological uptake and inflammatory uptake may complicate tumor delineation and, in turn, the construction of MTV. The considerable time and effort required to produce MTV—especially if using the manual method—preclude these metabolic parameters from entering daily clinical practice. However, several automated 3D VOI generating software packages have recently been developed to address this challenge [31–33].

The availability of tumor-specific PET radiotracers multiplies the benefits of these metabolic parameters. The present study is the first to evaluate the prognostic value of MTV and TLR on pretreatment ¹⁸F-FAMT PET/CT in patients with NSCLC. Previous reports have shown the advantage of MTV of ¹⁸F-FAMT for tumor delineation for accurate volume prediction [21, 34]. Indeed, we found that MTV of ¹⁸F-FAMT was useful for prognostic purposes.

However, our study had several limitations. The first is the predefined threshold method for delineation of lesion edges; this threshold choice greatly influenced the measurement of MTV, TLG, and TLR. The threshold of SUV 2.5 for ¹⁸F-FDG was chosen because it is widely used for tumor delineation [12]. For ¹⁸F-FAMT in NSCLC lesions, this was the first study to comprise tumor volume rather than a single-pixel SUV_max value. Thus, we investigated thresholds from SUV 1.2 to 1.8 in a smaller number of patients in advance to determine the optimum threshold for ¹⁸F-FAMT; SUV 1.2 was found to be optimal for generating a 3D VOI that covered the whole tumor mass in all cases. Second, patients were examined using two different PET/CT scanners. Second, the patients were examined with two different PET/CT scanners. This might have affected the quantitative accuracy of PET data. However, both scanners are routinely cross-calibrated to ensure the comparability of SUV in our hospital. Third, actual tumor uptake of ¹⁸F-FAMT was relatively low relative to that of ¹⁸F-FDG [35]. Low uptake may induce false-negative findings if it is used as a single tool for NSCLC staging. However, at our hospital, ¹⁸F-FAMT PET/CT studies are always performed along with ¹⁸F-FDG PET/CT. We believe that ¹⁸F-FAMT PET/CT can provide additional information to what ¹⁸F-FDG PET/CT provides. Since molecular targeting therapy needs additional information on amino acid metabolism, ¹⁸F-FAMT PET/CT can provide important information for predicting therapeutic effects. Fourth, only primary tumors were evaluated in patients with metastases. Metabolic information about metastatic tumors may be of additional prognostic value. Thus, MTV, TLG, and TLR may have been underestimated in some cases; however, MTV of ¹⁸F-FAMT was proven to be a good prognostic indicator. We presumed that metabolic information about metastatic tumors might be insufficient to interfere with the prognostic value of MTV of ¹⁸F-FAMT. Fifth, this study involved a relatively small number of patients with heterogeneous characteristics at clinical stage I to IV. A study with a larger number of patients is required to further validate our results.

The MTV of ¹⁸F-FAMT was found to be an independent risk factor and may be a better predictor of OS than ¹⁸F-FDG in NSCLC cases. Thus, the MTV of ¹⁸F-FAMT could be valuable for guiding decision-making during NSCLC patient management.