Preclinical Applications of 3-deoxy-3-18f Fluoro-thymidine in Oncology - a Systematic Review
Theranostics. 2017; 7(1): 40–50.
Preclinical Applications of 3'-Deoxy-3'-[eighteenF]Fluorothymidine in Oncology - A Systematic Review
Sonja Schelhaas
1European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Germany.
Kathrin Heinzmann
twoComprehensive Cancer Imaging Centre, Imperial Higher London, United kingdom.
Vikram R. Bollineni
threeEuropean Organization for Enquiry and Treatment of Cancer Headquarters, Brussels, Kingdom of belgium.
Gerbrand One thousand. Kramer
fourDepartment of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, Holland.
Yan Liu
3European Organization for Research and Treatment of Cancer Headquarters, Brussels, Belgium.
John C. Waterton
fiveImaging Sciences, University of Manchester, Manchester, U.k..
Eric O. Aboagye
2Comprehensive Cancer Imaging Centre, Imperial College London, UK.
Anthony F. Shields
6Section of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, U.s..
Dmitry Soloviev
7Cancer Research UK Cambridge Institute, University of Cambridge, UK.
Andreas H. Jacobs
1European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU) Münster, Münster, Frg.
8Department of Geriatric Medicine, Johanniter Infirmary, Bonn, Frg.
Received 2016 Jul one; Accepted 2016 Sep 16.
Abstract
The positron emission tomography (PET) tracer three'-deoxy-three'-[18F]fluorothymidine ([18F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [18F]FLT uptake has plant express use every bit a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [18F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [18F]FLT studies, comprising 174 reports, nosotros identify the factors governing [18F]FLT uptake in tumors, among which thymidine kinase one plays a primary role. The majority of publications (83 %) report that decreased [18F]FLT uptake reflects the effects of anticancer therapies. 144 times [18F]FLT uptake was related to changes in proliferation as adamant by ex vivo analyses. Of these approaches, 77 % depict a positive relation, implying a good concordance of tracer accumulation and tumor biology. These preclinical data bespeak that [18F]FLT uptake holds hope as an imaging biomarker for response cess in clinical studies. Understanding of the parameters which influence cellular [18F]FLT uptake and retention as well as the machinery of changes induced by therapy is essential for successful implementation of this PET tracer. Hence, our systematic review provides the background for the use of [18F]FLT in future clinical studies.
Keywords: positron emission tomography, FLT, Oncology.
Introduction
Not-invasive molecular imaging with positron emission tomography (PET) is used in cancer enquiry to identify and stage tumors and appraise tumor response to anti-cancer treatments 1. The most established tracer for PET applications is two-[xviiiF]-fluoro-2-deoxy-D-glucose ([xviiiF]FDG), whose uptake is regulated by glucose metabolism 2. Due to the Warburg effect, uptake of [18F]FDG in tumors is generally high 3, making information technology a practiced candidate for visualization of neoplastic lesions. On the other hand, metabolically active organs similar middle and encephalon, and glycolytic cells in inflammatory lesions accrue this tracer besides. To overcome the drawbacks of [18F]FDG, Shields et al. proposed 3'-deoxy-3'-[xviiiF]fluorothymidine ([eighteenF]FLT) equally a radiotracer for imaging actively proliferating cells 4. [xviiiF]FLT is taken upwardly by cells by the same mechanisms as the nucleoside thymidine. This ship pace is facilitated by nucleoside transporters, peculiarly by the human equilibrative nucleoside transporter 1 (hENT1) 5. One time within the jail cell, [18F]FLT is phosphorylated by the enzyme thymidine kinase one (TK1), which results in the intracellular accumulation of the tracer. Accumulation of [18F]FLT reflects the thymidine relieve pathway, specifically activity of the cytoplasmic grade of TK1, which in turn is considered to be tightly linked to the S-phase of the prison cell proliferation cycle six (Fig. i ). The other important thymidine-to-DNA pathway is the de novo Dna synthesis pathway 7. The balance of de novo and salvage pathways is of crucial importance for the accumulation rate of [eighteenF]FLT 8 , 9.
Mechanisms of cellular [18F]FLT retentivity. Similar to thymidine in the salvage pathway, [18F]FLT is taken up from the extracellular milieu by specialized nucleoside transporters or via passive improvidence. Inside the prison cell [eighteenF]FLT is phosphorylated by thymidine kinase 1 (TK1), the enzyme also responsible for phosphorylation of thymidine. TK1 action is dependent on adenosine triphosphate (ATP). The phosphorylated course of thymidine (TMP) is further phosphorylated to thymidine diphosphate (TDP) and thymidine triphosphate (TTP), which is subsequently incorporated into the Dna. The phosphorylated course of [18F]FLT cannot be incorporated into Deoxyribonucleic acid simply is trapped inside the prison cell lx. Techniques like PET or gamma counter measurements are capable of quantifying the rate of accumulation of [18F]FLT within cells. An alternative thymidine metabolism pathway is the de novo synthesis. The cardinal enzyme of this pathway is thymidylate synthase (TS), which methylates deoxyuridine monophosphate (dUMP) to TMP. The two pathways merge at the level of TMP. Studies describing the importance of the different factors for [xviiiF]FLT uptake are described in detail in the Supplementary Results.
[xviiiF]FLT PET has previously been rarely used for tumor therapy follow-up in clinical trials. This is in part due to limited knowledge of the factors determining [18F]FLT uptake and therapy-induced changes of its retention. The Innovative Medicine Initiative Joint Undertaking funded projection QuIC-ConCePT aims to qualify several imaging biomarkers for assessing the pharmacodynamic response of tumors to anti-cancer drugs x. [18F]FLT uptake is one of these imaging biomarkers. To ameliorate empathize how uptake of this radiotracer reflects cellular proliferation, nosotros herein summarize the electric current literature on its preclinical and in vitro applications in oncology in a systematic review. Nosotros focus on the uptake of this tracer in untreated cells and tumors and evaluate the use of [xviiiF]FLT in monitoring therapy response to anti-cancer treatments. A detailed descriptive analysis and give-and-take of the manufactures can exist found in the Supplementary Results. In this manuscript we present the overall summary of the preclinical studies, discuss the confounding factors of [18F]FLT uptake and review its utility to monitor tumor response to therapy. These data are complemented by an overview of the selected study designs and recommendations and implications for future preclinical and clinical studies.
Materials and Methods
Nosotros performed a systematic search to accost the question whether [18F]FLT accumulation reflects cell biology in untreated and treated tumors in preclinical model systems. Thereby, nosotros adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) argument 11 (see PRISMA checklist in Supplementary Table S1). The search was performed in the bibliographic database Embase.com, which also includes the Medline database. The search was conducted with a combination of terms related to [18F]FLT and neoplasm (see Supplementary Methods) either to exist included in the title or abstract and the written report blazon filter "preclinical" was practical. Pick criteria were (i) published in English as a full paper in a peer-reviewed journal (no briefing abstracts), (ii) published between Jan 1998 and January 2016 and (iii) preclinical and / or in vitro information. A unmarried person screened the manuscripts to confirm that inclusion criteria were met. Farther details of the search strategy tin be found in the Supplementary Methods.
Results
Study identification and selection
The search strategy identified a total of n = 388 publications describing the use of [18F]FLT in the field of oncology. These were manually screened to ostend that the inclusion criteria were met. In addition, n = ix papers were establish through non-automated literature search, that were missed by the search strategy. These were also included, resulting in a total of n = 174 publications being eligible for inclusion in this review. Fig. ii describes the procedure of study identification according to the PRISMA guideline.
Design of experimental studies
The studies varied considerably in pattern, which is described in detail in the Supplementary Results (chapter 3.8). Overall, colorectal cancer is the almost normally used cancer blazon addressed. [18F]FLT PET images were most frequently acquired threescore min subsequently tracer injection for a duration of x min. However, the optimal time window might depend on the tumor model chosen. In contrast, therapy protocols were less harmonized. For case, drug applications varied from daily to weekly intervals, hampering a direct comparison and meta-assay of the data. These variances announced to restate the variances in the clinical state of affairs 12. More harmonized protocols are needed to reliably evaluate the role of [18F]FLT PET in predicting therapy response in the dispensary.
[18F]FLT uptake in untreated tumors
n = 45 publications characterize [18F]FLT uptake in untreated tumors. A detailed descriptive analysis of the misreckoning factors identified in these studies tin be found in the Supplementary Results (chapter three.2). In summary, it appears that uptake of the tracer is primarily determined past TK1 activity and the balance between save and de novo DNA synthesis pathways. Just as well other factors such every bit the presence of hENT1 or thymidine are of importance (see Table 1 and Fig. 1 ). Furthermore, [eighteenF]FLT appears to be more than tumor specific than [18F]FDG with regards to inflammatory lesions, fifty-fifty though [18F]FLT is also detected in some inflammatory tissues involving proliferating allowed cells (see also Supplementary Results, chapter iii.2.2).
Table 1
Summary of the factors important for cellular [18F]FLT uptake.
| Baseline [18F]FLT uptake in tumors and its change in response to therapy varies profoundly as a result of an overall residue of some or all of the factors below: |
| - TK1 expression levels |
| - TK1 activity |
| - ATP levels, equally a cofactor for TK1 activeness |
| - TS levels and activity (de novo Deoxyribonucleic acid pathway), competing with the salvage DNA synthesis |
| - TP expression and activity, influencing endogenous tumor thymidine levels |
| - Thymidine levels in tumor, reflecting the nucleotide turnover rates |
| - Expression of nucleoside transporters, which are essential for the ship of [eighteenF]FLT (notably hENT1) |
| - Delivery of the tracer |
| - Claret-brain barrier hampers [eighteenF]FLT uptake in brain tumors |
| - Thymidine levels in claret plasma, which are competing with [18F]FLT |
| - Animal body temperature |
| - Anesthetics used |
| - Oxygen breathing |
| - Tumor vascularity, and the changes thereof by antiangiogenic treatments |
Changes of [xviiiF]FLT uptake in treated tumors
north = 147 studies use [xviiiF]FLT to monitor treatment response. Of these, next to radiotherapy, due north = 21 unlike chemotherapeutic agents and n = 46 targeted agents were employed. A comprehensive description and discussion of these publications is presented in the Supplementary Results (chapter iii.iii-3.seven).
In summary, north = 122 studies describe a decline of [18F]FLT later tumor treatment in responsive tumor models (83 % of the 147 studies evaluating treatment response, Fig. 3A) which is in line with reduced proliferation of the tumor. Several of these studies study unchanged [18F]FLT when proliferation is non changed, for instance at very early time points after therapy initiation. Likewise in resistant models, [18F]FLT uptake is not altered upon handling, underlining that changes in [eighteenF]FLT accumulation are specific for changes in tumor proliferation, as demonstrated in north = fourteen studies thirteen - 25.
Graphical demonstration of the operation of [18F]FLT after therapeutic treatment of preclinical in vivo tumor models. (A) Of the n = 147 therapy follow upwardly studies included in this review, [18F]FLT is decreased in n = 122 cases and hence readily parallels therapy response. n = 12 studies employ agents that inhibit TS, inducing an upregulation of the thymidine salvage pathway and hence [18F]FLT uptake. Therefore, increased [18F]FLT in early time-frames later drug administration reflects the mechanism of action of the drug. (B) due north = 57 studies employed [18F]FLT and [18F]FDG for monitoring of treatment response. In n = 33 of these studies [18F]FLT appears to be superior to [xviiiF]FDG.
north = 14 of the 122 reports with reduced [xviiiF]FLT accumulation after therapy, demonstrate that at the cease of a treatment bike, [eighteenF]FLT levels might non be distinguishable from baseline, reflecting recovery of tumor proliferation equally shown by respective immunohistochemistry nine , xv , 26 - 37. Hence, for successful treatment monitoring, the imaging time point is of crucial importance. All the same, since therapy protocols differ substantially in timing (single administration, daily administration, therapy on two sequent days, weekly therapy, etc.) no common conclusion tin can be drawn on a general fourth dimension window that is best suitable for cess of treatment response in preclinical studies. Furthermore, these findings likewise suggest that an early refuse in [18F]FLT uptake does not rule out the possibility that at after time points treatment efficacy is not maintained, which can partly be related to a express half-life of drugs within the trunk. Consequently, early imaging might assistance to answer the question whether the drug reaches the target and affects Deoxyribonucleic acid synthesis pathways. Yet, information technology cannot predict treatment outcomes without corresponding growth or survival studies.
n = 12 studies (8.2 %) use agents targeting TS and draw an increased [xviiiF]FLT uptake early afterward handling initiation. Most of these studies report a transient upregulation of TK1, which explains the increase in tracer uptake. This transient increase in [xviiiF]FLT uptake can be referred to as flare phenomenon and can be attributed to the cellular machinery of the therapeutic amanuensis. Nevertheless, reduced cellular proliferation can be observed past [eighteenF]FLT PET at later time points. In the post-obit, these agents are grouped together every bit TS inhibitors, comprising agents of the grouping of antimetabolites, just also kinase inhibitors 38 or combination therapies 39.
In n = xiii therapy approaches (8.8 %) [18F]FLT failed to predict treatment response (i.e. unchanged tracer uptake despite effective therapy every bit assessed by tumor growth inhibition, immunohistochemistry of proliferation or similar). These studies cannot be attributed to a specific drug form. In most cases a reason for the failure is hypothesized, such every bit suboptimal timing of imaging in the instance of antibiotic therapy 40, or low uptake of [18F]FLT in the tumors nine , 41 , 42. The latter might exist related to preferential use of the thymidine de novo pathway past the tumor, which farther complicates interpretation of changes in [18F]FLT uptake afterward handling 43. Two studies describe that unchanged [18F]FLT uptake is in line with unaltered Ki67 staining 24 , 44. Therefore, [18F]FLT accurately reflects the proliferative action of the tumor (truthful negative). Other studies draw that the pharmacological properties of the respective drug (like balmy upregulation of TK1 or genetic alterations of the tumor, like p53 knockout) might non allow [eighteenF]FLT to be used for therapy follow up 45 - 49. This leaves only ane study (0.seven %) describing an inexplicable failure of [xviiiF]FLT in predicting therapy response xiii.
Of note, all of the north = 15 studies employing radiotherapy show that [18F]FLT reliably predicts treatment response. For all other therapy approaches, failures could be noted. Consequently, [18F]FLT uptake appears to be an excellent imaging biomarker to monitor response to radiotherapy.
Whenever studies also employed [18F]FDG PET to monitor therapy response, we reported this also in the detailed description in the Supplementary Results. Of these n = 57 studies, [18F]FLT is superior to [18F]FDG (i.eastward. changes are more pronounced or occur at an earlier fourth dimension point) in due north = 33 cases (58 %), and it is comparable in n = 17 studies (30 %) (Fig. threeB). Yet, these two tracers provide different data as they measure unlike pharmacodynamic events.
Some in vivo studies provided numeric quantitative imaging data, either from PET images or from gamma counter measurements. This allowed us to estimate the changes of [18F]FLT uptake relative to baseline or to a respective control, as presented in Fig. 4 (see likewise Supplementary Table S2). Each data point represents one outcome of a study. Most studies provide more than than one data point since they report on different time points, different model systems, etc. (come across Supplementary Table S2 for details). When corresponding data were available, standard deviations were displayed.
Overview of the relative change of [18F]FLT afterward tumor therapy in preclinical in vivo models sorted according to therapy approach. Wherever possible, quantitative data were extracted from the publications and calculated as percent change either relative to baseline (left column) or to a corresponding command (correct column). Each information point represents a single issue of a written report. The standard deviation could not exist extracted from all publications. Rectangles correspond results of a unmarried assay. Green rectangles correspond data points of tumors that have regained their proliferative capacity at the end of a treatment cycle (as proven past immunohistochemistry). Bluish rectangles represent information points of resistant tumors. Red rectangles represent results of tumors with very depression baseline [18F]FLT uptake. Detailed results are displayed in Supplementary Tabular array S2.
Of the overall north = 299 information points displayed in Fig. 4 , n = 190 are statistically significant. The other information points originate from resistant tumors (blueish) or tumors that recovered (dark-green). In other cases, [18F]FLT uptake might have been adamant nether circumstances that too do not result in a change of tracer accumulation, for instance if the therapy dose employed was too low or the time betoken was very early on after start of treatment. Furthermore, for some information points, statistical information was not provided.
43 % of the results displayed, relate the alter to a control group, whereas the bulk are comparisons with baseline uptake. We were non able to encounter any major differences between these analyses. In the clinical setting changes in tracer uptake are generally compared to a baseline scan before treatment initiation. Yet, nether certain circumstances, comparing to a control grouping might be preferable. For instance, [18F]FLT uptake might exist unchanged upon treatment, while the signal from an untreated control is significantly increased. This is possible with cytostatic treatments, which do affect tumor growth, whereas no change of [eighteenF]FLT PET measurement before and after treatment can be noted (see e.k. fifty). This is supported by the ascertainment that individual prison cell uptake of [18F]FLT is non e'er afflicted by cytostatic treatments 51.
A maximum [eighteenF]FLT reduction of 97 % relative to baseline was reported 52. No differences between the different therapeutic classes were noted. However, a definite conclusion is hampered by the great variability of the experimental setups and low sample size of some handling groups. This impedes proper statistical evaluation of the data.
Nosotros also sorted the data co-ordinate to tumor type investigated, quantification mode employed, or day of image conquering relative to treatment initiation (Supplementary Fig. S9). Withal, we were not able to detect any specific groups that take a very pronounced reduction of [eighteenF]FLT. The only remarkably different group is the 1 comprising the TS inhibitors, inducing an increase in tracer uptake. We displayed the results in a carve up graph due to the variances in scaling. The increase of [18F]FLT uptake in this grouping is up to a factor of five with loftier variabilities.
Relation of [eighteenF]FLT uptake to proliferation
Several studies employ ex vivo tumor analyses to validate in vivo imaging findings. In doing so, many studies pursued more than than one approach of ex vivo validation. n = 32 publications calculated correlations of [18F]FLT with proliferation equally assessed by tumor growth or histological markers of proliferation, equally summarized in Supplementary Table S3. A multitude of studies depict that changes in [18F]FLT are linked to changes in tumor volume. Of these, n = 14 reports calculated a correlation. n = 102 approaches related [18F]FLT uptake to histological proliferation markers (mostly Ki67, but also PCNA or BrdU). Of these, only n = 21 studies did non discover any clan of [eighteenF]FLT aggregating and proliferation. A link of [xviiiF]FLT with TK1 expression or activeness was assessed in north = 42 studies; of these only n = 12 were not able to relate these two parameters. Association of [18F]FLT accumulation with either of the proliferation markers TK1 and Ki67 appears to exist comparable. Overall, xx % of the approaches calculated a correlation (Fig. 5 ). 57 % report that changes in [18F]FLT can be attributed to changes in proliferation markers. Nonetheless, no correlation was calculated, which does not necessarily imply that there is no correlation. In the remaining 23 % the proliferation markers were not related to tracer uptake. This number reflects the multitude of factors that can affect uptake and retention of [18F]FLT (see Tabular array ane ), confounding the link between [18F]FLT uptake and cellular proliferation. Notwithstanding, 83 % of the studies successfully employed [18F]FLT to monitor handling response in tumors (see Fig. iiiA). It is likely that the number of imitation negative studies is college than reflected in this review because negative results are not published on a regular basis. Also from the feel within the QuIC-ConCePT consortium we know that changes in [18F]FLT uptake might be disconnected from the tumor response to treatment despite of the use of a suitable model (unpublished observations).
Overview of relations of [eighteenF]FLT with parameters of cellular proliferation. This pie chart depicts the relations observed in the studies investigated in this review. Cellular proliferation comprises immunohistochemistry of Ki67, PCNA, BrdU and TK1, as well as TK1 action or expression analyses. Supplementary Fig. S10 depicts the corresponding data sorted more specifically for TK1 and other markers of proliferation. "Relation observed" relates to non-quantitative observational studies. Correlations with correlation coefficients > 0.7 were considered potent.
To appraise the preferential publication of positive results (i.east. publication bias), statistical approaches like a funnel plot would be needed. However, due to heterogeneities in study design and the generally depression sample sizes commonly employed in preclinical studies, this is not viable here. In addition, many studies are not fully compliant with the ARRIVE guidelines for reporting preclinical studies 53, then it is sometimes impossible to verify that valid experimental designs and analyses were employed.
Discussion
Here, we systematically review the literature of preclinical [18F]FLT applications in oncology. Despite a range of confounding factors affecting [18F]FLT uptake, especially TK1 expression and activity (come across likewise Table 1 ), numerous studies demonstrate that [18F]FLT can be used to monitor handling response in appropriate tumor models. However, when interpreting [18F]FLT PET findings to delineate proliferating tumors or assess therapy response, certain considerations and pre-requisites have to be taken into account, like the machinery of action of the therapy.
Complementary to a recently published review focusing on [xviiiF]FDG and [xviiiF]FLT PET imaging in preclinical studies for monitoring anti-cancer treatments 54, nosotros attempted to systematically cover experimental applications of [xviiiF]FLT in the field of oncology to reply the question whether changes in [xviiiF]FLT accumulation are indeed related to tumor biology.
A biomarker, such as an imaging biomarker, is "a physical sign or laboratory measurement that occurs in clan with a pathological process and that has putative diagnostic or prognostic utility" 55. In oncology the gold standard for prognostic utility is overall survival (or at least progression-free survival). This is seldom measured in preclinical studies. In animals usually tumor size is measured which is the preclinical equivalent of objective response in humans using response evaluation criteria in solid tumors (RECIST) 1. Only rarely is objective response acceptable as a surrogate for overall survival. The ability of changes in [18F]FLT uptake as a biomarker to predict tumor shrinkage (which is just another biomarker) is of some interest. More important here, notwithstanding, is association of [xviiiF]FLT with underlying pathological processes (biological validation). Key questions include 56: (i) Do drug-induced changes in [18F]FLT uptake faithfully reflect drug-induced changes in histopathological proliferation? (ii) Does the temporal development of drug-induced changes in [xviiiF]FLT uptake faithfully reflect the temporal evolution of drug-induced changes in histopathological proliferation? (iii) Practice increasing doses of drug induce graded changes in the [18F]FLT uptake which reverberate graded changes in histopathological proliferation? (iv) For which drug classes do these relationships hold? (v) Where practice these correlations pause downwards and why? (vi) Are findings reproducible betwixt laboratories? Preclinical studies play an essential part in imaging biomarker validation, equally it is hard to accost these questions in man, and the studies reviewed hither help to address every single one of these questions.
Following more than 15 years of research using [eighteenF]FLT, recent reports note that tumor proliferation imaging with this tracer may non be straightforward 57. From clinical experiences [18F]FLT PET is non e'er correlated with the Ki67 proliferation index, considered as the gold standard of proliferation, and fifty-fifty a reverse correlation is observed in some tumors. Therefore, in a systematic review Chalkidou et al. point out that apart from technical difficulties inherent to PET imaging, there might be biochemical reasons underlying tumor biology explaining the variability of results 58. Moreover, results from Vanderbilt University evidence that the magnitude of [18F]FLT uptake should not be considered equally a surrogate of proliferative index 8. Zhang et al. concluded that "[18F]FLT PET imaging does non always 'light up' proliferating tumors" 31.
Diverse factors tin can bear on [18F]FLT uptake (summarized in Table 1 ), specifically TK1, TS and hENT1 expression and activity, as well as endogenous thymidine levels. It appears that different parameters play different roles in various experimental and therapeutic scenarios. Fifty-fifty though the balance of the thymidine de novo and salvage pathway is of crucial importance, in that location is not a unmarried factor responsible for [eighteenF]FLT uptake in general. The interplay between the different determinants is circuitous. This should be considered when designing and interpreting [eighteenF]FLT PET studies.
Even though [18F]FLT is not a marker of cellular proliferation per se, it is capable of reflecting therapy-induced changes in prison cell proliferation of many tumor types. 83 % of the studies investigating alterations in [18F]FLT uptake afterward tumor treatment report that tracer accumulation is reduced, reflecting reduced tumor proliferation. n = 111 approaches underpin these findings by corresponding ex vivo analyses of cellular proliferation. The specificity of the tracer to reflect changes in tumor proliferation is emphasized by n = fourteen studies showing that [18F]FLT uptake is not altered in resistant models. These studies imply that [18F]FLT PET tin can exist employed for monitoring of response to anti-cancer treatments in the clinical situation. Nevertheless, it is probable that the results described in this review might have literature bias as negative results are non e'er published. Potentially, the inclusion of conference abstracts, which are more probable to describe negative results, would reduce this bias.
It should exist kept in mind, that in full general the report design of preclinical research is less standardized than clinical approaches. Parameters that vary include tumor blazon, PET imaging protocol, fashion of PET quantification, number of subjects and groups, number of imaging time points, and type and number of interventions. The impact of these factors on report event is difficult to estimate. Therefore, the number of directly comparable studies is very limited. This hampers statistical evaluation as usually done in meta-analyses. Analyses such every bit forest plots, funnel plots or ROC analysis could not exist pursued. Fifty-fifty though we summed upwardly some factors, conclusions are rather based on a qualitative approach. This is one of the major limitations of this systematic review.
Fifty-fifty though our review supports the implementation of [18F]FLT PET in clinical research, information technology needs to be determined in future larger scale clinical trials the extent to which our findings can be translated. The number of clinical studies up to now is limited. The QuIC-ConCePT consortium recently published a systematic review on [18F]FLT PET uptake as a mensurate of handling response in cancer patients, following an coordinating search strategy. This review revealed that [eighteenF]FLT PET is indeed a skilful predictor of early response to systemic-, radio- and concurrent chemotherapy 59. Furthermore, this article points out that the fourth dimension point of imaging is of importance to assess handling response accurately. This finding is well in line with the observations made in preclinical studies, equally presented here. The promising nature of [18F]FLT PET as a tool to monitor tumor therapy response has too been highlighted by other clinical [18F]FLT reviews 12 , 60 - 62. However, information technology should be kept in mind that [18F]FLT uptake might not be a reliable biomarker of proliferation in all instances, as pointed out in both, clinical 58 , 62 and preclinical [54, this review] systematic reviews.
Sanghera et al. noted a vast diversity in report protocols 12, which is in line with our personal observations. Variances in uptake fourth dimension, acquisition method, and fourth dimension per bed position could influence quantitative measurements and analysis and thereby decrease comparability of results. As the optimal fourth dimension window for imaging might depend on the model employed, nosotros recommend that this time frame should be determined and used in preclinical studies. Future clinical trials should follow harmonized protocols in analogy to those proposed for [18F]FDG as outlined eastward.g. past the PERCIST criteria ane or respective recommendations past the European Association of Nuclear Medicine 63. Some further suggestions for harmonizing clinical [eighteenF]FLT study protocols have been proposed by Peck et al. 64. The missing standardization of protocols probably represents 1 of the major challenges for reliable implementation of [eighteenF]FLT PET in clinical trials.
Only when clinical acquisition protocols have been standardized, the full clinical validation of [eighteenF]FLT will be possible, i.due east. demonstration that acute changes in [18F]FLT accumulation help forecast overall survival or progression free survival. Biological validation of [eighteenF]FLT uptake is feasible via histological examination of tumor specimens, allowing relation of changes in tracer uptake to tumor biological science. This can sometimes be washed in clinical trials, where it is possible to recover biopsy specimens or tumors excised past surgery. However, this is not always possible in patients. To comprehensively sympathize the tumor biological science underlying [eighteenF]FLT uptake, preclinical studies of imaging pathology correlation are of great value. The aim of this review on preclinical [eighteenF]FLT applications was to substantially amend the understanding of these factors.
Whether or not preclinical studies employing [18F]FLT PET for monitoring cancer therapy response are predictive for cancer patients is the subject area of another systematic review by the QuIC-ConCePT consortium, which is currently in training. Frequently, preclinical studies have employed subcutaneous xenografts, arising from cells cultured nether laboratory conditions, as they are frequently reproducible, straightforward to implement, and risks to welfare are easily managed. However, patient derived xenografts 65 or genetic cancer models 66 appear to more closely reflect clinical cancers, and may be more predictive. Moreover, the utilize of combination therapies, as also employed in the clinic, might help in gaining more clinically relevant information.
Based on the first promising clinical results and the detailed understanding of the biology underlying [18F]FLT aggregating in tumors, gained peculiarly from preclinical studies, as described in our review, we are positive that [18F]FLT PET holds promise as a therapy response assessment tool in cancer patients. Moreover, it reports on completely different biology than does the more clinically familiar tracer [eighteenF]FDG, which accumulates in glycolytic inflammatory cells and cancer cells. Hence, [18F]FLT accumulation and its changes should exist further explored as an imaging biomarker in handling response studies in the clinical situation. The following issues should be taken into account, when applying [eighteenF]FLT measurements in the preclinical setting:
-
Low [18F]FLT uptake at baseline (SUVmax < 1; T/B < 1) is likely an indication that the investigated tumor primarily depends on de novo thymidine synthesis or there may be high levels of thymidine in the rodent strain being studied. Consequently, [eighteenF]FLT is likely not to exist a reliable tracer in these models.
-
The optimal time window for PET image acquisition should be carefully chosen and should be determined for each model in dynamic imaging studies.
-
All imaging parameters and protocol details should be thoroughly documented and included in hereafter publications to allow readers to appraise the quality of the study performed and to relate findings to other publications. These parameters include PET acquisition protocol (time of prototype acquisition, duration of browse), fourth dimension signal of paradigm acquisition (relative to treatment initiation and / or tumor implantation), PET image analysis details (reconstruction algorithms, quantitation parameters), therapy protocol (drug dose, route of assistants, application schedule), numbers of animals studied, and numerical results, including deviations. The Go far guidelines should exist followed 53 and negative results should be published.
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Drugs impacting TK1 (similar TS antagonists or antifolates) may induce an [eighteenF]FLT flare effect. This might mask possible reduction of [18F]FLT uptake due to decreased proliferation early after drug administration. Upward to now it is not known, how this flare effect might be related to treatment event. Hence, early [18F]FLT imaging of treatment response to drugs affecting TK1 cannot be recommended if the primary objective of the study is prediction of tumor growth arrest rather than target modulation.
-
Whenever possible, ex vivo correlation analyses with proliferation markers should exist performed to validate in vivo PET results.
-
Tumors are heterogeneous dynamic tissues which might demonstrate heterogeneous [18F]FLT uptake and therapy response uptake patterns. Care should be taken to use comparable parameters and corresponding tumor areas in correlation analyses to avoid sampling errors.
Supplementary Material
Supplementary tables and figures.
Acknowledgments
Nosotros thank E.P. Jansma (Medical Library, VU University Medical Center, Amsterdam, Holland) for assistance with the search strategy and Due south. Collette (European Organization for Inquiry and Handling of Cancer Headquarters, Brussels, Belgium) for aid in writing the manuscript.
Funding
The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking (www.imi.europa.eu) under grant agreement number 115151, resource of which are composed of financial contribution from the European Wedlock's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution. Please refer to the Supplementary Data for a listing of all consortium members.
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