The value of [¹¹C]-acetate PET and [¹⁸F]-FDG PET in hepatocellular carcinoma before and after treatment with transarterial chemoembolization and bevacizumab

Hepatocellular carcinoma (HCC) is one of the most malignant neoplasms [1, 2]. The incidence of HCC is still growing [1, 2]. Early detection of HCC may play the most important role for the prognosis of HCC [1, 2]. Usually, thorough staging is performed, including computed tomography (CT), abdominal ultrasound (US), and magnetic resonance imaging (MRI) [2]. However, each of the above-mentioned methods has limitations. [1, 3]. For many patients who have non-resectable, intermediate stage HCC, transarterial chemoembolization is recommended as the preferred treatment option [4, 5]. Several studies have demonstrated the survival benefit of chemoembolization [5]. It has been demonstrated that vascular endothelial growth factor (VEGF) overexpression is a prognostic indicator of poor survival in patients with HCC [6]. VEGF is further up-regulated immediately after chemoembolization, and VEGF levels after treatment are an independent predictor of tumor response and survival [7]. Bevacizumab is a humanized murine monoclonal antibody targeting VEGF and blocks its binding to its receptors, thereby preventing the formation of new blood vessels and inhibiting the growth of existing tumors and metastases [8]. It has been demonstrated that the treatment with bevacizumab in patients with HCC may lead to prolonging of life time with approximately six-month stability in patients with previous rapid tumor growth [9].

Positron emission tomography (PET) using [¹⁸F]-FDG has been applied successfully in detecting many malignant diseases; however, it has a high false negative rate of approximately 40–50% in the detection of HCC (10). Some studies [10‐12] have shown that [¹¹C]-acetate PET is useful in the localization of HCC lesions. Up to now, no data are available on the comparison between [¹¹C]-acetate PET and [¹⁸F]-FDG PET in the evaluation of therapy response in patients with HCC after treatment with bevacizumab, and the relation of [¹⁸F]-FDG PET or/and [¹¹C]-acetate PET findings towards survival is not quite known. Based on our previous study [11], we prospectively investigated HCC patients in this study with the following purposes: (1) to evaluate the role of [¹¹C]-acetate PET and [¹⁸F]-FDG PET in the staging of HCC; and (2) to evaluate the therapy response by using [¹¹C]-acetate PET and [¹⁸F]-FDG PET, as well as (3) to assess whether [¹⁸F]-FDG PET or/and [¹¹C]-acetate PET predict survival in HCC patients after the treatment with TACE and bevacizumab or placebo.

Our present study explores the utility of combining [¹⁸F]-FDG and [¹¹C]-acetate PET as a diagnostic or prognostic approach to HCC. The sensitivity of [¹¹C]-acetate PET for the diagnosis of HCC in patients with HCC was higher than that of [¹⁸F]-FDG PET (68% versus 45%, respectively). The combination of the two tracers increased the sensitivity of PET to 73%, Therefore, the use of both [¹⁸F]-FDG and [¹¹C]-acetate PET may be a valuable option to detect HCC. These findings are consistent with previous studies that radio-labeled acetate PET could be a valuable for detecting HCC and had greater diagnostic performance than [¹⁸F]-FDG PET [10]. The sensitivity of [¹¹C]-acetate PET for the detection of HCC is in our study close to that reported by Park et al. [17], but is lower than that published by Hwang et al. [18]. They report a detection rate of 83% using [¹¹C]-acetate and a sensitivity of 40% for [¹⁸F]-FDG PET, respectively. Other studies, such as that by Ho et al. report a sensitivity of 87% with [¹¹C]-acetate and of 47% for [¹⁸F]-FDG [10], the combination of the two tracers increased the sensitivity of PET to 100% [10]. They conclude that performing PET with both radio-pharmaceuticals seemed to be the best diagnostic option.

In the present prospective study, we investigated the ability of [¹⁸F]-FDG and [¹¹C]-acetate PET to assess metabolic response in HCC patients treated with TACE and bevacizumab compared with those in HCC patients treated with TACE and placebo. We found significantly higher acetate metabolic response rate in patients who were treated with TACE and bevacizumab than in patients treated with TACE and placebo. This indicates that bevacizumab may be more effective against HCC as compared with placebo. To the best of our knowledge, this is the first study regarding the assessment of the therapy response by using [¹¹C]-acetate. Although the treatment with TACE and bevacizumab seems more effective than the therapy with TACE and placebo, the OS in patient group treated with TACE and bevacizumab is significantly shorter than that in the group treated with TACE and placebo [13]; this difference in survival seems to be mainly due to the significantly higher incidence of high-grade and even fatal vascular and septic side effects in patients treated with TACE and bevacizumab [13]. Bevacizumab has been known to cause several side effects including variceal bleeding, arterial hypertension and thrombosis [19, 20]. During this study, two fatal variceal bleeding events, several thromboembolic events, and one myocardial infarction, as well as abscess of the liver occurred only in the bevacizumab group (13). Our result found that the OS in the patient group treated with TACE and bevacizumab is significantly shorter than that in the group treated with TACE and placebo in all patients with negative acetate PET. This might have implication for clinical practice that patients with negative acetate PET should be more careful with the treatment with bevacizumab.

Several studies demonstrated that FDG-PET could better assess the tumor viability than CT after TACE [21] or radiofrequency ablation (RFA) [22] or transarterial selective internal radionuclide therapy (SIRT) with [⁹⁰Y]-glass microsphere [23]. The results of our present study have also shown that the FDG metabolic response rate was also higher in the patients treated with TACE and bevacizumab than in patients treated with TACE and placebo. However, there was no statistically significant difference.

[¹⁸F]-FDG avidity appears to be more frequent in HCCs with a poor prognosis than in those with a good prognosis [24]. Several studies have shown that [¹⁸F]-FDG avidity is associated with an aggressive HCC phenotype, microvascular invasion [24], poor tumor differentiation [10, 25], and recurrence after surgical resection [26] or transplantation [27, 28]. Our study supports these previous findings. In the TACE and placebo group, patients with lesions showing [¹⁸F]-FDG uptake had significantly poorer prognosis than those with lesions that did not show [¹⁸F]-FDG uptake. Patients with positive [¹¹C]-acetate lesions had also poor prognosis as compared with those with negative [¹¹C]-acetate, which, however, did not reach the level of significance in our patient cohort. In patients treated with TACE and bevacizumab, there were no significant differences in the prognoses between the patients with positive acetate PET and the patients with negative acetate PET, as well as between the patients with positive FDG PET and the patients with negative FDG PET; this may due to the significantly higher incidence of side effects in this group of patients as compared with the TACE and placebo group. The present results demonstrated that uptake of [¹⁸F]-FDG or/and [¹¹C]-acetate may be a marker of poor prognosis in patients. Recent study proposed [¹¹C]-acetate having prognostic value for prostate cancer [29]. Our study has shown that in the TACE and placebo group, patients with the most unfavorable outcome during clinical follow-up were those with lesions showing [¹⁸F]-FDG or [¹¹C]-acetate uptake. The results suggest that a negative PET may be associated with better overall survival and provide prognostic value beyond standard clinical information and CT-based anatomical staging.

Ho et al. [10] have reported that the well-differentiated HCC tumors are [¹¹C]-acetate avidity and the poorly differentiated types are shown by [¹⁸F]-FDG. Interestingly, our study has shown that the poorly differentiated HCC are detected by both [¹⁸F]-FDG and [¹¹C]-acetate and that some well differentiated HCCs are positive both in [¹⁸F]-FDG PET and [¹¹C]-acetate PET. A few of tumors in patients with well differentiated HCC are detected by [¹⁸F]-FDG and many tumors in patients with well differentiated HCC were positive in [¹¹C]-acetate PET. More interestingly, different tracer avidities were shown in one patient with two lesions in this study. These may be partly explained by the heterogeneity of HCC. We can assume that different grades of HCC lesions may exist in one patient. Hepatocellular carcinoma (HCC) is a highly heterogeneous from both clinical and molecular points of view [30]. However, there are very few reports on intra-tumor molecular heterogeneity in HCC in vivo. Our study showed the different tracer avidities in one patient with HCC lesions demonstrating the molecular heterogeneity in HCC. Aware of heterogeneity of HCC tumors is important since one of the key issues is to determine if this diversity significantly impacts predictions based on single biopsies, and ultimately, clinical decision making in the precision medicine. The potential clinical implications of this heterogeneity will also be pivotal to choose the effective molecular therapies and to understand resistance to molecular therapies.

This study has some limitations. One of the limitations is the size of the study population was modest, in which we had few poorly differentiated HCC lesions. Another limitation is that the choice of HCC treatment could also affect the clinical outcome. Indeed, as we reported earlier (13), patients who received TACE and bevacizumab had significantly higher incidence of high-grade and even fatal vascular and septic side effects as compared with the patients who were treated with TACE and placebo.

Our study suggests that combining [¹⁸F]-FDG with [¹¹C]-acetate PET could be useful for clinicians in the management of HCC patients. The use of dual-tracer PET might also provide relevant prognostic and molecular heterogeneity information. Thus, this approach might be valuable for the choose the effective molecular therapies and to identify patients who would most benefit from molecular therapies.