Therapy assessment in prostate cancer using choline ... - Springer Link

Eur J Nucl Med Mol Imaging (2017) 44 (Suppl 1):S78–S83 DOI 10.1007/s00259-017-3723-3

REVIEW ARTICLE

Therapy assessment in prostate cancer using choline and PSMA PET/CT Francesco Ceci 1 Stefano Fanti 1

&

Ken Herrmann 2,3 & Boris Hadaschik 4 & Paolo Castellucci 1 &

Received: 4 May 2017 / Accepted: 5 May 2017 / Published online: 25 May 2017 # Springer-Verlag Berlin Heidelberg 2017

Abstract While PET with non-FDG tracers (mainly choline and Ga-PSMA) has commonly been used for restaging in men with biochemically recurrent prostate cancer, as well as for primary staging, it is only recently that a few preliminary studies have addressed the possible use of PET for monitoring the response to systemic therapy of metastatic disease, especially innovative treatments such as abiraterone and enzalutamide. This article aims to evaluate the role of PET imaging with different non-FDG radiotracers for assessment of therapy in advanced prostate cancer patients. Keywords Prostate cancer . Pet/Ct . Choline . PSMA . Therapy assessment . mCRPC

Background Therapeutic concepts in advanced prostate cancer Prostate cancer (PCa) is the most common cancer and the second most common cause of cancer-related deaths in men in Europe [1]. In general, PCa starts out as an androgen* Francesco Ceci [email protected]

1

Nuclear Medicine Unit, S. Orsola-Malpighi University Hospital, University of Bologna, Via Massarenti, 9, 40138 Bologna, Italy

2

Department of Nuclear Medicine, University Hospital Essen, Essen, Germany

3

Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

4

Department of Urology, University Hospital Essen, Essen, Germany

dependent tumor; thus androgen-deprivation therapy (ADT) represents the backbone of treatment for metastatic hormonesensitive PCa. ADT can also be administered with adjuvant intent after primary treatment in men with a high risk of relapse and/or positive lymph nodes [2]. Moreover, ADT can represent an option in selected patients presenting with biochemical relapse only after primary treatment [3]. Even with the use of ADT for advanced patients, disease progression usually occurs after a median of 12–24 months, despite castrate levels of serum testosterone (≤50 ng/dL), defining a state called castration-resistant prostate cancer (CRPC) [4]. A notable feature of CRPC is the persistent role of androgen receptor (AR) signaling in driving cancer cell proliferation [5]. Based on these assumptions, the AR remains a critical therapeutic target for CRPC treatment. Two novel hormonal agents (abiraterone acetate and enzalutamide) were recently approved for treatment of metastatic CRPC (mCRPC) in both the pre-chemotherapy and postchemotherapy setting, confirming that prostate cancer cells continue to be largely androgen-dependent and AR signaling-guided [6–9]. The incorporation of these secondgeneration hormonal agents in the management of mCRPC, together with other, non-hormonal treatments (docetaxel, cabazitaxel, radium-223) [3], has expanded prognostic expectations among PCa patients. However, the availability of many treatment options that are not directly comparable raises the problem of identifying the ideal sequence of treatment administration so as to define the appropriate management of mCRPC. As a result, various agents are currently available to the uro-oncologist for treatment of patients with advanced disease. The possibility for accurate and early assessment of the response to therapy will thus have a major impact on mCRPC management, enabling a more tailored therapy. In addition to improved life expectancy, the collateral effects/ toxicity and costs of futile therapy will be reduced.

Eur J Nucl Med Mol Imaging (2017) 44 (Suppl 1):S78–S83

Therapy response assessment in advanced prostate cancer Although novel hormonal agents and taxane-based chemotherapy represent breakthroughs in the treatment of mCRPC, some patients have no response to these agents, demonstrating primary (or innate) resistance. Most of those who respond initially will go on to develop secondary (or acquired) resistance over time. In particular, it is well known that up to 45% of mCRPC patients do not respond to taxane-based chemotherapy [3]. Thus, the early identification of non-responders is crucial for avoiding the administration of futile and expensive therapies. Since the introduction of PSA screening in the 1980s, PCa diagnosis and management have been guided by this biomarker. PSA levels have been shown to be associated with disease burden [10] and are included in many prognostic tools for survival. In patients with metastatic disease, the assessment of PSA levels over time is routinely used for both evaluation of therapy response and outcome prediction. However, this correlation becomes more complicated in advanced disease states [11] that are characterized by increasing disease heterogeneity due to the complex mechanisms involved in the development of castration-resistant PCa [12, 13]. Moreover, the assessment of therapy response performed by PSA can be impaired by flare phenomena [14] and by the presence of active visceral metastases not producing PSA [15]. As a consequence, conventional imaging methods, including computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy (BS), have been proposed as possible tools for evaluating the response to therapy. Standardized imaging is critical for patient management, biomarker development and therapeutic clinical trials [16]. Imaging provides information on disease volume and distribution, likely prognosis, changes in biological behavior, therapy-induced changes, duration of response, emergence of treatment resistance, and the host’s reaction to the therapies administered [17, 18]. The currently accepted standard for therapy response assessment is the use of objective response criteria including CT evaluation (RECIST 1.1) [18]. However, the use of RECIST 1.1 criteria has proved to have several limitations, especially with respect to therapy response assessment in the bone [17, 18]. Bone scans, conversely, tend to remain active even after the tumor is responding, thus underestimating the response to therapy [19]. The use of whole-body MRI (WB-MRI) has recently been proposed for investigating advanced PCa. WB-MRI detects bone metastases with higher sensitivity than bone scans [16, 20] and provides a clearer categorization of bone metastasis response, unlike bone scans, which only identify disease progression. In this scenario, recommendations were recently developed as well as standardized response guidelines for WB-MRI in PCa. The Metastasis Reporting

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and Data System for Prostate Cancer guidelines (METRADS-P) has established consensus recommendations on the performance, quality standards and reporting of WBMRI for use in all oncologic manifestations of advanced PCa [19]. Nevertheless, WB-MRI is not without limitations: it cannot be performed on all MRI scanners, and few radiologists have been trained in interpreting WBMRI, which has prevented its widespread implementation [19]. Thus, the use of WB-MRI has been confined to a few academic expert centers. Positron emission tomography (PET) functional imaging is a widely used technique. PET imaging, which enables the study of cancer cell metabolism or receptors, is a valid tool for early prediction of response to therapy in many solid tumors. The assessment of treatment-induced changes by PET/ CT, rather than morphological changes alone, may be an early and reliable alternative to other indicators of treatment benefit such as radiological progression-free survival (rPFS) or PSA. Increasing PSA levels predict disease progression with good accuracy; however, decreasing PSA is not always related to homogeneous response to therapy. PET imaging has the potential for greater accuracy than PSA trends or morphological imaging, especially for early response assessment. Furthermore, PET/CT may provide additional data on the extent of active disease, in particular the site(s) and number of active lesions. Thus, the assessment of therapy response by means of PET/CT may enable more tailored treatment approaches, possibly leading to increased survival and superior quality of life. However, there are only few preliminary data in the literature supporting the value of PET/ CT-based response assessment in advanced PCa.

Choline-based PET imaging Therapy response assessment Choline, a substrate for the synthesis of phosphatidylcholine, and with up-regulated expression in PCa cells [21], has been proposed within the last decade as a valid biomarker for PET imaging in PCa [22]. Studies have shown that 11C- and 18Fcholine PET/CT is a superior diagnostic tool for investigating PCa in comparison to conventional imaging [23]. Choline PET/CT demonstrated its highest accuracy in the recurrence setting [22], particularly in patients showing biochemical recurrence after radical therapy. However, as has happened for other solid tumors, PET/CT with metabolic radiotracers have also been proposed for assessing the response to different chemotherapeutic agents. In PCa, a common treatment strategy proposed for mCRPC patients is docetaxel as the first line of chemotherapy. Recently, Ceci et al. [24] investigated the role of 11C-choline PET/CT for evaluating the response to docetaxel in a cohort of 61 mCRPC patients. The authors

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compared the radiologic response evaluated with 11C-choline PET/CT with the PSA response. Progression of disease was defined as the appearance of a new PET-positive lesion, whereas PSA response was defined as a decrease in the PSA level of ≥ 50% after chemotherapy. Interestingly, progressive disease, assessed with 11C-choline PET/CT, was observed in 44% of patients presenting a PSA response. The authors also demonstrated that a higher tumor burden in the baseline PET/ CT (expressed as more than ten PET-positive bone lesions before chemotherapy) was significantly associated with an increased probability of disease progression. Thus, they concluded that 11C-choline PET/CT could be considered in patients with decreasing PSA levels after docetaxel but clinical suspicion of progression, in order to assess potential radiological progression of the disease despite PSA response (Fig. 1). More recently, Schwarzenböck et al. [25] prospectively evaluated the value of 11C-choline PET/CT in monitoring early and late response to a standardized first-line treatment with docetaxel in a cohort of 32 mCRPC patients. Patients were referred for 11C-choline PET/CT before docetaxel and after one and ten chemotherapy cycles. The results of PET/CT were compared with RECIST 1.1 and clinical criteria-based therapy response assessment, including PSA, for defining progressive disease (PD) and non-PD. No significant correlation was observed between changes in choline uptake in 11C-choline PET/CT and therapy response assessment based on RECIST 1.1 and clinical criteria during the early and late course of docetaxel. Therefore, the authors suggested limited use of choline PET/CT for assessing response to therapy in men with first-line docetaxel treatment. However, as reported by the authors, the use of RECIST has limitations in the evaluation of bone metastases, as increased sclerosis of bone metastases during therapy might be misinterpreted as PD. Patients with mCRPC can also be treated orally with novel hormonal agents (abiraterone acetate and enzalutamide) in both the pre-chemotherapy and post-chemotherapy setting. These agents have confirmed efficacy with good results in terms of biochemical response together with fewer side effects compared to taxane-based chemotherapy [6–9]. De Giorgi et al. [26] investigated the role of 18F-choline PET/CT in the early evaluation of abiraterone and outcome prediction in 43 patients with mCRPC. Monthly evaluation of serological PSA response and safety were performed; 18F-choline PET/ CT was performed at baseline before abiraterone and after 3 and 6 weeks of therapy. The authors observed a decline in PSA of ≥50% in 49% of patients, with a discrepancy between PET/CT and PSA in 52.4% of the whole population (22/42). Importantly, in multivariate analysis, only 18F-choline PET/ CT (progression vs. non-progression) was significantly associated with progression-free survival and overall survival. Thus, the authors concluded that early 18F-choline-PET/CT is prognostic of clinical outcome in mCRPC beyond PSA response. The same group subsequently published data on a


cohort of 36 mCRPC patients treated with enzalutamide. Similar to the earlier study, monthly evaluation of serological PSA response and safety were performed, and 18F-choline PET/CT was performed at baseline and after 3 and 6 weeks of therapy. Early 18F-choline PET/CT progression predicted radiological progression 3 months in advance of CT in 66% of patients and was discordant with the decrease in PSA level in 36.1% of patients. In multivariate analysis, a decrease in PSA level and 18F-choline PET/CT were significant predictors of progression-free survival [27]. Finally, these results were partially confirmed by Maines et al. [28], who evaluated the role of 18F-choline PET/CT in monitoring the response to enzalutamide in 30 mCRPC patients. The authors observed that the maximum standardized uptake value (SUVmax) measured by PET before enzalutamide treatment was significantly related to biochemical recurrence-free survival, radiologic progression–free survival, and overall survival. Despite the increasing interest for radium-223 in the treatment of bone metastasis in mCRPC, to the best of our knowledge, at present, there are no studies specifically designed to assess the role of choline PET imaging to evaluate the response to radium223 therapy. To date, very few data have been published regarding therapy response assessment using choline-tracers in PCa. In addition, there is still no consensus regarding the criteria that should be used to evaluate the response to treatment with choline PET/CT. Furthermore, both EORTC and RECIST 1.1, which are typically used as radiological criteria for therapy response assessment, present many limitations when applied to mCRPC patients. Nonetheless, the use of semiquantitative analysis for the assessment of drug efficacy as well as the appearance of new active lesions has been validated in different solid tumors for FDG PET/CT. In this regard, Oprea-Larger and collaborators [29] demonstrated that the measurement of SUV normalized to the area under the blood activity concentration curve (SUVauc) correlated better with full kinetic analysis than did standard SUV. The authors enrolled 12 patients with metastatic prostate cancer; in this population, the repeatability of SUVauc was comparable to that of standard SUV, indicating that differences in 18F-choline uptake of 30% or more likely represented treatment effects. Choline PET/CT as predictor of patient outcome The use of 11C-choline PET/CT as a predictive tool in patients with recurrent disease was recently explored by Giovacchini et al. in two large patient cohorts [30, 31]. First [30], the authors retrospectively analyzed patients with recurrent PCa in order to evaluate whether 11C-choline PET/CT performed during ADT could predict PCa-specific survival. The median follow-up after 11C-choline PET/CT was 4.5 years, and the 11C-choline PET/CT detection rate was 57%. The median PCa-specific survival was statistically significantly different:


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Fig. 1 68-year-old mCRPC patient with PSA of 23 ng/mL. The patient had a baseline 11Ccholine PET/CT before start of abiraterone (a). After 6 months of therapy, the PSA decreased to 3.4 ng/mL. Subsequently, the patient was restaged with 11Ccholine PET/CT to evaluate the response to therapy, revealing a decreased choline uptake in the majority of lesions (b)

16.4 years in patients with negative 11C-choline PET/CT results and 11.2 years in patients with positive results. The authors later [31] performed a study with the same methodology in a cohort of 302 hormone-naïve PCa patients with biochemical recurrence after radical prostatectomy. The median follow-up after 11C-choline PET/CT was 7.2 years, and the 11C-choline PET/CT detection rate was 33%. The 15-year PCa-specific survival probability was statistically significantly different: 42.4% in patients with positive 11C-choline PET/

CT results and 95.5% in patients with negative results. Given these findings, it can be assumed that positive 11C-choline PET/CT results can predict adverse biology and poorer PCaspecific survival if performed in the recurrence setting both in hormone-naïve patients and in patients with ADT. Similarly, Kwee et al. [32] investigated the prognostic value of the metabolically active tumor volume measured with 18Ffluorocholine PET/CT in 30 mCRPC patients. Statistical analysis demonstrated significant differences in survival between

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groups stratified by median net metabolically active tumor volume.

Non-choline PET imaging: Is there a role for PSMA PET/CT? Beyond choline, new tracers have recently been introduced for imaging PCa, with 68Ga-PSMA and anti-3-18F-FACBC having shown the most promising results thus far [33, 34]. These radiotracers demonstrated higher sensitivity and specificity than choline for restaging PCa in the setting of biochemical recurrence. However, the efficacy of these new radioligands as indicators of treatment efficacy and predictors of patient outcome in mCRPC patients has not yet been sufficiently assessed. At present, the best results in terms of accuracy in the context of both staging and restaging have been obtained with PSMA-targeting imaging ligands. PSMA, the glutamate carboxypeptidase II, is a membrane-bound metallo-peptidase over-expressed in PCa cells [35]. New urea-based molecular probes targeting the external domain of the prostate-specific membrane antigen (PSMA-HBED-CC, PSMA I&T, PSMA617, PSMA-1007) have recently been developed for PET imaging. However, the interaction between PSMA and the administration of ADT in humans has not been extensively validated. Novel in vitro results [36] suggested that an increase in PSMA cellular expression dependent on intensified ADT occurred in both hormone-sensitive and castration-resistant cell lines. Thus, the uptake of PSMA-binding tracers could theoretically be stimulated by therapeutic effective short-term variation in pre-medication in all stages of ADT response. The interactions between PSMA expression and hormonal ablation must be considered in the interpretation of diagnostic PSMA imaging as well as in the optimal timing of PSMAbased therapies. Despite these interesting pre-clinical findings, it remains unclear whether PSMA PET/CT could be used as a diagnostic test to assess the response to novel hormonal agents targeting the androgen receptor axis. Furthermore, it is still not known whether a receptor-targeting radiopharmaceutical, instead of a metabolic tracer, would have the same value for treatment response monitoring in mCRPC treated with novel hormonal therapies or taxane-based chemotherapy.


randomized trials validating these preliminary results represents the main drawback. Nevertheless, the use of PET/CT (with choline or other radiotracers) for accurate and early assessment of response to chemotherapy or novel hormonal agents will most likely have an important impact on the management of men with metastatic PCa. This approach could result in more tailored therapies, especially for patients presenting with decreasing PSA levels during treatment while functional imaging may show heterogeneous responses and/or progression of disease. Accordingly, individual patients could be switched to radiotherapy of non-responding lesions, or to a second line of systemic therapy. Furthermore, considering the relevant cost of these therapies, the availability of a diagnostic test able to predict treatment response (earlier than laboratory and radiological imaging) could represent a promising approach for monitoring mCRPC, saving time and money. As a result, in addition to improved life expectancy, the collateral effects/ toxicity and costs of futile therapy will be reduced. Finally, an understanding of which PET tracer is most accurate in assessing early response will be crucial.

Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Considering the retrospective design of the study, formal consent is not required.

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The preliminary results available in the recent literature suggest a promising role for PET imaging as a tool for assessing and predicting the response to systemic therapies in advanced PCa. However, at present, the lack of prospective and

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