Early monitoring of external radiation therapy by [18F]-fluoromethylcholine positron emission tomography and 3-T proton magnetic resonance spectroscopy: an experimental study in a rodent rhabdomyosarcoma model

doi:10.1016/j.nucmedbio.2010.03.005

Nuclear Medicine and Biology

Volume 37, Issue 5, July 2010, Pages 645-653

https://doi.org/10.1016/j.nucmedbio.2010.03.005 Get rights and content

Abstract

Purpose

To assess early radiation therapy (RT)-induced variations in total choline (tCho) concentration measured by proton magnetic resonance spectroscopy (H-MRS) and in ¹⁸F-labelled fluoromethylcholine (FCH) uptake measured by PET in a rodent tumour model.

Methods

Nine rats bearing syngenic rhabdomyosarcoma grafts in both thighs were irradiated (13 Gy, one fraction). H-MRS data and FCH-PET were acquired in the same imaging session prior to and 3, 9 and 16 days after external RT. Total choline concentration was expressed in arbitrary units as the area under the curve of the 3.2-ppm peak on H-MR spectra. FCH uptake was expressed as maximum standardized uptake value (SUV_max) and as the % of injected dose per gram (%ID/g) after precise tumour delineation on hybrid PET-MR images. Pre- and post-RT data were compared using the Student's paired t test, and results were expressed as mean±S.D.

Results

Seventeen tumours were available for analysis. A mean drop in choline concentration of 45% was observed 3 days after irradiation (P<.001), whereas a concomitant mean increase in SUV_max of 41% was observed (P=.006). Choline concentration reincreased on later time points.

Conclusions

Opposite trend between increased FCH uptake and decreased tCho peak was observed at 3 days. Later (9 and 16 days), uptake remained stable and tCho peak reincreased.

Introduction

Early treatment monitoring of cancer therapies is warranted for precociously switching to the most appropriate strategies in case of insufficient treatment response [1]. Advanced magnetic resonance imaging (MRI) techniques recording molecular and perfusion indexes have demonstrated relevance in the purpose [2], [3], [4]. Proton MR spectroscopy (H-MRS) by enabling quantification of choline and downstream metabolites as the area under the curve (AUC) of the 3.2-ppm peak of proton spectra yields early and accurate indication on treatment response in brain, breast, prostate and liver cancers [5], [6], [7]. Positron emission tomography (PET) using [¹⁸F]-fluoromethylcholine (FCH) as tracer is the alternative in vivo imaging technique which intuitively addresses the same metabolic cascade of cell membrane anabolism [8], [9], [10]. Until now, early changes in FCH uptake induced by external radiation therapy (RT) have only been investigated on cellular cultures [11]. We therefore designed the present experimental study in a rodent model of syngenic rhabdomyosarcoma to determine whether quantitative indexes derived from both modalities should evolve in a similar way after external RT.

Section snippets

Animals and grafting technique

The study was designed in compliance with our institutional ethical committee (EC) guidelines for laboratory animal experimentation (EC no.: UCL/MD/2007/021). Fourteen male WAG/Rij rats (Harlan Nederland, Horst, The Netherlands), aged 16 weeks and weighing between 250 and 300 g, were used. According to laboratory animal welfare prescriptions [12], they were housed three per cage and received water and food ad libitum. Fragments of about 1 mm³ from a syngenic rhabdomyosarcoma were grafted

Alginate moulding and cohort survival throughout the experimental course

Alginate moulding was easy, fast and well tolerated. None of the irradiated group of nine rats died between the two first imaging sessions (D0 and D3). In turn, two of five rats (long-term group) died between D9 and D16, mainly from overall status worsening and repeated anaesthesias.

Choline concentration at H-MRS

High-quality proton spectra showing a well-delineated tCho peak at 3.2 ppm were obtained for all tumours (Fig. 2).

Discussion

Early detection of therapy-induced alterations in neoplastic tissues using repeatable and innocuous in vivo techniques is a crucial issue in cancer treatment monitoring [20]. Structural imaging modalities like computed tomography (CT) and magnetic resonance imaging (MRI) give accurate indices of treatment response by assessing decrease in tumour size in responders, but only at a significantly delayed phase after treatment initiation [21]. MR- and PET-based molecular imaging techniques enable

Acknowledgments

François-Xavier Hanin and Raymond Bausart are acknowledged for their help during PET data acquisitions and analysis. Léon ter Beek, Ph.D., (MR physicist, Clinical R&D Department, Philips Healthcare) is also warmly acknowledged for his assistance during H-MRS data acquisition and post-processing.

References (38)

KurhanewiczJ. et al.
Three-dimensional magnetic resonance spectroscopic imaging of brain and prostate cancer
Neoplasia
(2000)
RommelD. et al.
Alginate moulding: an empirical method for magnetic resonance imaging/positron emission tomography co-registration in a tumor rat model
Nucl Med Biol
(2008)
IwataR. et al.
[¹⁸F]Fluoromethyl triflate, a novel and reactive [¹⁸F]fluoromethylating agent: preparation and application to the on-column preparation of [¹⁸F]fluorocholine
Appl Radiat Isot
(2002)
IwataR. et al.
A simple loop method for the automated preparation of [¹¹C]raclopride from [¹¹C]methyl triflate
Appl Radiat Isot
(2001)
SeierstadT. et al.
Noninvasive monitoring of radiation-induced treatment response using proton magnetic resonance spectroscopy and diffusion-weighted magnetic resonance imaging in a colorectal tumor model
Radiother Oncol
(2007)
GrovesA. et al.
Non-[¹⁸F]FDG PET in clinical oncology
Lancet Oncol
(2007)
ZeiselS.H.
Choline: essential for brain development and function
Adv Pediatr
(1997)
VillaA. et al.
Choline and phosphatidylcholine fluorescent derivatives localization in carcinoma cells studied by laser scanning confocal fluorescence microscopy
Eur J Cancer
(2005)
MilosevicM. et al.
The relationship between elevated interstitial fluid pressure and blood flow in tumors: a bioengineering analysis
Int J Radiat Oncol Biol Phys
(1999)
BrindleK.
New approaches for imaging tumour responses to treatment
Nat Rev Cancer
(2008)

ArtemovD. et al.

Magnetic resonance imaging of cell surface receptors using targeted contrast agents

Curr Pharm Biotechnol

(2004)

LeachM. et al.

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

Br J Cancer

(2005)

McDonaldD. et al.

Imaging of angiogenesis: from microscope to clinic

Nat Med

(2003)

MeisamyS. et al.

Neoadjuvant chemotherapy of locally advanced breast cancer: predicting response with in vivo (1)H MR spectroscopy—a pilot study at 4 T

Radiology

(2004)

ChenC. et al.

Early response of hepatocellular carcinoma to transcatheter arterial chemoembolization: choline levels and MR diffusion constants—initial experience

Radiology

(2006)

GlundeK. et al.

Choline metabolism in cancer: implications for diagnosis and therapy

Expert Rev Mol Diagn

(2006)

PodoF.

Tumour phospholipid metabolism

NMR Biomed

(1999)

KweeS. et al.

Combined use of F-18 fluorocholine positron emission tomography and magnetic resonance spectroscopy for brain tumor evaluation

J Neuroimaging

(2004)

HolzapfelK. et al.

Effects of irradiation on the [methyl-³H]choline uptake in the human prostate cancer cell lines LNCaP and PC3

Strahlenther Onkol

(2008)

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^☆: This work was supported by a grant from the Fonds National de la Recherche Scientifique (FNRS-FWO) of Belgium and by a grant from the Fonds Spéciaux de Recherche (FSR) from the Université catholique de Louvain of Belgium.

View full text

Early monitoring of external radiation therapy by [18F]-fluoromethylcholine positron emission tomography and 3-T proton magnetic resonance spectroscopy: an experimental study in a rodent rhabdomyosarcoma model☆

Abstract

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Animals and grafting technique

Alginate moulding and cohort survival throughout the experimental course

Choline concentration at H-MRS

Discussion

Acknowledgments

Neoplasia

Nucl Med Biol

Appl Radiat Isot

Appl Radiat Isot

Radiother Oncol

Lancet Oncol

Adv Pediatr

Eur J Cancer

Int J Radiat Oncol Biol Phys

New approaches for imaging tumour responses to treatment

Nat Rev Cancer

Magnetic resonance imaging of cell surface receptors using targeted contrast agents

Curr Pharm Biotechnol

The assessment of antiangiogenic and antivascular therapies in early-stage clinical trials using magnetic resonance imaging: issues and recommendations

Br J Cancer

Imaging of angiogenesis: from microscope to clinic

Nat Med

Neoadjuvant chemotherapy of locally advanced breast cancer: predicting response with in vivo (1)H MR spectroscopy—a pilot study at 4 T

Radiology

Early response of hepatocellular carcinoma to transcatheter arterial chemoembolization: choline levels and MR diffusion constants—initial experience

Radiology

Choline metabolism in cancer: implications for diagnosis and therapy

Expert Rev Mol Diagn

Tumour phospholipid metabolism

NMR Biomed

Combined use of F-18 fluorocholine positron emission tomography and magnetic resonance spectroscopy for brain tumor evaluation

J Neuroimaging

Effects of irradiation on the [methyl-3H]choline uptake in the human prostate cancer cell lines LNCaP and PC3

Strahlenther Onkol

Early monitoring of external radiation therapy by [¹⁸F]-fluoromethylcholine positron emission tomography and 3-T proton magnetic resonance spectroscopy: an experimental study in a rodent rhabdomyosarcoma model☆

Effects of irradiation on the [methyl-³H]choline uptake in the human prostate cancer cell lines LNCaP and PC3