18F-FDG-PET/CT can identify histopathological non-responders to platinum-based neoadjuvant chemotherapy in advanced epithelial ovarian cancer
Introduction
Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) can be used in advanced epithelial ovarian cancer (EOC) patients as an alternative to primary debulking surgery (PDS) [1]. However, the selection of patients referred to NACT must be based on careful preoperative evaluation, and NACT should only be reserved for patients with advanced stage III–IV EOC [2]. NACT response evaluation is equally important, as the patients who do not respond to NACT are also not likely to benefit from IDS. It is essential to identify these patients in order to avoid the risk of unnecessary surgical complications and the delay of second-line chemotherapy.
Computed tomography (CT) imaging and measurement of the serum tumor marker CA125 have been traditionally used for both treatment response evaluation and follow-up of EOC patients [3], [4]. Treatment response evaluation studies have mainly been performed in PDS settings [5], [6], and the number of studies focused on NACT response evaluation is limited [7], [8]. There is still inconsistency whether CA125 response during NACT predicts IDS outcome [9], [10], [11]. Furthermore, the clinical role of the novel serum tumor marker human epididymis protein 4 (HE4) has not yet been clarified, even though it may be useful for predicting the possibility of optimal cytoreduction in primary surgery [12] and IDS [13]. A study by Menczer and co-workers suggested that CT-imaging is not optimal for NACT response evaluation [14]. Currently, there are no generally accepted criteria for predicting which patients are unlikely to benefit from IDS. The establishment of such criteria would require better methods for estimation of NACT response.
18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging has been studied for use in EOC staging and operability assessment [15], [16], [17]. We recently reported that it is superior to CT for the evaluation of preoperative extra-abdominal disease spread [18]. 18F-FDG-PET/CT might also be useful for the selection of patients for NACT [19]. Avril et al. [8] studied 18F-FDG-PET/CT-imaging in NACT patients and reported metabolic response after both the first and third cycles of NACT to predict patient's outcome. Nishiyama et al. [20] evaluated the potential of 18F-FDG-PET/CT in predicting NACT response in eight advanced ovarian cancer patients. Martoni et al. [21] evaluated the use of 18F-FDG-PET/CT for the identification of patients likely to benefit from prolonged NACT. Other than the results of these three studies, there are no data on the use of 18F-FDG-PET/CT for NACT response evaluation, and the clinical role of 18F-FDG-PET/CT-imaging has not been established.
NACT-induced histopathological changes reflect direct local response [22], [23], [24]. Degenerative changes, such as fibrosis, necrosis, macrophage infiltration and tumor-induced inflammation, are indicative of the efficacy of chemotherapy. Ki-67 antigen expression, a marker of proliferative activity, has also been shown to decrease during NACT [25]. In this study, we used a well-characterized cohort of primarily inoperable EOC patients treated with NACT to evaluate how the 18F-FDG-PET metabolic response correlated with local histopathological response seen at IDS. Our aim was to see whether 18F-FDG-PET/CT is useful for identifying patients who will not respond to NACT. We also evaluated how the metabolic changes observed by 18F-FDG-PET/CT correlated with serum CA125 and HE4 profiles and Ki-67.
Section snippets
Patients
The study population consisted of 26 advanced, primarily inoperable ovarian cancer patients treated with NACT. The patients were recruited into this prospective clinical trial at the Department of Obstetrics and Gynecology, Turku University Hospital, Finland between December 2009 and March 2014. The patient characteristics are presented in Table 1. The study exclusion criteria were medical histories of diabetes or previous cancer. Five patients with progressive disease did not proceed to IDS
SUVmax value change during NACT and histopathology
The reduction in omental SUVmax was significantly corresponded with the extent of the histopathological evidence of treatment response (p = 0.004, Odds Ratio (OR) = 0.9, Confidence Interval (CI) = 0.84–0.97). The results are presented in Fig. 3. Based on the ROC analysis, a cut-off value of 57% for the decrease in omental SUVmax was found to be able to differentiate histopathological responders from non-responders with a sensitivity of 89%, a specificity of 88% and an AUC of 0.91. The ROC curve is
Discussion
For EOC, there is no consensus on how to define the metabolic response to NACT observed by 18F-FDG-PET/CT. To the best of our knowledge, this study is the first to show that a substantial metabolic response indicated by 18F-FDG-PET/CT is necessary to achieve a clear histopathological response to NACT. The main results of this study were that the decrease in omental SUVmax after NACT was associated with omental histopathological response seen at IDS and that an omental SUVmax decrease of less
Conflicts of interest
None.
Acknowledgments
This study was financially supported by the Clinical Research (EVO) fund of the Turku University Hospital, a Tyks-Sapa research grant and a grant from the Finnish Cancer Foundation.
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