Purpose: To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [18F]-3′deoxy-3′-fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer.

Experimental Design: This was a prospective unblinded study in 20 patients with American Joint Committee on Cancer (AJCC) stage II–IV breast cancer unresponsive to first-line chemotherapy or progressing on previous therapy. Individuals underwent a baseline dynamic FLT-PET scan followed by a scan 2 weeks after initiating the first or second cycle of docetaxel. PET variables were compared with anatomic response midtherapy (after 3 cycles).

Results: Average and maximum tumor standardized uptake values at 60 minutes (SUV60,av and SUV60,max) normalized to body surface area ranged between 1.7 and 17.0 and 5.6 and 26.9 × 10−5 m2/mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (P = 0.0003 for SUV60,av and P = 0.0002 for SUV60,max). Reduction in tumor SUV60,av was associated with target lesion size changes midtherapy (Pearson R for SUV60,av = 0.64; P = 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV60,av in responders were due, at least in part, to reduced net intracellular trapping of FLT (rate constant, Ki). Docetaxel significantly reduced Ki by 51.1% (±28.4%, P = 0.0009).

Conclusion: Changes in tumor proliferation assessed by FLT-PET early after initiating docetaxel chemotherapy can predict lesion response midtherapy with good sensitivity warranting prospective trials to assess the ability to stop therapy in the event of non–FLT-PET response. Clin Cancer Res; 17(24); 7664–72. ©2011 AACR.

Translational Relevance

This study investigated the use of [18F]-3′deoxy-3′-fluorothymidine (FLT) PET as an imaging biomarker to measure early response to docetaxel chemotherapy in breast cancer. We found that early changes in tumor FLT uptake predicted lesion size reduction midtherapy. This technology will be particularly useful in those patients where early response to therapy may aid definitive treatment. Further verification of this work in a larger population, could permit the ability to stop therapy in the event of non–FLT-PET response sparing patients of cumulative toxicity.

Taxanes are some of the most commonly used drugs in the treatment of breast cancer today. A molecular imaging biomarker which could provide early accurate prediction of response or resistance in vivo would be of great benefit to oncologists. The cytotoxic activity of taxanes is promoted by stabilizing cellular microtubule assembly (1, 2). This leads to inhibition of mitotic cell division (the G2–M phase of the cell cycle; ref. 2) and cell death by apoptosis (3). Docetaxel is approved for the treatment of patients with locally advanced or metastatic breast and non–small cell lung cancer (4) who have undergone anthracycline-based chemotherapy and failed because of tumor progression or relapse. The drug has shown effectiveness against tumors resistant to anthracyclines or paclitaxel (5, 6) and good response rates (55%–68%) in the neoadjuvant setting (7, 8), at the expense of well-known myelosuppressive and other toxicities.

In patients undergoing chemotherapy, systemic toxicity remains the major limitation to adequate dosing. The ability to predict early response after 1 to 2 cycles of docetaxel would avoid unnecessary toxicities in patients unlikely to respond with potential impact on clinical outcomes and quality of life, particularly in the palliative setting. We explored the performance of [18F]-3′deoxy-3′-fluorothymidine positron emission tomography (FLT-PET) as an early biomarker of tumor response in this setting. FLT uptake into tumor cells is regulated by equilibrative nucleoside transporter (ENT-1) and thymidine kinase1 (TK1; refs. 9–11); the latter controlled during cell division transcriptionally in the G1 to S-phase of the cell cycle (12). FLT uptake has been shown to strongly correlate with cell proliferation in untreated patients with breast cancer and further that response by PET imaging is detectable as early as 1 week following fluorouracil-epirubicin-cyclophosphamide (FEC) chemotherapy (13, 14). It is, however, unknown whether the antiproliferative activity of taxanes, an effect that is largely G2–M in nature, could be detected in patients by FLT-PET. We studied the effects of docetaxel on FLT-PET parameters in this setting.

Patients

This was a prospective, unblinded, single institution study in patients with American Joint Committee on Cancer (AJCC) stage II–IV breast cancer, including primary breast cancer being unresponsive to first-line chemotherapy (via ultrasound scanning done by the same radiologist to minimize operator-dependent errors), or metastatic disease progressing on previous therapy (with either new lesions appearing or >20% increase in maximum diameter of previous target lesions). Patients underwent a baseline dynamic FLT-PET scan for 66.5 minutes followed by a similar posttreatment scan conducted approximately 14 days after the first or second cycle of docetaxel therapy (dose of docetaxel: 100 mg/m2). Primary patients were selected if they were not responding or progressing on chemotherapy. Metastatic patients were those who were documented to have progressive disease on last computed tomographic (CT) scan from prior therapy. The main inclusion criteria were histologically confirmed invasive breast cancer with at least one measurable lesion outside the bone or liver, accurately measured in one dimension (longest diameter recorded) as 20 mm or greater using conventional techniques. This was done to reduce the effect of partial volume effect (15, 16). No chemotherapy or radiotherapy was permitted for at least 3 weeks before undergoing first FLT-PET scan. Patients having only bone or liver metastasis were excluded as physiologic uptake of FLT is high in bone and liver and would have obscured any tumor(s) in these organs. The study received ethical approval from the Hammersmith Hospital Research Ethics Committee and a license to inject FLT into subjects from the Administration of Radioactive Substances Advisory Committee. The study was conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent.

Study design and statistical considerations

Previous test–retest reproducibility studies showed that changes in FLT standardized uptake value (SUV) of more than 20% or net irreversible uptake (Ki) of more than 31% could be classified as radiotracer responsive with 95% confidence interval (SD: 10%–15%; ref. 14). Published data indicate a 40% response rate (worse case) to docetaxel therapy in patients with metastatic cancer (6, 8). This would dilute the expected “group” effect from 0.31 to 0.124 and inflate the variability for measuring change to 18%. Power calculation (paired statistics) suggested that a number (n = 20) of patients would give to the design a minimum power of 0.80 to detect a group difference in FLT at a 0.05 error rate. Comparisons of tumor results were done on a lesion-by-lesion basis assuming non-Gaussian distribution (Wilcoxon matched pairs test or Mann–Whitney test). The association between FLT retention variables and midtherapy lesion response was explored using Pearson correlation coefficient (R, for continuous data) or χ2 and Bland–Altman plots (for categorical data). Statistical analyses were conducted using GraphPad Prism version 4.00 for Windows (GraphPad Software; http://www.graphpad.com).

PET imaging protocol and radiology

FLT was manufactured as previously described (13) with 99.6% radiochemical purity and a mean specific radioactivity of 147,584 MBq/μmol. PET scanning was conducted on the GE-Discovery PET-CT scanner (GE-Healthcare) with a 15.7 cm field of view. Patient preparation for PET has been previously described (13). FLT [mean: 210 (±8) MBq] was injected as a slow bolus in about 5 mL of saline followed by emission scanning for 66.5 minutes. The dose of radioactivity used was in accordance with suggested limits described by Vesselle and colleagues (17). Data were binned into 28 frames and reconstructed. Volumes of interest were drawn on at least 4 slices of tumor (using the combined PET and CT volume) to obtain the activity concentration within the volumes of interest. SUV was calculated by normalizing tumor radiotracer concentration (kBq/mL) to injected radioactivity (in kBq) and body surface area as previously described (13, 14). Average SUV (SUV60,av) or the maximum pixel value (SUV60,max) were determined. Kinetic modeling of PET data was conducted to calculate Ki (13, 14).

Tumor target lesion size was measured by ultrasound (for primary lesions) or CT (for metastatic disease) prior to treatment and after 3 cycles of docetaxel, and response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (18). Response by FLT-PET was defined as more than 20% change for SUV (>31% change for Ki; ref. 14).

Clinical results and visualization of lesions by PET

Twenty patients (11 primary and 9 metastatic; average age, 54 years; average tumor size, 38.4 mm) successfully completed both pre- and posttreatment FLT-PET scans (Table 1). All lesions were seen on FLT-PET (Fig. 1). In most patients, posttreatment FLT-PET was conducted approximately 14 days after initiating cycle 1; in 6 patients (patient no. 3, 4, 5, 9, 15, and 17), the posttreatment PET was conducted 2 weeks after initiating cycle 2 of docetaxel either due to patients being extremely unwell from chemotherapy or failure of FLT production. Two individuals (no. 11 and 12) developed grade III toxicity to docetaxel after the first cycle (needing hospitalization for neutropenic sepsis) and treatment was then changed to weekly paclitaxel based on the clinicians decision. Patient no. 11 had 1 cycle of docetaxel and 3 cycles of paclitaxel and patient no. 12 had 1 cycle docetaxel and 2 cycles of paclitaxel prior to RECIST assessment. PET uptake data for these 2 cases have been presented, but these data were not used for further comparison with RECIST response.

PET imaging outcome

The median (±SD) pretreatment SUV60,av of tumors was 6.47 × 10−5 (±4.1 × 10−5) m2/mL and that for SUV60,max was 12.6 × 10−5 (±6.11 × 10−5) m2/mL (Supplementary Table S1). In contrast, the median SUV60,av in normal breast tissue and normal lung were 1.12 × 10−5 (±0.4 × 10−5) m2/mL and 0.99 × 10−5 (±0.33 × 10−5) m2/mL, respectively. The visual baseline uptake of FLT was low in 3 tumors (patient no. 4, 8, and 9). Of interest to use FLT-PET for assessing early response, single-agent docetaxel chemotherapy resulted in a significant decrease in FLT uptake (Fig. 1 and Table 2; P = 0.0003 for SUV60,av and P = 0.0002 for SUV60,max; Wilcoxon matched pairs test, for all tumors). The median percentage decrease of SUV60,av for all tumors was 30.7% (median absolute decrease of 2.32 × 10−5 m2/mL) and for SUV60,max, a decrease of 17.5% was observed (median absolute decrease of 3.37 × 10−5 m2/mL). The median decrease in SUV60,av in PET responders measured 40.2% versus 10.5% in nonresponders (Mann–Whitney test: P = 0.01). In one metastatic breast tumor of the lung (patient no. 17), the tumor had 30.2% and 41.8% reductions of SUV60,av and SUV60,max, respectively, after 2 cycles of docetaxel with complete radiological response on CT after 3 cycles of docetaxel. For comparison, tumor SUV normalized to body weight rather than body surface area are shown in Supplementary Table S2.

Comparison of PET outcome with categorical target lesion response

We compared PET response with clinical outcome for individual target lesions (Table 2). Overall (excluding patient no. 11 and 12), there was 1 complete responder, 12 partial responders, and 5 patients with stable disease. In 2 patients (no. 6 and 14), new metastatic tumor deposits were detected outside the PET field of view during the subsequent routine clinical cross-sectional imaging. We investigated whether reductions in tumor FLT uptake early after initiating therapy were associated with target lesion size changes after 3 cycles (Fig. 2). There was a significant correlation between FLT-PET early signal change and lesion size midtherapy (Fig. 3A). Pearson correlation coefficient was R = 0.64 (P = 0.004) for SUV60,av; this association was less significant for SUV60,max (R = 0.53; P = 0.02). Categorization of the target lesion size data into two RECIST (19) classes (complete + partial response vs. stable disease) and of the FLT-PET SUV data into two classes (reduction < 20% vs. reduction > 20%), confirmed a valid association (χ2 test) when the PET measure was SUV60,av (P = 0.05) but not SUV60,max (P = 0.16). On the basis of the RECIST stratification (19), 13 of 18 tumors responded to therapy (Table 2), and the median percentage decrease in SUV60,av and SUV60,max in these tumors were 40.2% and 34.1%, respectively. FLT-PET SUV60,av correctly detected 11 of the 13 RECIST responders. One tumor (patient no. 9) showed a significant decrease in SUV60,av of 31.2%, but this was deemed borderline stable disease by tumor size measurement using ultrasonography, with tumor size reduction of 21.8%. This is clearly depicted on Bland–Altman plots devised to further explore the association between categorical target lesion size response and changes in PET semiquantitative parameters (Fig. 3B). The parameter, SUV60,av, appeared to have better sensitivity to predict categorical lesion size response than SUV60,max. Using the 20% change in SUV60,av as (prospective) cutoff point to stratify patients as PET responders (14), the sensitivity and specificity of SUV60,av to predict categorical tumor size response were 0.85 and 0.80, respectively. SUV60,max was less robust with sensitivity of 0.62 but equal specificity of 0.80. With respect to predicting no lesion response, both SUV60,av and SUV60,max conducted well except in one patient (patient no. 9).

Kinetic analysis of tumor FLT uptake

We assessed the steady-state net irreversible flux constant for transfer of FLT from plasma to tumor (Ki; Table 3) as a means of explaining the SUV data. This was done by a metabolite-corrected modified Patlak graphical approach as previously described (13, 20). The median (±SD) Ki at baseline was 2.95 × 10−4 (±2.44 × 10−4) mL plasma/mL tissue/s and with good fits (low SD of fit). Drug treatment significantly reduced Ki (Wilcoxon matched pairs test: P = 0.0009) with a median percentage change (±SD) of 51.12% (±28.39%) mL plasma/mL tissue/s. For patient no. 9, it was not possible to calculate Ki accurately due to low uptake that decreased toward the end of the scan (possibly due to dephosphorylation or contribution of labeled metabolites). The drug did not affect FLT metabolism. The median (±SD) percentage of parent FLT in plasma at 60 minutes was 77.6 (±0.07)% and 76.5 (±0.07)%, respectively, before and after docetaxel. Like SUV60,av, Ki also showed a significant association with midtreatment target lesion size change (Pearson R = 0.56; P = 0.02; Table 3). With the exception of patients 6 and 13, Ki was found on lesion-by-lesion comparison to be low (>31%) in tumors that had low SUV60,av (of >20%). This signifies that changes in tumor uptake could be explained largely by net irreversible retention of the radiotracer.

The future of taxane therapy includes defining optimal combinations and dosing frequency and strategies to reduce toxicity, as well as trials of novel second-generation taxanes. We showed that early in the course of therapy, an FLT-PET reduction may predict response to docetaxel. FLT-PET has been shown to image proliferation in breast and lung tumors with high reproducibility and accuracy (14, 21, 22). Furthermore, decreases in FLT uptake depicting reductions in cell proliferation within 1 to 2 weeks have been reported in breast cancer (14) and non–Hodgkin lymphoma (23). Most patients in this present trial showed an early reduction in FLT-PET 2 weeks after commencing the first or second cycle of docetaxel. This FLT-PET response study of taxanes in patients are in keeping with intrinsic reductions in FLT uptake reported by Dittmann and colleagues in breast cancer cells (24) and hormone-refractory prostate cancer xenografts (25). This suggests that the activity of docetaxel is detectable by FLT-PET.

The PET technique estimates phosphorylation of FLT to FLT-phosphate. The wide range of pretreatment FLT uptake values may be explained by the wide variation in proliferation (13, 26, 27). Other mechanisms including relative use of salvage versus de novo precursors for DNA synthesis could also influence FLT uptake (28, 29). We used the SUV at 60 minutes as a semiquantitative measure of this biochemical activity. In most patients, tumor FLT SUV60,av was higher than the 95% confidence limit of normal breast (1.9 × 10−5 m2/mL). In patient 8 who received 5 cycles of FEC before entering the study, baseline tumor FLT uptake although detectable above background, was only 1.73 × 10−5 m2/mL. In general, however, baseline FLT uptake did not appear to be confounded by prior treatment. We used a prospective threshold (14) to define statistically significant FLT response. Overall, the magnitude of tumor FLT reduction was as expected more in clinical responders than nonresponders. Changes in tumor FLT SUV did not differ between patients who had a posttreatment scan after 1 or 2 cycles or between primary and metastatic disease (Mann–Whitney test: P = 0.6).

We found a good association between changes in FLT uptake and changes in lesion size. This was confirmed when the data were categorized (Fig. 3). In this study, 2 tumors showed significant reductions in SUV60,av but were classified borderline stable disease (Fig. 3). Despite these important differences, changes in SUV60,av (after 1 or 2 cycles) overall predicted changes in tumor size after 3 cycles with high sensitivity and specificity (0.85 and 0.80, respectively). Analysis of receiver operating characteristics indicated that the optimal sensitivity and specificity (100% and 57.1%, respectively; data not shown) would be achieved when the cutoff value was 11.8%. Notably, using that cutoff point, the high sensitivity was linked to a much lower specificity. Of interest, FLT-PET test–retest reproducibility studies by de Langen and colleagues (30) in non–small cell lung and head and neck cancers suggested that a cutoff value of more than 15% qualified as response. Similarly, Shields and colleagues reported a cutoff point of 21% as FLT-PET response in lung cancer (31). We did not consider new lesions in the determination of sensitivity and specificity, as only target lesions in the PET field of view were assessed. Future studies should consider whole body PET imaging to permit additional lesions to be detected. Lack of a significant change in FLT-PET will indicate futile treatment and signify a change to alternative treatment. In contrast, an FLT-PET response will indicate reduction in proliferation that probably warrants another assessment (say after 1 additional cycle) to confirm efficacy.

Muzi and colleagues have suggested that, unlike labeled thymidine, FLT phosphorylation may be reversible in somatic tumors making simple variables such as SUV60,av liable to error (32). Hence, we evaluated the net unidirectional flux (constant, Ki) of FLT from plasma into the intracellular space (via transport and phosphorylation) at steady state. A linear phase was discernible in the graphical plots for most patients indicating net retention. Noisy fits were obtained for tumors (patient no 4, 8, and 9) with low proliferation (SUV60,av < 3 × 10−5 m2/mL; Ki < 1 mL plasma/mL tissue/s). Patient 9 had an uptake profile characterized by an initial positive linear slope followed by a downward slope, consistent with dephosphorylation of FLT-phosphate. Further compartmental analysis supported this assertion; there was a reasonable association between Ki and k3 (R = 0.42, P = 0.02; data not shown). These data indicate that although simple measures of FLT phosphorylation may have value for widespread clinical use, analysis may be limited in low proliferative tumors, in this case, tumors with SUV60,av values of 3 × 10−5 m2/mL (1.2 when normalized to body weight) or less.

There were limitations of this study that are worthy of discussion. Both primary and metastatic patients, who may respond differently to docetaxel (4, 5, 8), were included in this study potentially impacting on heterogeneity of response. Notably, however, target lesion changes measured after 3 cycles did not appear to differ between the 2 groups (Mann–Whitney test: P > 0.05). While the overall sample size was small (sample size powered to detect a 20%–31% change in PET variables), this represents a single tumor type group of patients and with the same treatment and allowed detailed assessment of both simple measures of uptake, as well as more detailed analysis of radiotracer kinetics. In this study, tumor size reduction after 9 weeks was used for comparison with changes in tumor FLT uptake at 2 weeks after cycle 1 or 2. Given that FLT-PET changes occur rapidly after treatment (14), a potential limitation of the study was the assessment of PET response after 2 cycles in 6 patients (compared with one cycle in the rest). The reduction in tumor SUV was, however, not statistically different between the 2 groups (Supplementary Table S3, and, therefore, reported separately but combined for analysis). For these patients who had FLT studies after 2 cycles, the benefit of using FLT to predict response would be less obvious. Another limitation is the use of RECIST rather than histopathology for comparison. RECIST response was determined at the physician's discretion earlier after cycle 2 in one patient (patient 14) due to suspicion of clinical disease progression. Though this could be seen as a limitation of the study, it did not affect the overall prediction of response with FLT-PET. RECIST after 3 cycles is often used to assess whether a drug has biologic activity, though its correlation with survival is imperfect (18). It will be interesting in future studies to investigate histologic markers of proliferation (primary disease; this will involve repeat biopsies) and/or progression-free and overall survival as endpoints in a larger more homogeneous setting. Finally, on the basis of our prospective cutoff value, two patients would potentially have been denied further docetaxel treatment on the basis of early PET response. This highlights the ethical challenge of defining the ideal cutoff value for response, that is, when sensitivity is not high enough. Decreasing the cutoff value should improve sensitivity but at the cost of specificity.

In aggregate, FLT-PET is a promising imaging biomarker to detect early response to docetaxel in breast tumors and could potentially enable tailoring of therapy to individual patients warranting prospective trials to assess the ability to stop therapy in the event of non–FLT-PET response. As a next step, the promising results should be confirmed in larger trials in a more homogeneous setting and with longer follow-up, with disease-free survival and perhaps overall survival as additional endpoints. SUV60,av reductions were due, in part, to inhibition of tracer retention and correlated with target lesion size response after 3 cycles of chemotherapy. The outcome of this study may have general application for testing of new taxanes or new taxane regimes.

No potential conflicts of interest were disclosed.

The authors thank Laura Maher for helping with patient recruitment and radiographers, radiochemists, and blood laboratory staff at Hammersmith IMANET.

The study was supported by the United Kingdom Medical Research Council grant (U1200.02.005.00001.01), Cancer Research UK grant (C37/A5610; C2536/A10337), Experimental Cancer Medicine Centers grant (C37/A7283), and Biomedical Research Centre (BRC) award to the Imperial College Academic Health Sciences Centre (AHSC).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
Biganzoli
L
,
Cufer
T
,
Bruning
P
,
Coleman
R
,
Duchateau
L
,
Calvert
AH
, et al
Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial
.
J Clin Oncol
2002
;
20
:
3114
21
.
2.
Nabholtz
JM
,
Falkson
C
,
Campos
D
,
Szanto
J
,
Martin
M
,
Chan
S
, et al
Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial
.
J Clin Oncol
2003
;
21
:
968
75
.
3.
Fabbri
F
,
Carloni
S
,
Brigliadori
G
,
Zoli
W
,
Lapalombella
R
,
Marini
M
. 
Sequential events of apoptosis involving docetaxel, a microtubule-interfering agent: a cytometric study
.
BMC Cell Biol
2006
;
7
:
6
.
4.
Lyseng-Williamson
KA
,
Fenton
C
. 
Docetaxel: a review of its use in metastatic breast cancer
.
Drugs
2005
;
65
:
2513
31
.
5.
Hortobagyi
G
. 
Docetaxel in breast cancer and a rationale for combination therapy
.
Oncology (Williston Park)
1997
;
11
:
11
5
.
6.
Jones
SE
,
Erban
J
,
Overmoyer
B
,
Budd
GT
,
Hutchins
L
,
Lower
E
, et al
Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer
.
J Clin Oncol
2005
;
23
:
5542
51
.
7.
Smith
IC
,
Heys
SD
,
Hutcheon
AW
,
Miller
ID
,
Payne
S
,
Gilbert
FJ
, et al
Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel
.
J Clin Oncol
2002
;
20
:
1456
66
.
8.
Estevez
LG
,
Cuevas
JM
,
Anton
A
,
Florian
J
,
Lopez-Vega
JM
,
Velasco
A
, et al
Weekly docetaxel as neoadjuvant chemotherapy for stage II and III breast cancer: efficacy and correlation with biological markers in a phase II, multicenter study
.
Clin Cancer Res
2003
;
9
:
686
92
.
9.
Perumal
M
,
Pillai
RG
,
Barthel
H
,
Leyton
J
,
Latigo
JR
,
Forster
M
, et al
Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography
.
Cancer Res
2006
;
66
:
8558
64
.
10.
Barthel
H
,
Perumal
M
,
Latigo
J
,
He
Q
,
Brady
F
,
Luthra
SK
, et al
The uptake of 3′-deoxy-3′-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels
.
Eur J Nucl Med Mol Imaging
2005
;
32
:
257
63
.
11.
Paproski
RJ
,
Wuest
M
,
Jans
HS
,
Graham
K
,
Gati
WP
,
McQuarrie
S
, et al
Biodistribution and uptake of 3′-deoxy-3′-fluorothymidine in ENT1-knockout mice and in an ENT1-knockdown tumor model
.
J Nucl Med
2010
;
51
:
1447
55
.
12.
Sherley
JL
,
Kelly
TJ
. 
Human cytosolic thymidine kinase
.
J Biol Chem
1988
;
263
:
8350
8
.
13.
Kenny
LM
,
Vigushin
DM
,
Al-Nahhas
A
,
Osman
S
,
Luthra
SK
,
Shousha
S
, et al
Quantification of cellular proliferation in tumor and normal tissues of patients with breast cancer by [18F]fluorothymidine-positron emission tomography imaging: evaluation of analytical methods
.
Cancer Res
2005
;
65
:
10104
12
.
14.
Kenny
L
,
Coombes
RC
,
Vigushin
DM
,
Al-Nahhas
A
,
Shousha
S
,
Aboagye
EO
. 
Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography
.
Eur J Nucl Med Mol Imaging
2007
;
34
:
1339
47
.
15.
Hoetjes
NJ
,
van Velden
FH
,
Hoekstra
OS
,
Hoekstra
CJ
,
Krak
NC
,
Lammertsma
AA
, et al
Partial volume correction strategies for quantitative FDG PET in oncology
.
Eur J Nucl Med Mol Imaging
2010
;
37
:
1679
87
.
16.
van Heijl
M
,
Omloo
JM
,
van Berge Henegouwen
MI
,
van Lanschot
JJ
,
Sloof
GW
,
Boellaard
R
. 
Influence of ROI definition, partial volume correction and SUV normalization on SUV-survival correlation in oesophageal cancer
.
Nucl Med Commun
2010
;
31
:
652
8
.
17.
Vesselle
H
,
Grierson
J
,
Peterson
LM
,
Muzi
M
,
Mankoff
DA
,
Krohn
KA
. 
18F-Fluorothymidine radiation dosimetry in human PET imaging studies
.
J Nucl Med
2003
;
44
:
1482
8
.
18.
Eisenhauer
EA
,
Therasse
P
,
Bogaerts
J
,
Schwartz
LH
,
Sargent
D
,
Ford
R
, et al
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
.
Eur J Cancer
2009
;
45
:
228
47
.
19.
Therasse
P
,
Eisenhauer
EA
,
Verweij
J
. 
RECIST revisited: a review of validation studies on tumour assessment
.
Eur J Cancer
2006
;
42
:
1031
9
.
20.
Mankoff
DA
,
Shields
AF
,
Graham
MM
,
Link
JM
,
Krohn
KA
. 
A graphical analysis method to estimate blood-to-tissue transfer constants for tracers with labeled metabolites
.
J Nucl Med
1996
;
37
:
2049
57
.
21.
Tuohimaa
P
,
Pukkala
E
,
Scelo
G
,
Olsen
JH
,
Brewster
DH
,
Hemminki
K
, et al
Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation
.
Eur J Cancer
2007
;
43
:
1701
12
.
22.
Orem
J
,
Mbidde
EK
,
Lambert
B
,
de Sanjose
S
,
Weiderpass
E
. 
Burkitt's lymphoma in Africa, a review of the epidemiology and etiology
.
Afr Health Sci
2007
;
7
:
166
75
.
23.
Herrmann
K
,
Wieder
HA
,
Buck
AK
,
Schoffel
M
,
Krause
BJ
,
Fend
F
, et al
Early response assessment using 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin's lymphoma
.
Clin Cancer Res
2007
;
13
:
3552
8
.
24.
Dittmann
H
,
Jusufoska
A
,
Dohmen
BM
,
Smyczek-Gargya
B
,
Fersis
N
,
Pritzkow
M
, et al
3′-Deoxy-3′-[(18)F]fluorothymidine (FLT) uptake in breast cancer cells as a measure of proliferation after doxorubicin and docetaxel treatment
.
Nucl Med Biol
2009
;
36
:
163
9
.
25.
Oyama
N
,
Hasegawa
Y
,
Kiyono
Y
,
Kobayashi
M
,
Fujibayashi
Y
,
Ponde
DE
, et al
Early response assessment in prostate carcinoma by (1)F-fluorothymidine following anticancer therapy with docetaxel using preclinical tumour models
.
Eur J Nucl Med Mol Imaging
2011
;
38
:
81
9
.
26.
Buck
AK
,
Halter
G
,
Schirrmeister
H
,
Kotzerke
J
,
Wurziger
I
,
Glatting
G
, et al
Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG
.
J Nucl Med
2003
;
44
:
1426
31
.
27.
Urruticoechea
A
,
Smith
IE
,
Dowsett
M
. 
Proliferation marker Ki-67 in early breast cancer
.
J Clin Oncol
2005
;
23
:
7212
20
.
28.
Kenny
LM
,
Contractor
KB
,
Stebbing
J
,
Al-Nahhas
A
,
Palmieri
C
,
Shousha
S
, et al
Altered tissue 3′-deoxy-3′-[18F]fluorothymidine pharmacokinetics in human breast cancer following capecitabine treatment detected by positron emission tomography
.
Clin Cancer Res
2009
;
15
:
6649
57
.
29.
Moroz
MA
,
Kochetkov
T
,
Cai
S
,
Wu
J
,
Shamis
M
,
Nair
J
, et al
Imaging colon cancer response following treatment with AZD1152: a preclinical analysis of [18F]fluoro-2-deoxyglucose and 3′-deoxy-3′-[18F] fluorothymidine imaging
.
Clin Cancer Res
2011
;
17
:
1099
110
.
30.
deLangen
AJ
,
Klabbers
B
,
Lubberink
M
,
Boellaard
R
,
Spreeuwenberg
MD
,
Slotman
BJ
, et al
Reproducibility of quantitative 18F-3′-deoxy-3′-fluorothymidine measurements using positron emission tomography
.
Eur J Nucl Med Mol Imaging
2009
;
36
:
389
95
.
31.
Shields
AF
,
Lawhorn-Crews
JM
,
Briston
DA
,
Zalzala
S
,
Gadgeel
S
,
Douglas
KA
, et al
Analysis and reproducibility of 3′-Deoxy-3′-[18F]fluorothymidine positron emission tomography imaging in patients with non-small cell lung cancer
.
Clin Cancer Res
2008
;
14
:
4463
8
.
32.
Muzi
M
,
Mankoff
DA
,
Grierson
JR
,
Wells
JM
,
Vesselle
H
,
Krohn
KA
. 
Kinetic modeling of 3′-deoxy-3′-fluorothymidine in somatic tumors: mathematical studies
.
J Nucl Med
2005
;
46
:
371
80
.