¹⁸F-FET PET for planning of thermotherapy using magnetic nanoparticles in recurrent glioblastoma

Abstract

Purpose: Thermotherapy using magnetic nanoparticles (nano cancer therapy) is a new concept of local tumour therapy, which is based on controlled heating of intra-tumoural injected magnetic nanoparticles. The aim of this study was to evaluate the usefulness of PET with a recently introduced amino acid tracer O-(2-[¹⁸F]fluoroethyl)-]L-tyrosine (FET) for targeting the nanoparticles implantation.

Materials and methods: Eleven patients with glioblastoma recurrences underwent MR and FET-PET imaging for planning of the nano cancer therapy. Thereafter, the gross tumour volumes (GTV) were defined, taking into consideration the results of both imaging tools.

Results: The MRI-based mean GTV was 24.3 cm³ (range 2.5–59.7) and the PET-based mean GTV 31.9 cm³ (range 5.2–77.9). On the average the MRI identified an additional 8.9 ± 4.7 cm³ and the FET-PET scan—an additional 16.5 ± 15.2 cm³ outside of the common GTV (15.4 ± 11.0 cm³). The mean final GTV accounted to 33.8 cm³ (range, 5.2–77.9). The additional information of FET-PET led to an increase in GTV by 22–286% in eight patients and to a decrease of 23% and 26%, respectively, in two patients. In one patient, the final GTV was defined on the basis of MRI data only.

Conclusions: FET-PET adds important information on the actual tumour volume in recurrent glioblastomas and is highly valuable for defining the target volume for the nano cancer therapy.

• ¹⁸F-FET
• positron emission topography
• recurrent glioblastoma
• nano cancer therapy

Introduction

Thermotherapy using magnetic nanoparticles (designated nano cancer therapy) is a new approach of localized thermotherapy, in which nanosized iron-oxide particles are directly injected into a tumour and subsequently heated in an alternating magnetic field. This method was developed by Jordan and co-workers [1–3], who carried out comprehensive pre-clinical investigations, which proved the feasibility and effectiveness of this innovative approach for the treatment of diverse malignancies, including prostate cancer, breast cancer and glioma [1], [4–7]. Clinical studies were initiated [8] and their first results support the potential value of the nano cancer therapy for successful treatment of tumours in deep body regions.

An important pre-requisite for the successful nano cancer therapy is the coverage of the whole tumour volume with magnetic nanoparticles, which is required for sufficient heat deposition. In case of recurrent glioblastomas, the viable tumour tissue should be exactly delineated and differentiated from therapy-induced tissue alterations such as peritumoural oedema, post-operative scar and radiation necrosis. MRI is of limited ability at this task [9], [10]. Nuclear medicine imaging (SPECT, PET) with amino acids tracers provides essential information on tumour metabolism and was shown to be highly valuable for diagnosis of recurrent glioma [11–16]. Its usefulness for planning of radiation therapy of primary and recurrent gliomas was already proven by several investigations [17–21]. PET using the recently introduced amino acid tracer O-(2-[¹⁸F]fluoroethyl)-]L-tyrosine (FET) allows a more precise estimation of tumour borders than MRI [22]. Although the FET is not incorporated into proteins and its accumulation only reflects amino acid transport, the uptake of FET has been shown to be closely correlated with that of the well-studied PET tracer of protein synthesis ¹¹C-methionine [23]. The ¹¹C-methionine is of limited availability due to the short physical half-life of the ¹¹C label and can be used only in few PET centres, equipped with a cyclotron. Therefore, the FET, which is labelled with ¹⁸F (half-life, 110 min) represents a reasonable alternative to ¹¹C-methionine for the clinical applications. The advantage of the FET-PET over the SPECT using ¹²³I-iodo-methyl-thyrosine is the improved discrimination of anatomic structures and the better tumour-to-brain contrast [24].

The aim of the present study was to investigate the impact of FET-PET on planning of nano cancer therapy of recurrent glioblastomas.

Materials and methods

Patients

Included were 11 consecutive patients (four females, seven males; median age 44 years, range 25–75 years) with recurrent glioblastomas, who were candidates for nano cancer therapy. The inclusion criteria were a Karnofsky index ≥ 60, expansion of the tumour to a maximum of 6 cm and supratentorial and unifocal localization. Patient characteristics and pre-treatment data are given in Table I. In all patients, failure of the initial treatment was estimated based on serial MRI scans (interval to PET examination <3 days). A written informed consent was obtained from all patients for the PET examinations. The study was approved by the local ethical committee.

Table I.  Demographic data and history of 11 patients with recurrent glioblastoma.

Pat. No.	Age (years)	Sex	Location	Pre-treatment
1	34	F	R FL	Surg, Rad, Chemo
2	57	M	L TL	Surg, Rad
3	25	M	L Thalamus	Surg, Rad, Chemo
4	55	M	L FL	Surg
5	69	M	L TL	Surg, Rad, Chemo
6	44	F	L OL	Surg, Chemo
7	41	M	L TL	Surg, Rad
8	38	F	L FL	Surg, Rad, Chemo
9	40	M	R FL	Surg, Rad, Chemo
10	75	F	L TL	Surg, Rad, Chemo
11	58	M	L TL	Surg, Rad, Chemo

M = male; F = female; L = left side; R = right side; FL = frontal lobe; TL = temporal lobe; OL = occipital lobe; Surg = Surgery; Rad = Radiation therapy; Chemo = Chemotherapy.

Methods

PET studies were performed using an ECAT-EXACT 47 scanner. The patients took a protein-low diet for 8 h prior to PET investigation. Transmission scans using a ⁶⁸Ge/⁶⁸Ga rod source were collected immediately after intravenous administration of 250 MBq ¹⁸F-FET (acquisition time 10 min). Thereafter, emission scans were acquired for 30 min. PET slices were reconstructed by filtered back projection using a Hanning filter (cut-off 0.4).

After coregistering of PET and MRI data, the gross tumour volumes (GTV) were delineated separately, based on MRI and PET data. The GTV were delineated manually in the MR images as areas with Gd-enhancement and in the fused MRI/PET images as areas showing activity concentration above 75% of the maximal value inside the tumour. Thereafter, the final GTV were defined in the fused MRI/PET images, taking into consideration the results of both imaging tools as well as individual anatomical and clinical particulars. The resulting data were transferred to the neurosurgical navigation system (Stealth Station, Medtronic, MN) and used for stereotactic guidance of the nanoparticles instillation. Thereby three-to-nine cylindrical nanoparticle depots were placed within the GTV following a pre-instillation plan created by Nanoplan® (MagForce Nanotechnologies AG, Berlin, Germany), a 3-dimensional AMIRA-based software for nano cancer therapy. The common GTV of FET-PET and MRI and the final GTV were measured in fused MRI/PET images. Intra-individual differences in GTV between both modalities were analysed using a paired t-test, considering a p value < 0.05 as statistically significant (SPSS v. 10 (Chicago, IL)).

Results

The individual volumes and differences in the GTV between FET-PET and MRI are given in Table II. The mean GTV, as estimated in MRI, was 24.3 cm³ (range 2.5–59.7 cm³), whereas the mean GTV in the PET-based planning was 31.9 cm³ (range 5.2–77.9 cm³). The difference was not statistically significant (p = 0.072). Taking the common GTV into account, FET-PET revealed an average of 16.5 cm³ as additional GTV and did not cover an average of 8.9 cm³ of the MRI defined GTV.

Table II.  Results of volumetric measurements using Gd-enhanced MRI and FET-PET in 11 patients with recurrent glioblastomas.

	GTV MRI (cm^3)	GTV FET (cm^3)	Common GTV (cm^3)	GTV MRI less common GTV (cm^3)	GTV FET less common GTV (cm^3)	Final GTV (cm^3)	Change in GTV by FET-PET (cm^3/%)
1	59.7	76.8	39.7	20.0	37.1	59.7	0*
2	11.3	43.6	6.2	5.1	37.4	43.6	+32.3/+286
3	2.5	5.2	1.9	0.6	3.3	5.2	+2.7/+108
4	15.1	18.3	9.3	5.8	9.0	24.1	+9.0/+60
5	39.9	40.2	31.3	8.6	8.9	48.5	+8.7/+22
6	44.0	26.2	19.6	14.4	6.6	26.2	−7.8/−23
7	13.6	14.8	6.6	7.0	8.2	22.0	+8.4/+62
8	31.7	23.3	17.5	14.2	5.8	23.3	−8.4/−26
9	19.9	18.4	6.4	13.5	12.0	30.7#	+10.8/−54#
10	5.3	6.6	1.2	4.1	5.4	10.7	+5.4/+102
11	34.8	77.9	30.1	4.7	47.8	77.9#	+43.1/+128#
Mean	24.3	31.9	15.4	8.9	16.5	33.8	+9.4
SD	13.3	21.7	11.0	4.7	15.2	20.9	16.8(±79%)

GTV = gross tumour volume; SD = standard deviation.

*The additional volume, defined using FET-PET, was not accessible for nano cancer therapy and thus did not contribute to the PV; # no therapy was performed; ± mean percentage change (absolute value).

The mean final GTV which was used for nano cancer therapy planning was 33.8 cm³ (range 5.2–59.7 cm³). The implementation of FET-PET data led to the increase in the mean final GTV by 9.4 cm³, as compared to volumes determined with MRI only. Looking at the individual therapy planning, the final GTV was increased by 22–286% in eight patients (a representative case is shown in Figure 1) and decreased in two patients by 23% and 26%, respectively. The observed relation between the MRI- and PET-based volumes was in the individual cases complex: in five out of eight patients, whose overall final GTV was increased by FET PET, some Gd-enhancing, but FET negative areas were found as well (Pat. No. 2, 4, 5, 7, 10, Table II). In two of the 11 studied patients, FET-PET showed no viable tumour in the areas which showed growth in the previous serial MRI investigations. The mean percentage of therapy relevant GTV alteration was 79%. In one patient (No. 1), FET-PET demonstrated a bihemispheric spread of the tumour with infiltration of the sagittal sinus, which was not detected by MRI. The additional tumour volume shown by FET-PET was not accessible for implantation of nanoparticles and, therefore, did not contribute to the final GTV. In two of the 11 patients, the nano cancer therapy was not performed owing to unexpected extensive tumour spread demonstrated by FET-PET (Pat. No. 11) and because of incompliance (Pat. No. 9).

Figure 1. A 41-year-old male patient (No. 7) suffering from recurrent glioblastoma in the left temporal lobe. The FET-PET scan (A) shows a larger tumour extension than the corresponding Gd-enhanced MR scan (C); see also the fused image (B). The discrepancies between tumour borders, defined on the PET and MR scans, are shown in the transversal MR image (D) and in the 3D surface-based reconstruction (E). The blue-coloured line/surface marks the MRI-based tumour borders and the rose-coloured line/surface marks the PET-based tumour borders. The green-coloured surface in the image E marks the ventricular system.

Discussion

The particularity of planning the nano cancer therapy of recurrent glioblastomas owes to the definition of the target volume for instillation of the nanoparticles. The visible tumour mass (GTV) was the basis of planning the nano particle depot position. One took care during the planning process to ensure a safety margin between a selected isotherm and the GTV. In this study, FET-PET influenced the therapy planning, leading to a change of the final GTV in 10/11 patients (the mean change accounted for 74%). In one patient (No. 11), the results of PET investigation lead to modification of the therapeutic strategy. The lack of statistical significance of differences between the MRI- and PET-based GTV in this study can be explained by the relatively small number of patients. Another possible reason might be related to the presence of bi-directional changes in GTV when comparing MRI to FET-PET, both at the inter-individual and intra-individual level. Indeed, on the average, the MRI identified an additional 8.9 ± 4.7 cm³ and the FET-PET scan—an additional 16.5 ± 15.2 cm³ outside of the common GTV (15.4 ± 11.0 cm³). The fact that the inclusion of the FET-PET data in the therapy planning led to an increase rather then a decrease in the final GTV (mean increase was 9 cm³) is in accordance with the results of Grosu et al. [17], who found the mean relative increase in PTV by 5 cm³ using ¹²³I-IMT SPECT. The pathophysiological explanation for this phenomenon is most likely an increased amino acid uptake of tumour tissue without a brain-barrier disruption. This consideration is backed by the results of the histopathology-based studies by Pauleit et al. [22] and Kracht et al. [21], which showed amino acid accumulation being a more reliable indicator for the presence of tumour tissue than a brain-barrier damage, detected by the contrast enhancement in MRI. The less commonly observed appearance of contrast enhancing regions in areas without amino acid uptake can be explained by a non-specific breakdown of the blood–brain barrier following surgery and radiation therapy [11], [13], [14], [21].

Apart from the superior definition of the tumour volume, the rationale for the use of the ¹⁸F-FET-PET in planning of the nano cancer therapy is the suitability for post-treatment evaluation (see example in Figure 2), since MRI cannot be used post-treatment because of susceptibility artifacts, caused by the magnetic nanoparticles. The usefulness of FET-PET for evaluation of the response to the nano cancer therapy is currently under investigation in the clinic.

Figure 2. A 44-year-old female patient (No. 6) with recurrent glioblastoma in the left occipital lobe, showing an increased amino acid accumulation (A). CT examination (C), performed 1 day after PET-guided injection of nanoparticles and the fused PET/CT scan (B) allow assessment of their distribution. The control examinations 13 weeks after nano cancer therapy (D–F) show a significant reduction in the amino acid accumulation (PET) and building of necrotic/oedematous zones around the nanoparticles deposits (CT).

Conclusion

FET-PET, as an adjunctive to MRI, reveals relevant information for therapy planning in patients with recurrent glioblastoma and thus proves to be valuable as a planning tool for novel therapy approaches such as nanoparticle mediated hyperthermia.