Prognostic Value of 18F-Fluorocholine PET Parameters in Metastatic Castrate-Resistant Prostate Cancer Patients Treated with Docetaxel

Background and Aim The availability of new treatments for metastatic castrate-resistant prostate cancer (mCRPC) patients increases the need for reliable biomarkers to help clinicians to choose the better sequence strategy. The aim of the present retrospective and observational work is to investigate the prognostic value of 18F-fluorocholine (18F-FCH) positron emission tomography (PET) parameters in mCRPC. Materials and Methods Between March 2013 and August 2016, 29 patients with mCRPC were included. They all received three-weekly docetaxel after androgen deprivation therapy, and they underwent 18F-FCH PET/computed tomography (CT) before and after the therapy. Semi-quantitative indices such as maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) with partial volume effect (PVC-SUV) correction, metabolically active tumour volume (MATV), and total lesion activity (TLA) with partial volume effect (PVC-TLA) correction were measured both in pre-treatment and post-treatment 18F-FCH PET/CT scans for each lesion. Whole-body indices were calculated as sum of values measured for each lesion (SSUVmax, SPVC-SUV, SMATV, and STLA). Progression-free survival (PFS) and overall survival (OS) were considered as clinical endpoints. Univariate and multivariate hazard ratios for whole-body 18F-FCH PET indices were performed, and p < 0.05 was considered as significant. Results Cox regression analysis showed a statistically significant correlation between PFS, SMATV, and STLA. No correlations between OS and 18F-FCH PET parameters were defined probably due to the small sample size. Conclusions Semi-quantitative indices such as SMATV and STLA at baseline have a prognostic role in patients treated with docetaxel for mCRPC, suggesting a potential role of 18F-FCH PET/CT imaging in clinical decision-making.


Introduction
Prostate cancer (PC) is the first most common cancer in men worldwide, and its incidence is increasing in countries of higher socioeconomic development [1,2]. e condition of metastatic castrate-resistant prostate cancer (mCRPC) has a poor outcome with a median overall survival (OS) of 20 months; thus, beyond palliation of symptoms and maintenance of a good quality of life, prolongation of survival remains largely an elusive goal [3,4]. During the last decades and particularly in the past few years, chemotherapeutic agents (docetaxel and cabazitaxel) [5], antiandrogen drugs (abiraterone and enzalutamide) [6,7], and radium-223 dichloride have been introduced for the treatment of mCRPC [8]. e optimal timing of the different treatments has not yet been established, due to the paucity of prognostic markers for sequence and clinical management decisions.
During treatment of mCRPC, the use of PSA, a glycoprotein mainly produced by prostate tissue, as a marker of response should be carefully evaluated. PSA fluctuations are well known and described during active treatments, often not due to a disease progression but to the effects of drugs on PSA production. In addition, conventional radiology has limitation in detecting tumour biology and behaviour during treatment. Positron emission tomography/computed tomography (PET/CT) has been widely used for the evaluation of PC by using several radiopharmaceuticals. A recent paper by Wallit and colleagues analyses the clinically available PET radiotracers for PC imaging and their mechanisms of actions: 18 F-fluorodeoxyglucose ( 18 F-FDG) for the evaluation of treatment response in metastatic bone disease; 18 Fsodium fluoride ( 18 F-NaF) for bone metastasis detection; 11 C-choline and 18 F-choline ( 18 F-FCH) for the staging of high-risk patients and in presence of biochemical relapse with high PSA levels; 68 Ga-labeled prostate-specific membrane antigen ( 68 Ga-PSMA) highly sensitive for biochemical relapse with low PSA levels; the novel 18 F-fluciclovine ( 18 F-FACBC) appearing superior to choline in the setting of biochemical relapse [9][10][11].
ere are several data in literature regarding the use of 11 C-choline PET/CT in patients with PC treated with docetaxel both in neadjuvant and advance setting [12,13], but its role for the assessment of the treatment response and for predicting patient outcome still remains unclear.
In comparison to CT, 18 F-FDG PET/CT, and 11 Ccholine PET/CT, 18 F-FCH PET/CT showed higher sensitivity and specificity in detection of metastatic lesions in patients with PC [14]. Its role in treatment monitoring and outcome prediction beyond PSA response of patients with mCRPC treated with abiraterone and enzalutamide has been already described [15][16][17][18].
To our knowledge, there are no data available on the use of 18 F-FCH PET parameters as prognostic markers in patients affected by PC and treated with docetaxel for advanced disease. e aim of this study was to explore the prognostic role of 18 F-FCH PET/CT in patients treated with three-weekly docetaxel for mCRPC by using accurate PET biomarkers corrected for partial volume effect (PVE) [19].

Patients and Study Design.
e present study is a retrospective, monocentric, observational trial that involved consecutive patients with a histological diagnosis of prostate cancer fulfilling PCWG3 criteria [20] for CRPC (baseline serum testosterone <50 ng/dl, progressive disease to androgen deprivation therapy).
is study was approved by the institutional ethics committee, and all patients signed written informed consent. e research was conducted according to the principles of the Declaration of Helsinki.
We considered eligible patients who had not yet received chemotherapy for advance disease, had a measurable disease according to PET Response Criteria in Solid Tumours (PERCIST) version 1.0 [21], and had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2 and appropriate cardiac, hepatic, renal, and bone marrow function.
e study was conducted between March 2013 and August 2016. Data collection ended on 31st of December 2017 for analysis. e primary objective of this study is the identification of 18 F-FCH PET parameters that can predict clinical outcome in patients with mCRPC. As secondary objective, we evaluated the correlations between patients' clinical parameters and outcome.
2.1.1. Chemotherapy Protocol. Docetaxel was administered in three-weekly schedule (75 mg/m 2 day 1 every 21 days) as standard first-line chemotherapy for mCRCP according to the current guidelines [22]. e treatment was administered for a total of six cycles, and it was infused if clinical and biochemical parameters were permissive (conserved PS and no grade 3 or 4 adverse events according to Common Terminology Criteria for Adverse Events v4.03). Before the beginning of the therapy, patients underwent a baseline blood PSA assessment; PSA response and toxicity were evaluated before every dose administration. Dose adjustments and delays were planned to correspond with the type and grade of the observed toxicity. Concomitant medications such as antiemetic drug, granulocyte colony stimulating factors (G-CSF) for the secondary prevention of neutropenic fever, bisphosphonate treatments, and steroids were allowed. e mean radiopharmaceutical dose injected to the patients was 213 MBq (range: 176-346 MBq). 18 F-FCH PET/CT images were acquired in median 22 days (range: 8-38) before starting the treatment with docetaxel and in median 26 days (range: 14-58) after the treatment.

18 F-FCH PET/CT
Images' acquisition was performed after an uptake time of approximately 60 min on a Discovery-690 VCT (General Electric Medical Systems, GEMS, Milwaukee, WI) scanner [23]. 18 F-FCH PET/CT data were acquired for 3 minutes per bed position and reconstructed by using OSEM algorithm (3 iterations, 18 subsets, full width at half maximum (FWHM) of smoothing filter equals to 5 mm) including time of flight and resolution recovery.

18 F-FCH PET/CT Image Analysis and Interpretation.
A qualitative evaluation of 18 F-FCH PET/CT images was firstly performed by two nuclear medicine physicians, and then an expert nuclear medicine physician selected the lesions easily identifiable and accurately evaluable on 18 F-FCH PET/CT images before and after the chemotherapy in order to be semi-quantified. Too small lesions (volume < 1 cm) and lymph node clusters were excluded.
Semi-quantitative analysis of PET/CT lesions was performed by using a validated segmentation method [24]. 18 F-FCH PET parameters were extracted considering partial volume effect correction (PVC) in order to get accurate PET biomarkers by using a validated method developed by Gallivanone and colleagues [25,26]. More precisely, the following parameters were extracted from each segmented lesion on pre-treatment and post-treatment 18 F-FCH PET images: maximum standardized uptake value (SUV max ), mean standardized uptake value (SUV mean ) corrected for PVE (PVC-SUV), metabolically active tumour volume (MATV), and total lesion activity (TLA). TLA was calculated as MATV multiplied by the PVC-SUV (TLA � MATV × PVC-SUV), and thus, TLA was corrected for PVE.
In order to extract whole-body indices for each patient and each 18 F-FCH PET parameter (SUV max , PVC-SUV, MATV, and TLA), the sum of values measured for each lesion was calculated (SSUV max , SPVC-SUV, SMATV, and STLA, respectively).

Statistical Analysis.
e distributions of the categorical variables are described by counts and frequencies or by median and range, whereas those of continuous and count variables are described by median and interquartile range. PFS was defined as the time between the date of the beginning of docetaxel and the date of progression. OS was defined as the time between the date of the starting of docetaxel and the date of death or last follow-up.
Univariate and multivariate hazard ratios for selected potential predictors of PFS and OS were performed using a Cox proportional hazards regression model. PFS and OS were estimated using the Kaplan-Meier method. p < 0.05 was considered as significant for all analyses. All statistical analyses were performed using SPSS version 24.

Patients and Study Design.
We enrolled 29 patients, whose baseline characteristics are reported in Table 1. Patients' median age at the beginning of docetaxel treatment was 71 (range: 42-82). In a median follow-up period of six years, 14% (n � 4) patients obtained a complete metabolic response (CMR); 52% (n � 15) a partial metabolic response; 7% (n � 2) a stable metabolic disease; 27% (n � 8) a progressive metabolic disease (PMD) as best response to treatment. Median PFS was 13.5 months (range 2.3-37.6 months), and median OS was 37 months (range 4.7-66 months). A PSA increase compared to baseline was seen in 5 patients (17%), whereas a PSA decline ≥50% was seen in 14 patients (47%). At the time of the analysis, 15 patients were still alive.
Since there was a statistically significant association between SMATV and PFS, a ROC curve analysis was performed, and it showed that patients with an SMATV value >27 cc at PET1 have a 20% higher probability of having progression during docetaxel treatment (HR 1.19, range 0.56-2.53, p � 0.63) with a sensibility value of 73%, a specificity value of 58%, and an AUC of 0.64 (p � 0.23).
As regarding the secondary objectives, a significant correlation between PSA and PFS was found since patients with a PSA decline ≥50% had a better outcome (median PFS 12.8 months, range 9.5-15.8) than patients with a PSA decline <50% (median PFS 9.7 months, range 9.5-13.7) (log rank test � p < 0.001). Patients with a PSA increase of during docetaxel treatment had a poor outcome (median PFS 6.2 months, range 5. Considering the metastatic sites, patients with bone and lymph node lesions had a better outcome than patients with visceral involvement (PFS 11.6 months, range 9.6-13.3, vs 9.1 months, range 5.2-12.9, respectively, p � 0.04; OS 38.4 months, range 34.8-41.9, vs 29.4 months, range 5.2-53.9, respectively, p � 0.25).

Discussion
To our knowledge, this is the first study that evaluated the role of 18 F-FCH PET uptake before and after docetaxel treatment as a means of predicting long-term clinical outcomes in mCRPC.
Docetaxel is one of the treatment options in patients affected by metastatic PC; however, no approved biomarkers can predict the outcome to this therapy. 11 C-Choline and 18 F-FCH PET/CTare widely used diagnostic techniques, and recent studies have evaluated the role of 18 F-FCH PET indices in predicting treatment outcomes in CRPC patients [15][16][17][18]27]. For the first time, Kwee and colleagues [28] assessed the potential usefulness of 18 F-FCH PET parameters in mCRPC patients, quantifying whole-body tumour burden on the basis of SUV max , metabolic tumour volume (MTV), and TLA. ey found that MTV and TLA measurements proved to strongly correlate in the Kaplan-Meyer analysis.
Afterwards, Caroli and colleagues retrospectively evaluated 18 F-FCH PET parameters in 94 patients treated with enzalutamide or abiraterone for mCRPC [16]. At univariate analysis, they described that the median sum of MTV (SMTV), SUV max (SSUV max ), and TLA (STLA) resulted significant for OS and PFS, whereas, in multivariate analysis,    [17].
De Giorgi and colleagues evaluated the utility of 18 F-FCH PET parameters to detect an early response to abiraterone [15]. e authors concluded that a radiologic response to 18 F-FCH PET/CT was associated to a better outcome compared to having obtained only a biochemical response.
Recently, Ceci and colleagues [29] have assessed the role of 11 C-choline PET/CT to determine the response to docetaxel in a cohort of 61 patients with metastatic PC. e authors compared the radiologic response obtained with 11 C-choline PET/CT and PSA response. e study had demonstrated incongruent results between the two methodologies since a radiologic progression was observed in 44% of patients with a biochemical response.
Another study by Schwarzenböck and collegues [13] evaluated the relationship between changes of SUV max and SUV mean of 11 C-choline PET as a predictive biomarker of early and late response to docetaxel treatment in mCRCP. However, they did not find any significant correlation between the changes in choline uptake and the objective responses evaluated with RECIST and clinical criteria. e results from our study suggest that 18 F-FCH PET parameters could be used to predict the clinical outcome of patients with mCRPC treated with docetaxel after progressing to androgen-deprivation therapy. In particular, SMATV and STLA 18 F-FCH PET parameters are the most promising imaging biomarkers, taking into account the metabolic tumour volume and activity. In fact, their mean baseline values seem to predict long-term clinical outcomes, thus suggesting that metabolic imaging may be useful to select the best treatment for individual patients and open new perspectives in clinical decision-making. Imaging biomarkers may help to tailor treatments as patients with higher levels of basal metabolic activity (and therefore a poorer prognosis) may benefit from more aggressive treatments. In this context, it is still uncertain whether pretreatment metabolic imaging may also play a predictive role.
Our study benefits also from the use of a validated method to obtain tumour metabolic volume. As underlined in different publications and in particular in a work by Soret and colleagues [19], proper tumour active metabolic region assessment is paramount because it influences the measurement of different semi-quantitative indices to be evaluated as imaging biomarkers. In this study, we used a segmentation procedure that was validated on lesions that reliably simulate realistic tumour conditions (non-spherical and non-homogeneous), estimating volume with 92% of accuracy [24]. Furthermore, in order to obtain accurate quantitative indices of glucose consumption, a PVC method was applied to quantitative indices ensuring an accuracy for quantification up to 93% for lesions >1 cm as sphereequivalent diameter.
We did not find any correlation between 18 F-FCH PET parameters and survival. is is possibly due to the small sample size and the few number of events at the time of data analysis; as already well known from the literature, our findings demonstrated the prognostic role of visceral metastasis involvement.

Conclusions
Our findings suggest that 18 F-FCH PET parameters, such as SMATV and STLA at baseline, have a prognostic role in patients treated with docetaxel for mCRPC and may be more useful than commonly used PET indices such as SUV mean and SUV max . e study has some limitations due to the retrospective nature, the small sample size, and the single institution setting. Further investigation and larger studies are needed in order to find a significant correlation between 18 F-FCH PET indices and OS.
Data Availability e 18 F-FCH PET/TC data used to support the findings of this study are available from the corresponding author upon request.