Abstract
In patients with recurrent glioblastoma multiforme (GBM), local minimally invasive treatment modalities have gained increasing interest recently because they are associated with fewer side effects than open surgery. For example, local tumor coagulation by laser-induced interstitial thermotherapy (LITT) is such a minimally invasive technique. We monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value.
THE PROGNOSIS OF PATIENTS suffering from recurrent glioblastoma multiforme (GBM) is poor. The median survival after resection is less than 6 months. 1 A meta-analysis performed by Barker and colleagues confirmed that the resection of recurrent GBM increases the median survival time by no more than 13 weeks. 2 Additionally, open resection is suited for only 30% of these patients. 2 Therefore, new therapy concepts are currently being investigated.
In particular, local treatment modalities have gained increasing interest 3 because they are associated with fewer side effects than open surgery. For example, local tumor coagulation by laser-induced interstitial thermotherapy (LITT) is such a minimally invasive technique. The LITT technique allows laser energy to be delivered without open surgical access directly into deeper tissue. The basic principle of LITT is the absorption of laser light and its conversion to heat. LITT using an Nd:YAG laser has been demonstrated to be capable of inducing direct interstitial malignant glioma destruction by protein denaturation while minimally involving healthy parenchyma.4–6 In patients with recurrent malignant gliomas, LITT is an important minimally invasive treatment option, especially when patients are not suitable for open resection. However, only a few centers worldwide perform LITT as a routine procedure. Therefore, widespread use of LITT is limited to date.
Owing to multiple interventions during the course of glioma (usually resection, radiochemotherapy, and adjuvant chemotherapy), evaluation of the specific effect of one therapeutic intervention remains difficult; therefore, diagnostic methods that can provide information about short-term therapeutic effects are needed. Monitoring metabolic changes in tumors has been shown to be a reliable indicator of tumor response.7–11 Tumor resistance may be detected early on, and in the case of tumor resistance to the therapy applied, another salvage therapeutic option can be provided. For example, in a previous study, the effects of LITT using 18F-fluorodeoxyglucose (FDG) could be monitored successfully in patients with low- and high-grade gliomas. 12 Because of the high rate of glucose metabolism in normal brain tissue, however, it is often difficult to distinguish tumor tissue from normal brain tissue by FDG positron emission tomography (PET).
Metabolic tracers, for example, positron emitter–labeled amino acids, can be used to monitor tumor activity. 13 For example, positron emission tomography with 11C-methyl-L-methionine (MET-PET) has been used to study the effects of radiotherapy on gliomas.14–17 Previous studies suggest that monitoring metabolic changes with MET-PET may provide an objective measure of response to temozolomide treatment; moreover, MET-PET may enable prediction of clinical outcome in glioma patients. 7 This makes it a valuable addition to conventional (ie, morphologic) magnetic resonance imaging (MRI) or contrast-enhanced computed tomography (CT).
Herein we explore the potential of MET-PET to monitor an experimental glioma therapy regimen using stereotaxy-guided LITT in a patient with supratentorial GBM after the first relapse.
Materials and Methods
PET/CT Imaging
The patient gave written informed consent to participate in the MET-PET studies. 11C-Methionine was synthesized as described previously. 18 All PET/CT studies were acquired on a combined PET/CT system with a full-ring dedicated PET scanner and a 16-slice CT scanner (Biograph 16 True Point, Siemens, Erlangen, Germany). Twenty minutes after injection of 740 MBq 11C-methionine, images of the brain were acquired from a static 10-minute emission scan (one bed position covering a 21.6 cm field of view along the z-axis). PET raw data were reconstructed into slices of 2.0 mm pixel size and 1.5 mm spacing using “TrueX” iterative reconstruction (three iterations, 21 subsets, taking into account system point-spread function, modeled scatter, and attenuation correction from non–contrast-enhanced CT with 130 kV, 110 mAs, 1.5 mm slice spacing, and pitch 0.75). Contrast-enhanced CT (130 kV, 110 mAs, pitch 0.75) was acquired with 80 mL nonionic contrast agent (Accupaque 350, GE Healthcare, Braunschweig, Germany) that was given intravenously as a bolus after PET acquisition.
MET-PET Data Assessment
As described previously, 19 tumor volumes were measured by performing a three-dimensional thresholding-based volume of interest analysis for MET uptake using the VINCI tool 20 (Figure 1, Figure 2, and Figure 3). The threshold for increased MET uptake was set to ≥ 1.3 in the contiguous tumor region.21,22
MET-PET imaging using a hybrid PET/CT system before laser-induced interstitial thermotherapy. Volumetry reveals a relatively large metabolically active tumor volume of 34.9 mL (bottom).
Follow-up MET-PET imaging using a hybrid PET/CT system on day 13 after laser-induced interstitial thermotherapy. A reduction in the metabolically active tumor volume (17.7 mL) is observed.
The third MET-PET scan on day 48 shows a further decrease in the metabolically active tumor volume (4.5 mL).
Laser-Induced Interstitial Thermotherapy
Before LITT, the patient underwent stereotactic planning MRI with his head fixed in an MRI-compatible stereotactic head frame. After coregistration of MRIs and MET-PET images, stereotactic coordinates of the metabolically active tumor center were calculated. A Teflon sheath (Somatex Medical Technologies, Teltow, Germany) was placed through a drill hole according to the defined target (1 to 2 cm proximal to the calculated metabolically active tumor center). Afterward, a sterile circumferentially laser light–emitting fiber (LITT standard applicator, diameter 1.1 mm, Dornier Medizintechnik, Germering, Germany) was passed through the sheath with its tip placed in the center of the metabolically active tumor according to the calculated depth. An Nd:YAG laser was connected to the fiber (λ = 1,064 nm; mediLas 4060 N, Dornier Medizintechnik, Germering, Germany). Three target points of the tumor were irradiated with steps up to 7,000 J (5–6 W/s in continuous mode). In total, 20,000 J were applied. After the end of the treatment, the laser fiber with its sheath was removed.
Case Presentation
A 58-year-old patient noticed severe headache 4 weeks prior to admission in December 2009. Neurologic examination on admission showed no relevant deficit. MRI revealed a contrast–enhancing, tumor-suspicious lesion in the right parietal and temporal lobe, which was resected in December 2009. Histopathologic findings confirmed a World Health Organization grade 4 GBM. After resection, external radiation therapy up to a total dose of 60 Gy with concomitant temozolomide (TMZ) chemotherapy (75 mg/m2 of body surface per day, 7 days per week from the first to the last day of radiotherapy) was performed over 6 weeks until March 2010. Subsequently, the first cycle of adjuvant TMZ chemotherapy was performed in April 2010 at a dosage of 200 mg/m2 of body surface per day over 5 days, with cycles repeated every 4 weeks. In July 2010, MRI after three cycles of adjuvant TMZ chemotherapy revealed local tumor recurrence. For treatment of tumor recurrence, chemotherapy with lomustine (110 mg/m2 of body surface every 6 weeks) was administered until August 2010. Despite the change in chemotherapy, MET-PET imaging using a hybrid PET/CT system showed a relatively large metabolically active tumor volume of 34.9 mL (see Figure 1).
For treatment of GBM recurrence, a further open resection, percutaneous stereotactic reirradiation, and escalation of chemotherapy were considered. These treatment options were, however, not favored by the patient. Therefore, to reduce the residual tumor minimally invasively, LITT was performed in September 2010. Follow-up MET-PET imaging using a hybrid PET/CT system on days 13 and 48 after LITT revealed a subsequent reduction in the metabolically active tumor volume (17.7 and 4.5 mL, respectively; see Figure 2 and Figure 3). MET-PET imaging results were in contrast to MRI findings on day 47 after LITT with ring-shaped contrast enhancement, most probably due to LITT treatment alterations in the blood-brain barrier (Figure 4).
MET-PET imaging results indicate decreased metabolic activity (bottom) and are in contrast to MRI findings on day 47 after laser-induced interstitial thermotherapy with ring-shaped contrast enhancement (upper row) of the tumor.
After LITT, the patient had a favorable outcome. He was able to walk without help until March 2011. Afterward, clinical signs and symptoms with recurrent epileptic seizures and a weakness of the left arm and leg were highly suspicious for tumor progression. After palliative care, the patient died in May 2011.
Discussion
Experience with radiolabeled amino acids concerning treatment monitoring is promising.7–11,23–25 Previously, various parameters derived from amino acid PET to assess treatment response could be identified. Some studies observed that a change in the maximal tumor to brain ratio is a reliable parameter to identify tumor progression, 26 whereas others found changes in the metabolically active tumor volume in amino acid PET to be more sensitive than standardized uptake values. 27
Our case of a patient with recurrent GBM demonstrates that MET-PET is useful for monitoring the short-term therapeutic effects of LITT, especially when patients are pretreated with a multistep therapeutic regimen. The LITT-induced therapeutic effect could be monitored using MET-PET for more than 6 weeks after LITT. The observed MET-PET metabolic pattern after LITT indicates a continuous decline in metabolically active tumor volume. Thus, MET-PET meets the clinical need for a method that is sufficiently sensitive to indicate early therapeutic efficacy and thereby enables monitoring of the metabolic tumor pattern during therapy.
Treatment planning studies with radiolabeled amino acids (eg, MET-PET), including assessment of outcome, are currently moving into the focus of interest. For example, it was demonstrated that complete resection according to PET tracer uptake in high-grade gliomas increases survival, whereas complete resection according to MRI contrast enhancement does not. 28 Thus, monitoring and guidance of those minimal invasive experimental therapy regimens using amino acid PET should be studied in larger patient samples to confirm its clinical value.
However, implementation of MET-PET into a daily clinical routine may be difficult owing to the fact that the method is restricted to a few centers with a cyclotron unit because of the short half-life of 11C. Novel 18F-radiolabeled amino acids (eg, O-(2-[18F]fluoroethyl)-L-tyrosine) and nucleoside analogue (eg, 3′-deoxy-3′-18F-fluorothymidine) are more convenient and may be an alternative to MET-PET in the near future.
Footnotes
Acknowledgment
Financial disclosure of authors and reviewers: None reported.