Evaluation of Thoracic Tumors With 18F-Fluorothymidine and 18F-Fluorodeoxyglucose-Positron Emission Tomography

doi:10.1378/chest.129.2.393

Chest

Volume 129, Issue 2, February 2006, Pages 393-401

https://doi.org/10.1378/chest.129.2.393 Get rights and content

Study objectives

18F-fluorodeoxyglucose (FDG) is the most widely used positron emission tomography (PET) imaging probe used for the diagnosis, staging, restaging, and monitoring therapy response of cancer. However, its specificity is less than ideal. A new molecular imaging probe (18F-deoxyfluorothymidine [FLT]) has been developed that might afford more specific tumor imaging. The aims of this study were as follows: (1) to compare the use of FDG-PET and FLT-PET for tumor staging, (2) to compare the degree of FDG and FLT uptake in lung lesions, and (3) to determine the correlation between PET uptake intensity and tumor cell proliferation.

Design

FDG-PET and FLT-PET scans were performed in 11 patients with solitary pulmonary nodules and another 11 patients with known non-small cell lung cancer (NSCLC). Tracer uptake was assessed quantitatively by standardized uptake values (SUVs). Histologic evaluation of tissue samples obtained from biopsy specimens or surgical resections served as the “gold standard.” Tumor cell proliferation was assessed by Ki-67 staining.

Results

Pathology verification was available from 99 tissue samples in the 22 patients (29 pulmonary lesions, 66 lymph node stations, and 4 extrapulmonary lesions). Thirty-three samples (33.3%) were positive for tumor tissue (22 pulmonary, 9 lymph node stations, and 2 extrapulmonary). FDG-PET findings were false-positive in three pulmonary lesions, while FLT-PET findings were false-positive in one lesion. There were two false-negative findings by FDG-PET and six false-negative findings by FLT-PET. FDG uptake of the malignant lesions was significantly higher than FLT (maximum SUV, 3.1 ± 2.6 vs 1.6 ± 1.2 [mean ± SD]; p < 0.05). A significant correlation was observed between FLT uptake of pulmonary lesions and Ki-67 labeling index (r = 0.60, p = 0.02) but not for FDG uptake (r = 0.27, p = not significant).

Conclusions

Compared to FDG-PET, detection of primary and metastatic NSCLC by FLT-PET is limited by the relatively low FLT uptake of the tumor tissue. Thus, FLT-PET is unlikely to provide more accurate staging information or better characterization of pulmonary nodules than FDG-PET. Nevertheless, the correlation between FLT uptake and cellular proliferation suggests that future studies should evaluate the use of FLT-PET for monitoring treatment with cytostatic anticancer drugs.

Section snippets

Patient Population

Patients undergoing clinical whole-body FDG-PET scans for characterization of indeterminate pulmonary nodules or staging of NSCLC were eligible for this prospective study. Patients with other malignancies and those who had received cancer treatment within the past 5 years were excluded. Twenty-two patients (11 women and 11 men; average age, 66 ± 11 years ± SD]) consented to undergo an additional FLT-PET scan. The study was approved by the UCLA Institutional Review Board.

The FLT-PET scans were

Pathology Findings

Tissue diagnosis of the pulmonary lesions was established through surgical resection or thoracotomy in 15 patients and by biopsy in 7 patients. Fourteen of the patients also underwent mediastinoscopy.

Pathology information from a total of 99 tissue samples obtained from these procedures was available for verification of and comparison between imaging findings of FDG-PET and FLT-PET. Twenty-nine samples were obtained from pulmonary lesions, 66 from lymph node stations (N1 or hilar or

Discussion

This prospective study confirms that FLT uptake in NSCLC is correlated with cellular proliferation, whereas no significant correlation was observed for FDG uptake. Furthermore, it shows that tumor FLT uptake is only half of FDG uptake, leading to a low sensitivity of FLT-PET for detection of NSCLC (58%).

Compared to previous reports,¹⁰¹¹¹²¹³ tumor FLT uptake was less closely correlated with cellular proliferation in this study (Table 4). Since the sample sizes of our study as well as of the

References (36)

ToyoharaJ et al.
Basis of FLT as a cell proliferation marker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines
Nucl Med Biol
(2002)
GriersonJR et al.
Radiosynthesis of 3′-deoxy-3′-[¹⁸F]fluorothymidine: [¹⁸F]FLT for imaging of cellular proliferationin vivo
Nucl Med Biol
(2000)
MountainCF
Revisions in the International System for Staging Lung Cancer
Chest
(1997)
HagaY et al.
Ki-67 expression and prognosis for smokers with resected stage I non-small cell lung cancer
Ann Thorac Surg
(2003)
PoleriC et al.
Risk of recurrence in patients with surgically resected stage I non-small cell lung carcinoma: histopathologic and immunohistochemical analysis
Chest
(2003)
DwamenaBA et al.
Metastases from non-small cell lung cancer: mediastinal staging in the 1990s: meta-analytic comparison of PET and CT
Radiology
(1999)
GouldMK et al.
Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis
JAMA
(2001)
KubotaR et al.
Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake
J Nucl Med
(1994)
ShrevePD et al.
Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants
Radiographics
(1999)
ShieldsAF et al.
Imaging proliferationin vivowith [F-18]FLT and positron emission tomography
Nat Med
(1998)

MierW et al.

[¹⁸F]FLT: portrait of a proliferation marker

Eur J Nucl Med

(2002)

RaseyJS et al.

Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells

J Nucl Med

(2002)

SeitzU et al.

Evaluation of pyrimidine metabolising enzymes andin vitrouptake of 3′-[¹⁸F]fluoro-3′-deoxythymidine ([¹⁸F]FLT) in pancreatic cancer cell lines

Eur J Nucl Med Mol Imaging

(2002)

VesselleH et al.

In vivovalidation of 3′deoxy-3′-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors

Clin Cancer Res

(2002)

BuckAK et al.

3-deoxy-3-[F-18]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules

Cancer Res

(2002)

BuckAK et al.

Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG

J Nucl Med

(2003)

DittmannH et al.

[(18)F]FLT PET for diagnosis and staging of thoracic tumours

Eur J Nucl Med Mol Imaging

(2003)

WienhardK et al.

Performance evaluation of the positron scanner ECAT EXACT

J Comput Assist Tomogr

(1992)

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Chest

Original ResearchEvaluation of Thoracic Tumors With 18F-Fluorothymidine and 18F-Fluorodeoxyglucose-Positron Emission Tomography

Study objectives

Design

Results

Conclusions

Section snippets

Patient Population

Pathology Findings

Discussion

Nucl Med Biol

Nucl Med Biol

Chest

Ann Thorac Surg

Chest

Metastases from non-small cell lung cancer: mediastinal staging in the 1990s: meta-analytic comparison of PET and CT

Radiology

Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis

JAMA

Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake

J Nucl Med

Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants

Radiographics

Imaging proliferationin vivowith [F-18]FLT and positron emission tomography

Nat Med

[18F]FLT: portrait of a proliferation marker

Eur J Nucl Med

Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells

J Nucl Med

Evaluation of pyrimidine metabolising enzymes andin vitrouptake of 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) in pancreatic cancer cell lines

Eur J Nucl Med Mol Imaging

In vivovalidation of 3′deoxy-3′-[(18)F]fluorothymidine ([(18)F]FLT) as a proliferation imaging tracer in humans: correlation of [(18)F]FLT uptake by positron emission tomography with Ki-67 immunohistochemistry and flow cytometry in human lung tumors

Clin Cancer Res

3-deoxy-3-[F-18]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules

Cancer Res

Imaging proliferation in lung tumors with PET: 18F-FLT versus 18F-FDG

J Nucl Med

[(18)F]FLT PET for diagnosis and staging of thoracic tumours

Eur J Nucl Med Mol Imaging

Performance evaluation of the positron scanner ECAT EXACT

J Comput Assist Tomogr

Original Research
Evaluation of Thoracic Tumors With 18F-Fluorothymidine and 18F-Fluorodeoxyglucose-Positron Emission Tomography

[¹⁸F]FLT: portrait of a proliferation marker

Evaluation of pyrimidine metabolising enzymes andin vitrouptake of 3′-[¹⁸F]fluoro-3′-deoxythymidine ([¹⁸F]FLT) in pancreatic cancer cell lines