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Publicly Available Published by De Gruyter April 29, 2014

Interstitial laser irradiation of cerebral gliomas – neurobiological background, technique and typical results

Interstitielle Laserbestrahlung von zerebralen Gliomen – Neurobiologischer Hintergrund, Technik und typische Ergebnisse
  • Wernholt von Tempelhoff EMAIL logo , Frank Ulrich and Hans-Joachim Schwarzmaier

Abstract

Background:

The most common type of primary brain tumors are gliomas. For patients unsuitable for open microsurgery having been treated by radiochemotherapy, laser irradiation has proven to be an alternative palliative option. From summer 1997 until winter 2006 we performed about 60 laser-interstitial thermotherapy (LITT) treatments, starting with patients with large recurrent tumors who had no other therapeutic option. In the present article we report about the neurobiological background, the technique and our experience with LITT of cerebral gliomas.

Materials and method:

For laser irradiation we used a specially designed light guide (LITT standard applicator; Trumpf Medizintechnik, Umkirch, Germany). The tip of this light guide is a special optical diffuser which is characterized by a homogeneous spherical or ellipsoid emission profile. The light guide was introduced into an appropriate protective sheath (Somatex, Teltow, Germany). For the laser light source, we used a continuous wave 1064-nm Nd:YAG laser (mediLas fibertom 4060 N; Dornier MedTech, Weßling, Germany). Laser irradiation was performed under general anesthesia in a 0.5 T open configuration magnetic resonance (MR) system (Signa SP; General Electric, Milwaukee, WI, USA). Usually, the tip of the light guide was positioned in the center of the tumor using the built-in localization system (Flashpoint 3000; IGT, Boulder, CO, USA) in combination, where appropriate, with a specially designed navigation system (Localite™, Bonn, Germany). The position of the light guide was then controlled using multiplanar reconstructions of T1-weighted sequences. For near real-time control, temperature monitoring was performed using an experimental software package based on the temperature-dependent shift of the MR signal. Laser irradiation was ceased when the temperature monitoring revealed a steady state temperature profile within the heated tissue. Since 2008 we have used traditional stereotactic targeting and methionine positron emission tomography/computed tomography (MET-PET/CT) instead of the ‘open’ MR system for planning and follow-up in LITT of brain tumors.

Results:

We started the LITT treatment of gliomas in the early 1990s (benign gliomas in eloquent regions/not suitable for surgery). In 1997 we started to treat patients with recurrent gliobastomas/anaplastic gliomas. All of these patients had an increased survival in comparison to the natural course of recurrent glioblastomas. There were no procedure-related deaths or permanent neurological deficits. Two factors seem to be important for the overall success of the LITT procedure: 1) an early enrollment in the LITT therapy after diagnosis of a tumor recurrence, and 2) a corresponding smaller tumor mass at the beginning of the therapy.

Conclusion:

Cytoreduction by laser irradiation seems to be a promising option for patients suffering from gliomas.

Zusammenfassung

Hintergrund:

Die häufigste Form primärer Hirntumoren sind Gliome. Für Patienten, die für eine offene Mikrochirurgie nicht in Frage kommen und bereits mittels Radiochemotherapie behandelt wurden, stellt die Lasertherapie nachweislich eine alternative palliative Behandlungsoption dar. Von Sommer 1997 bis zum Winter 2006 haben wir ca. 60 interstitielle Laser-Thermotherapie (LITT)-Behandlungen durchgeführt, beginnend mit Patienten mit großen Rezidivtumoren, für die es keine andere Therapiemöglichkeit gab. In dem hier vorliegenden Artikel berichten wir über den neurobiologischen Hintergrund, die Technik und unsere Erfahrungen mit der LITT von zerebralen Gliomen.

Material und Methode:

Für die Laserbestrahlung verwendeten wir einen speziell entwickelten Lichtleiter (LITT Standard-Applikator; Trumpf Medizintechnik, Umkirch, Deutschland). An der Spitze dieses Lichtleiters befindet sich ein spezieller optischer Diffusor, der sich durch ein homogenes kugel- oder ellipsoid-förmiges Abstrahlprofil auszeichnet. Der Lichtleiter wurde in einen entsprechenden Schutzkatheter (Somatex, Teltow, Deutschland) eingeführt. Als Laserlichtquelle verwendeten wir einen kontinuierlich abstrahlenden 1064 nm Nd:YAG-Laser (Medilas Fibertom 4060 N; Dornier MedTech, Weßling, Deutschland). Die Laserbestrahlung wurde unter Vollnarkose in einem offenen 0,5 Tesla MRT-System (Signa SP; General Electric, Milwaukee, WI, USA) durchgeführt. In der Regel wurde die Spitze des Lichtleiters im Zentrum des Tumors mit Hilfe des integrierten Lokalisierungssystems (Flashpoint 3000; IGT, Boulder, CO, USA) positioniert, ggf. – so vorhanden – in Verbindung mit einem speziell entwickelten Navigationssystem (Localite™, Bonn, Deutschland). Die Position des Lichtleiters wurde dann mittels multiplanarer Rekonstruktionen der T1-gewichteten MRT-Sequenzen gesteuert. Zur Therapiekontrolle in nahezu Echtzeit diente eine Temperaturüberwachung unter Verwendung eines experimentellen Softwarepakets auf Basis der temperaturabhängigen Verschiebung des MRT-Signals. Die Laserbestrahlung wurde beendet, sobald die Temperaturüberwachung ein stationäres Temperaturprofil innerhalb des erwärmten Gewebes zeigte. Seit 2008 wurde für die Planung und die Verlaufskontrolle der LITT von Hirntumoren anstelle des “offenen” MRT-Systems das traditionelle Stereotaxie-Verfahren in Kombination mit MET-PET/CT-Bildgebung eingesetzt.

Ergebnisse:

Wir begannen mit der LITT-Behandlung von Gliomen in den frühen 1990er Jahren, zunächst bei gutartigen Gliomen in eloquenten Regionen, die nicht für die Chirurgie geeignet waren. Ab 1997 wurden Patienten mit rezidivierenden Gliobastomem/anaplastischen Gliomen behandelt. Alle diese Patienten hatten eine erhöhte Überlebensrate im Vergleich zum natürlichen Verlauf des rezidivierenden Glioblastoms. Es gab keine verfahrensbedingten Todesfälle oder bleibende neurologische Defizite. Zwei Faktoren scheinen für den Gesamterfolg des LITT-Verfahrens wichtig zu sein: 1) Eine frühe Aufnahme der LITT-Therapie nach Diagnose eines Tumorrezidivs, und 2) eine entsprechend kleine Tumormasse zu Beginn der Therapie.

Schlussfolgerung:

Die Zytoreduktion durch Laserbestrahlung scheint eine vielversprechende Option für Patienten mit Gliomen zu sein.

1 Neurobiological background

1.1 Tumor entity and treatment modalities

High-grade gliomas represent more than 40% of the primary brain tumors. Their malignancy is characterized by their recurrence in spite of multimodal treatment, including radiochemotherapy. Gliomas always recur – with few exceptions – within several months depending on the predominant cell type. Of the high-grade gliomas, glioblastoma multiforme (GBM) is the most prevalent and one of the most aggressive tumors, being highly infiltrative, with tumor cells typically extending – in microscopic findings – several centimeters away from the tumor enhancement [1]. The tissue lying outside the tumor lesion and contrast enhancement, which can be identified by T2 prolongation on magnetic resonance imaging (MRI) or contrast enhancement or abnormalities on H-magnetic resonance spectroscopy (H-MRS), often infiltrates functional active parenchyma. In most neurological symptomatic patients, resection of infiltrated parenchyma includes important brain tissue and results in a post-operative neurological deficit. The fusion of functional MRI for cortical motor, sensory, and speech localization, and techniques such as pre-operative cortical stimulation will avoid additional harm to eloquent areas [2]. In addition to conventional therapies, local treatment modalities such as image-guided resection procedures, fluorescence-guided (ALA) surgery, intracavitary chemotherapy, or interstitial laser- and brachytherapy are continuously being improved and clinically tested [3].

Laser-induced interstitial thermotherapy (LITT) is a minimally invasive approach for the treatment of gliomas, especially in poorly accessible and eloquent regions, i.e., parts of the brain that control speech, motor functions, and senses. During the past two decades basic research in physics, engineering and experimental pathology has revealed the theoretical and technical background for LITT [4, 5]. The main mechanism of laser-tissue interaction is absorption of photons by the tissue chromophores. The exited state is then converted into thermal energy. If the tissue is heated above a defined temperature for a defined time, the tissue proteins are denatured. The heat distribution is at first determined by thermal conduction and convection by blood perfusion. The final extent of tissue denaturation is also dependent on thermal sensitivity of brain tumor cells.

During the last decade interstitial laser application has been adapted to ‘open’ MRI in operating rooms [6]. The most important feature of intra-operative magnetic resonance (MR) tomography is the integration of a frameless stereotactic navigational system to guide image acquisition by instruments such as biopsy needles or laser fibers. The real-time imaging mode is able to continuously monitor the position of the laser fiber in different planes. For therapy monitoring, advanced image processing software can be used during thermal ablation [7].

The primary aim of LITT is the destruction and removal of malignant cells accompanied by a decrease in tumor size. Persistent tumor cells at the margin of the surgical lesion after treatment determine the post-operative course. A secondary growth of residual neoplastic cells leads to the formation of recurrent tumor masses. LITT and other adjuvant local therapies, applied after microsurgery and radiochemotherapy, attempt to interfere with this regrowth.

1.2 Histological and immunohistochemical findings induced by LITT

1.2.1 Zones of lesion

Following laser irradiation, the laser lesion shows in experimental studies a typical architecture depending on the interval following laser treatment. The primary lesion shows differences in lesion diameter corresponding to the irradiation time and thermal energy deposition to the tissue. The typical architecture of a laser lesion consists of a central coagulation necrosis which is not apparent immediately after irradiation but is demarcated by a surrounding rim of edema adjacent to undamaged tissue [7, 8], visible in early MR controls and follow-ups. The necrosis becomes evident by a gradual loss of contrast medium enhancement (gadolinium, Gd) and early resorptive changes in the margins by day 3. A rim of granulation tissue is formed after 1 week and the edema spreads to the periphery. A cystic lesion with variable remnants of unresorbed necrotic tissue and a mesenchymal and glial reaction is what finally remains.

The immunohistochemical examination of specimens from these lesions shows a distinct staining pattern of several antibodies reactive to glial cells and neurons in relation to the different zones of the lesion. Non-specific and diffuse immunostaining can be found in the central necrotic zone only [9]. In several studies, no qualitative difference could be found in the general histological architecture of the LITT lesion between animals with implanted tumor cells and those without [9–11].

The zones of lesion are clearly defined as a central necrosis with a rim of edema. However it is interesting that distinct changes can be seen in the size of the lesion in areas of normal tissue when compared to neoplastic tissue. This might be due to different histological and therefore optical properties of these tissues with a resulting difference in the sensitivity to laser energy.

The optical properties of brain tissue are also altered by coagulation as a result of laser-tissue interactions. Laser-induced coagulation leads to a tissue-specific increase in absorption and scattering with a higher vulnerability of the tissue to laser light [12].

1.2.2 Astrocyte activation and reactive gliosis

The specific appearance of a LITT lesion in the course of time is mainly defined by resorptive changes by microglial cells or macrophages and a reactive gliosis. Immunohistochemical staining for the glial fibrillary acid protein (GFAP) clearly demonstrates astrocyte activation and the extent of gliosis. Increased numbers of GFAP-positive reactive astrocytes are present after 1 day in the marginal zone and their number further increases after 7 days.

After 2 weeks, the marginal zone of the lesion shows a distinct three-layered structure. The central necrotic zone is surrounded by a zone of edema containing an infiltration of granulocytes, lymphocytes and macrophages. A layer of GFAP-positive reactive astrocytes separates this zone of edema from the adjacent brain tissue that appears normal.

At the cellular level, different stages of astrocyte activation are detectable. One day after LITT, clumps of GFAP-positive cytoplasmic material coat the nuclear membrane. After 3 days, GFAP-staining appears in short cytoplasmic processes. The intensity of GFAP immunoreactivity in reactive astrocytes that surround the necrotic zone increases until the end of the second week. Later, sprouting capillaries and GFAP-positive reactive astrocytes extend into the zone of necrosis. After 1 month, a thin layer of GFAP-positive astrocytes surrounds a cystic defect [7].

1.2.3 Vascular effects

Following laser treatment, blood vessels generally appear engorged, containing leached erythrocytes of which only the membranes are stained. The tissue structure in general, however, is well-preserved. The densely packed and decolorized red blood cells seem to be a characteristic histological marker of the intravascular laser effect [10, 11]. Further vascular effects of laser irradiation include a thrombotic occlusion of the vessels inside the central laser lesion. These vascular structures are resorbed by invading mesenchymal cells during the course of regeneration. Vessels outside the margin of the laser lesion become the origin of outsprouting capillaries, invading deeper into the lesion with a functional importance for regenerative and proliferative processes. Also, these vessels clearly contain normal and undamaged erythrocytes 3 days after laser irradiation indicating a functional blood flow and the connection to the vascular tree [9, 11].

1.2.4 Membrane alterations

Fine structural analysis of the acute and chronic changes following laser treatment consistently shows damage of cellular and subcellular membranes in the central zone surrounding the laser tip. Cell membranes and nuclear membranes of nerve cells, glial cells and endothelial cells either exhibit local defects or are broken up into fragments. The subcellular membranes, in particular those of mitochondria also exhibit structural damage. The curled fragments often fuse to form small vesicles which may the result of a secondary heat effect.

Vascular cells such as erythrocytes similarly show membrane defects leading to a loss of hemoglobin. Only the basement membranes of capillaries and blood vessels seem to be resistant to the laser treatment. In contrast, investigation of the edema zone adjacent to the central necrosis exhibits no membrane ruptures [11]. These observations indicate that membrane alterations may play a leading role in the pathogenesis of laser-induced lesions. Intravascular erythrolysis, a common phenomenon after laser irradiation, seems to be caused by a leakage of hemoglobin through defects in the cellular membranes of erythrocytes and may lead to vascular occlusion with secondary tissue damage. The interstitial appearance of serum proteins such as albumin which do not cross the blood-brain-barrier and typically are not detectable in the interstitium under normal conditions can be attributed to membranous defects of the capillary endothelium [8, 11, 13]. The underlying laser-tissue interaction and the resulting histological changes are well-defined and have been characterized as central coagulation necrosis and peripheral edema, subsequent resorptive changes and the formation of a rim of granulation tissue.

In addition, various cellular changes of a degenerative and regenerative nature have been found on a functional-morphological level both in the brain and metastases. Such changes can be correlated with MRI appearances both under experimental and clinical conditions.

2 Open MRI technique

2.1 Procedure

By the end of 2006 we had the option to treat patients with recurrent malignant cerebral gliomas in an ‘open’ MRI system (Signa SP, General Electric, Milwaukee, WI, USA) which was part of an conventional operation theatre. We performed an image guided LITT therapy.

After positioning an MR-compatible Mayfield clamp and flexible head coil, the position of the burr-hole was optimized in the near real-time mode of the magnetic resonance tomograph (MRT). A stereotactic apparatus was fixed on the skull. The light guide was introduced into an appropriate protective sheath (Somatex, Teltow, Germany). For laser irradiation, we used a specially designed laser fiber (LITT standard applicator; Trumpf Medizintechnik, Umkirch, Germany). The tip of this fiber, consisting of an optical diffuser tip, is characterized by a homogeneous spherical or ellipsoid emission profile. The tip of the light guide was positioned in the center of the tumor mass using the built-in localization system (Flashpoint 3000; IGT, Boulder, CO, USA) in combination with a specially designed navigation system (Localite™; Bonn, Germany) if appropriate.

The position of the light guide was then controlled using multiplanar reconstructions of T1-weighted sequences. For laser intervention, light from a continuous wave 1064-nm Nd:YAG laser (mediLas fibertom 4060 N; Dornier Med Tech, Weßling, Germany) was applied. Laser output was monitored by an integrated power meter of the Nd:YAG laser in the laser head during treatment. The system was calibrated before treatment by a separate power meter (LMG universal); then 5–6 W were applied for 10–12 min. For near real-time control, temperature monitoring was performed using an experimental software package based on the temperature-dependent shift of the MR signal (T2 phase shift). Laser irradiation was ceased when the temperature monitoring revealed a steady state temperature profile within the treated area. In doing so, the surgeon was able to use all the advantages of the ‘open’ MR tomography. The procedure could be surveyed conventionally in the operating room, watching the in-built monitor, or from the control room. By the vertical gap there was free access to the patient at any time. Prior to laser therapy, a high-resolution image was acquired to depict the pathology selected for thermal treatment. This image was used for as a background image for calculated temperature maps in near real-time.

Since 2008 we have used traditional stereotactic targeting and methionine positron emission tomography/computed tomography (MET-PET/CT) instead of the ‘open’ MR system for planning and follow-up in LITT of brain tumors.

2.2 Fiber adaption

2.2.1 MR compatibility

LITT procedures in the ‘open’ MRI system are dependent upon MR-compatible and artifact-free instruments. A guiding device (NeuroGate; Daum Medical, Schwerin, Germany, and Snapper-Stereoguide; Magnetic Vision, Rüti, Switzerland) has been used in combination with the IGT Flashpoint system as an instrument for planning, guiding, and performing stereotactic laser procedures in ‘open’ MR. The device allows planning of an laser fiber trajectory from the surface of the patients head, fixed in a burr hole. If necessary, a biopsy specimen can be taken with this device for neuropathological diagnosis before LITT.

Targeting and positioning of the laser fiber are performed in the near real-time mode (Figure 1). When three-dimensional (3-D) T1-weighted images show the tip of the laser light guide in the targeted region (Figure 2), the laser therapy is performed.

Figure 1 Flashpoint navigation system in the ‘open’ magnetic resonance tomography system (Signa SP/I; General Electric, Milwaukee, WI, USA).
Figure 1

Flashpoint navigation system in the ‘open’ magnetic resonance tomography system (Signa SP/I; General Electric, Milwaukee, WI, USA).

Figure 2 T1-weighted image showing the light guide (black line, red arrow at tip of the fiber) in the target region (white arrow).
Figure 2

T1-weighted image showing the light guide (black line, red arrow at tip of the fiber) in the target region (white arrow).

2.2.2 Thermal stability and induced lesion size

The aim of interstitial thermal therapy is the thermal ablation of a defined tissue volume without adverse effects such as charring or shock waves due to vaporization at the probe tip. Consequently, the peak temperature at the probe tip must not exceed 100°C. This limits the peak power energy per given time and probe surface area. On the other hand a minimal radiant power density is required to achieve a sufficient temperature rise for tissue denaturation.

The high power density at the conventional fiber tip has often resulted in an overheating of the tissue surface, followed by vaporization and carbonization. In this situation, tissue irradiation no longer takes place and the heating process is caused by thermal conduction only. This problem was solved by using optical diffusers. Such diffusers emit laser light over the entire length of the fiber tip, significantly reducing the power density and allowing the operator to couple about 5–6 W into the brain tissue without adverse effects. The resulting laser lesion is also dependent on the length of the optical diffuser.

The final lesion size is determined by the exact optical properties (absorption, scattering) of the irradiated tissue as well as its blood perfusion. Color-coded temperature monitoring/mapping was performed using the experimental software package based on the temperature-dependent phase shift of the MR signal, as mentioned above (Figure 3).

Figure 3 Online-temperature monitoring during interstitial laser irradiation. In this color-coded temperature mode the spreading of heat around the fiber tip can be monitored in near-real time.
Figure 3

Online-temperature monitoring during interstitial laser irradiation. In this color-coded temperature mode the spreading of heat around the fiber tip can be monitored in near-real time.

Laser irradiation was ceased when temperature monitoring revealed a steady state temperature profile within the heated tissue. Figure 4 shows an early control T1-sequence with Gd.

Figure 4 Acute stage of the laser-induced lesion consists of a central (gray, brighter central zone) and peripheral zone (white ring, arrows).
Figure 4

Acute stage of the laser-induced lesion consists of a central (gray, brighter central zone) and peripheral zone (white ring, arrows).

3 Actual setup of LITT – therapy of gliomas under hybrid MET-PET/CT monitoring

Due to technical and political/financial reasons, since 2007 there have been no ‘open’ MR systems with integrated near real-time mode available in Germany. Consequently, our group returned to the initial stereotactic positioning of the fiber tip in the tumor in combination with methionine positron emission tomography/computed tomography (MET-PET/CT) instead of the ‘open’ MR system [14].

Using this technique resulted in an improved pre-operative target planning and post-operative control (see Chapter 4.3) allowing us to evaluate the neurobiological effects in addition to the mere morphological findings in the MRT.

The multiple interventions performed during the course of the disease in glioma patients (microneurosurgical resection, radiochemotherapy, and adjuvant chemotherapy), makes the evaluation of the specific effect of one therapeutic intervention very difficult. MET-PET performed after stereotactic-guided LITT in a patient with supratentorial GBM can – in addition to conventional MRI – provide information about short-term therapeutic effects. Monitoring metabolic changes in tumors may provide an indicator of tumor response. Tumor resistance may be detected early on and in the case of tumor resistance to the therapy applied, another salvage therapeutic option could be tried.

Metabolic tracers, e.g., positron emitter-labeled amino acids, have been proposed as indicators of tumor activity. MET-PET has been used to study the effects of radiotherapy on gliomas [14]. Previous studies suggest that monitoring metabolic changes with MET-PET may provide an objective measure of response to temozolomide treatment and furthermore it may enable prediction of clinical outcome in glioma patients. This makes MET-PET a valuable addition to conventional (i.e., morphological) MR or CT contrast-enhanced imaging.

4 Our experience: typical results and case presentations

4.1 Typical results

In Table 1, 18 patients receiving LITT were presented who were willing to take part in a follow-up survey. Sixteen patients suffered from a recurrence of a histologically confirmed glioblastoma of WHO grade IV and had undergone open microsurgery of the tumor at least once. All patients were non-surgical candidates at time of LITT. In high-grade patients conventional radiotherapy had been already performed and they had received standard chemotherapy with temozolomide.

Table 1

Tumor characteristics and energy application of recurrent glioblastoma multiforme and two low-grade astrocytomas (patient 17 and 18).

Patient numberTumor locationTumor volume (cm3)Karnofsky indexNumber of LITT sessions (n)Applied energy (kJ)
Session 1Session 2Session 3Session 4
1Parieto-occipital r.45.57043.04.45.05.0
2Temporo-parietal l.10.85034.55.3.10.0
3Parietal. l.8.07026.16.1
4Occipital r.22.87019.5
5Parietal r.28.47015.5
6Parieto-occipital l.24.070111.5
7Frontal r.79.88016.2
8Frontal l.20.67016.8
9Fronto-parietal r.17.77024.34.8
10Temporal r.18.18024.654.65
11Genu corp. callosum l.11.36035.55.06.0
12Parasagittal r.17.46019.0
13Temporo-parietal l.6.69018.7
14Fronto-temporal l.1.69018.0
15Parieto-occipital r.33.29015.4
16Frontal l.19.79018.6
17Parietal-operculum r.40.010028.59.0
18Anterior and middle parts of corpus callosum35.310017.5

r, right; l, left.

Two patients with low-grade gliomas had shown a stable, good condition, without neurological deficits for more than 5 years until now. In this small group of patients, there was no perioperative lethality. During the learning curve, in high-grade gliomas, the median survival increased to 11.2±2.0 months (Kaplan-Meyer method, Software SPSS Version 12.0). At the end of the study, 14 out of 16 patients were deceased. The cause of death was fatal venous thromboembolism in two cases. Three patients died of a systemic mycosis, a gastrointestinal bleeding and peritonitis after sigma perforation, respectively. The remaining deaths were due to a failure of central regulation as is typically seen in brain tumors.

In the following a few selected cases will be commented in more detail.

4.1.1 Case #1 (benign glioma)

A 30-year-old male (patient 17 in Table 1) was presented with a newly diagnosed intrinsic brain tumor of the right parietal operculum. Neuropathological examination was carried out intra-operatively and was later confirmed by histopathological specimens. These showed a glioma of predominantly astrocytic differentiation. The final diagnosis was an astrocytoma of WHO grade II (Figure 5A).

Figure 5 Astrocytoma of WHO grade II. Pre-LITT status in 2000 (A) and image-guided positioning of the therapy fiber tip into two ‘targets’ (B and C) during the same procedure/operation in 2000. Shrinking contrast enhancement post LITT with a typical ring enhancement immediately post LITT (D). Enhancement post 2nd LITT in 2003 (E) and in 2005 (F).
Figure 5

Astrocytoma of WHO grade II. Pre-LITT status in 2000 (A) and image-guided positioning of the therapy fiber tip into two ‘targets’ (B and C) during the same procedure/operation in 2000. Shrinking contrast enhancement post LITT with a typical ring enhancement immediately post LITT (D). Enhancement post 2nd LITT in 2003 (E) and in 2005 (F).

The stereotactic biopsy was followed by MR-guided LITT in April 2000. In total, 8500 J were applied, divided into two target points in the rostral and posterior section of the oval tumor (Figure 5B and C). There was no post-operative deterioration in the neurological findings. The early MR-control showed the typical ring-enhancements (zonation) with central signal reduction in the T1-Mode with Gd (Figure 5D). There was a clinical and an MR follow-up every 6 months. In October 2000, no clinical changes, and a reduced frequency of epileptic seizures were found. MR-control showed no tumor progress. The patient remained in a good condition. The neuroradiological findings revealed a tumor control with typical regressive signs and shrinking of the described ring enhancement. In August 2001, unchanged neurological findings were noted. The MR-control revealed no tumor growth, but new contrast enhancement. With regard to the neuroradiological findings, an additional LITT was performed in 2003 (Figure 5E). There has been no change in the neurological findings since that time and no tumor growth has been found either (Figure 5F).

4.1.2 Case #2 (benign glioma)

The second case is an example for the application of LITT in gliomas affecting the corpus callosum. A 42-year-old woman (patient 18 in Table 1), with a low-grade astrocytoma (WHO grade II) of the anterior and middle parts of corpus callosum, (Karnofsky index=100, minor paresis of the left hand) is presented. One LITT was performed for two targets.

After the first treatment, the MR follow-up showed regression and volume reduction for more than 4 years. After 2 months early MR effects (zonation) in the T1-sequence could be detected with Gd. After 4 months only the old residuals of the laser-induced coagulation necrosis and no progression could be observed. After 4 years, no more LITT-related changes were detected. MR-examinations just showed a paramedian scar without residual tumor and without any further growth. The clinical findings in the still ongoing observation time revealed no neurological deficits. The Karnofsky index remained at 100 and even the minor paresis of the hand disappeared (Figure 6A–D).

Figure 6 Astrocytoma of WHO grad II. Three years follow-up. (A) T1-wheighted sagittal reference image: slice covering maximum size. (B) After blood-brain barrier breakdown with contrast-enhancing rim: adjacent reactive changes in the primarily non-enhancing tumor in white matter and corpus callosum. (C) Shrinking lesion which is less enhanced, and (D) scar tissue with local cortical atrophy.
Figure 6

Astrocytoma of WHO grad II. Three years follow-up. (A) T1-wheighted sagittal reference image: slice covering maximum size. (B) After blood-brain barrier breakdown with contrast-enhancing rim: adjacent reactive changes in the primarily non-enhancing tumor in white matter and corpus callosum. (C) Shrinking lesion which is less enhanced, and (D) scar tissue with local cortical atrophy.

4.1.3 Case #3 (glioblastoma)

The neuroradiological examination (MRI, CT) of a 38-year old woman (patient 2 in Table 1) revealed a left temporal space occupying lesion. Open microsurgery was performed in February 2003. The histopathological finding was a glioblastoma (WHO grade IV). A small part of the tumor indirectly in contact with the brainstem could not be removed. In November 2003 an increasing growth and contrast enhancement of the known tumor remnants were noticed in the MRI follow-up (Figure 7A); there was no change in the clinical neurological findings. It was decided to perform a LITT of the tumor, accompanied by simultaneous chemotherapy with Temodal® (Figure 7B).

Figure 7 Glioblastoma multiforme of WHO grade IV. Three years follow-up. (A) Pre LITT in 2003. (B) Post LITT in 2003. (C) Shrinking tumor size after repeated LITT in 2005.
Figure 7

Glioblastoma multiforme of WHO grade IV. Three years follow-up. (A) Pre LITT in 2003. (B) Post LITT in 2003. (C) Shrinking tumor size after repeated LITT in 2005.

In August 2005, a slight growth of the tumor enhancement was diagnosed in the MRI without clinical deterioration. The small, already known tumor cyst near the brain stem, showed an increasing volume too. In September 2005, a second LITT procedure was performed (1 target point, 5300 J were applied) (Figure 7C). The cyst was punctured but did not collapse due to its connection to the cisternal CSF-space (cisterna ambience). The procedure was well-tolerated and the MRI control showed the typical pattern of ring-shaped Gd-DTPA enhancement. In March 2006 the described situation occurred again with tumor enhancement and an increase in the volume of the cyst. This resulted in a third LITT (2 target points, 10,000 J were applied) and a second cyst puncture, whereby the latter did not have a long lasting effect. This time a short lasting temporary paresis of the patient’s right arm occurred but vanished under symptomatic therapy.

4.2 Case presentation of MET-PET method

A 58-year-old patient reported having a severe headache 4 weeks prior to admission in December 2009. A neurological 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. Histopathological findings confirmed a GBM of WHO grade IV. After resection, external radiation therapy up to a total dose of 60 Gy, with concomitant temozolomide chemotherapy (75 mg/m2 of body surface each day for 7 days throughout the radiotherapy) was performed over 6 weeks until March 2010. Subsequently, the first cycle of adjuvant temozolomide chemotherapy was performed in April 2010 at a dosage of 200 mg/m2 of body surface per day over 5 days, with cycles being repeated every 4 weeks. In July 2010, MRI, after three cycles of adjuvant temozolomide chemotherapy, revealed local tumor recurrence. For treatment of tumor recurrence, chemotherapy with lomustine (110 mg/m2 of body surface) was administered every 6 weeks until August 2010. Despite the change of chemotherapy, MET-PET imaging using a hybrid PET/CT system showed a relatively large, metabolically active, tumor volume of 34.9 ml (Figure 8

Figure 8 Pre LITT. Right temporal recurrent glioblastoma. From [14] with permission.
Figure 8

Pre LITT. Right temporal recurrent glioblastoma. From [14] with permission.

). Further resection of the recurrent tumor was, however, not favored by the patient. Therefore, in order to reduce the residual tumor minimally invasive, LITT was performed in September 2010. Follow-up MET-PET imaging using a hybrid PET/CT system on day 13 and 48 after LITT revealed a subsequent reduction of the metabolically active tumor volume to 17.7 and 4.5 ml, respectively (Figures 9 and 10).

Figure 9 Day 13 post LITT. Reduced metabolic activity of the tumor. From [14] with permission.
Figure 9

Day 13 post LITT. Reduced metabolic activity of the tumor. From [14] with permission.

Figure 10 Day 48 post LITT. Further reduction of metabolic activity of the tumor. From [14] with permission.
Figure 10

Day 48 post LITT. Further reduction of metabolic activity of the tumor. From [14] with permission.

5 Discussion

In tumors with Gd-DTPA enhancement, in the MRI prior to LITT, there was no enhancement within the laser-induced lesion after LITT due to a temporarily modulated blood-brain barrier (BBB). The perifocal edema is not apparent immediately after LITT. It evolves 1–3 days later and regresses completely within less than a month, indicating that no persistent damage occurs within this zone.

In the majority of the induced lesions, the long-term development is uniform with variations in the zonal architecture in two lesions. In all patients the decrease of lesion size followed an exponential pattern with a half-life period of a few weeks. The shrinkage of the lesion is accompanied by a corresponding reduction of the size of the neoplasm. As the laser-induced enhancing rim persists over a long period, difficulties may arise in differentiating the residual laser lesion from recurrent tumor. The sequential time course of the laser-induced enhancing rim with an ongoing reduction of size may exclude a recurrent tumor that appears as increasing volume and new onset of mass effect [8].

These changes appear to be qualitatively equal, irrespective of the type of brain tumor, although differences, dependent on the grade of malignancy, may exist regarding the onset and size of recurrence. Primary effects of laser irradiation include a rupture of cell membranes and a fragmentation of subcellular components, resulting in irreversible tissue damage with secondary effect in the periphery. In callosal gliomas it could be seen that heat follows fiber tracts and tumor pathways, even into the contralateral hemisphere via commissural fibers.

The laser-tissue interactions are followed by reactive, proliferative and BBB changes. Levin et al. [15] demonstrated that the BBB within the zone of infiltrations, in the otherwise normal brain adjacent to the tumor mass, is unaffected. This is of particular importance since this zone contains the leaking edge of neoplastic cells with a large fraction of cycling cells that have a high growth fraction. LITT-induced modulation of the BBB facilitates a locoregional passage of chemotherapeutic agents into the brain tissue.

Literature reports on local heating techniques in GBM, such as laser irradiation, are rare. Although laser irradiation of brain tumors has been described early [8, 16, 17] most of the work refers to astrocytomas of WHO grade II–III and gliosarcomas [18]. In these studies, laser irradiation was performed with comparatively low irradiation doses [8, 16, 17] and less sophisticated application devices [8, 16]. Nevertheless, it was demonstrated that energy amounts between 2400 and 9120 J were sufficient to induce coagulation necroses between 18 and 35 mm in diameter [19].

We could demonstrate that this cytoreductive effect can also be repeatedly achieved in recurrent glioblastomas (rGBM) without causing any additional harm to the patient. It can be adapted to the geometry and size of the tumor and its progression with the course of time. However, the most important finding is the remarkably long survival of rGBM associated with the laser treatment. This survival is substantially longer than for example, the 5.4 months reported by Trent et al [20] for a monotherapy with temozolomide. Whether the underlying mechanism is a local cytoreduction only, or due to other laser effects cannot be deduced from the presented data.

In addition, thermal concepts may offer additional advantages in the therapy of high-grade gliomas because a moderate temperature increase within brain tissue is known to modulate the BBB. Studies in normal monkey brain revealed a defined time window where the BBB remains open after local application of microwave hyperthermia [19].

A local disruption of the BBB after laser irradiation has also been reported for astrocytomas of WHO grades II and III in patients after interstitial laser irradiation [8]. It could be shown in clinical trials that the disruption of the BBB in areas with otherwise uncompromised BBB can result in an improved clinical outcome of chemotherapy of brain tumors [18]. This is possibly due the fact that these areas of tumor infiltration into the surrounding healthy tissue with intact BBB are the most active parts of the tumor, characterized by a large fraction of cycling cells [21].

In addition, the drug concentration may be increased within the tumor tissue due to BBB modulation. The role of intratumoral concentration of temozolomide (by the direct intratumoral application of temozolomide) with respect to life expectation is demonstrated in D54 human MG xenocraft-challenged athymic rats [22].

6 Conclusion

The follow-up MR examinations clearly demonstrated a regression of the laser-irradiated parts of the tumor while simultaneously the non-laser irradiated parts exhibited significant progression. This is of particular importance because all parts of the tumor, whether being laser-irradiated or not, were prone to the same systemic chemotherapy. Especially in corpus callosal gliomas, we could show that the heat distribution corresponded to the migration pattern of glioma cells with heat crossing the corpus callosum along the fiber tracts into the contralateral hemisphere.

The technique of MR-guided local laser ablation has achieved a sophisticated level. Recent studies report about successful applications in brain metastases [23–25]. The recognized types and special neuropathological chances in thermal lesions may improve the understanding of the biological response and ablation range.

However, further exploration with well-designed and controlled clinical trials should be performed to finally define the role of LITT in the treatment of gliomas. Whether the underlying mechanism is a local coagulation only or at least in part a result of the modulation of the BBB or other laser effects is not clear from the presented data. The answer to these questions must also be left to future investigations.


Corresponding author: Dr. med. Wernholt von Tempelhoff, Universitätsklinikum Köln (AöR), Kerpener Str. 62, 50937 Köln, Germany, e-mail:

Acknowledgments

WvT and FU contributed equally to the original manuscript.

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Received: 2014-2-24
Revised: 2014-3-18
Accepted: 2014-3-19
Published Online: 2014-4-29
Published in Print: 2014-4-1

©2014 by Walter de Gruyter Berlin/Boston

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