INTRODUCTION. Keywords: Laser; Magnetic resonance; Monitoring. of Medicine at St Mary s, London, UK

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1 Lasers Med Sci 1999, 14: Springer-Verlag London Limited Monitoring of Interstitial Laser Thermotherapy with Heat-sensitive Colour Subtraction Magnetic Resonance Imaging: Calibration with Absolute Tissue Temperature and Correlation with Predicted Lesion Size S.W.T. Gould 1, N.V. Vaughan 1, W. Gedroyc 2, G. Lamb 2, R. Goldin 3 and A. Darzi 1 1 Minimal Access Surgical Unit, 2 Interventional Magnetic Resonance Unit, 3 Department of Pathology, Imperial College School of Medicine at St Mary s, London, UK Abstract. Magnetic resonance imaging (MR) is the most sensitive modality for monitoring interstitial thermotherapy (ILT). A real-time pulse sequence that assigns a colour spectrum to grey-scale changes could potentially increase the accuracy of MR-guided thermal surgery. This study aimed to calibrate this sequence with tissue temperature and then to determine whether it could be used to predict accurately the extent of tissue necrosis produced during the formation of a thermal lesion. Porcine livers were studied within a 0.5T Interventional MR Unit. A Nd:YAG laser fibre (λ=1064 nm) with adi#user tip was placed within the liver parenchyma adjacent to an MR compatible thermocouple. A template sagittal MR image containing the fibre tip was obtained. A 3 cm region of interest (ROI) was centred on the fibre. Thermal lesions were produced (5 W for 20 min) with real-time subtraction MR monitoring with colour overlay throughout (acquisition time 4 s). At 60 s intervals the pixel intensity value, temperature and colour at the laser tip were noted. Twenty burns were produced. Pixel intensity measurements were expressed as percentages of mean pixel intensity within the ROI to standardise measurements. Using the colour representing the temperature above which tissue necrosis would be expected to occur, predicted maximum lesion size was measured from the images and compared with histological assessment. There was a linear relationship between temperature and percentage pixel change (r 2 = 0.84). Six discrete colours were determined, all significantly di#erent from each other in terms of mean percentage pixel change (p<0.01) and mean temperature (p<0.01 except between orange and yellow, p=0.037). Green had a mean temperature of 55.6 ( 5) C, and thus predicted necrosis. Image-predicted maximum lesion size correlated closely with histology (r 2 =0.93). The colour changes produced by this unique pulse sequence have been calibrated with tissue temperature in vitro. The green colour represents the temperature above which necrosis would be expected to occur and can be used to accurately predict lesion size. This will potentially allow greater accuracy and safety for MR monitoring of ILT in vivo. Keywords: Laser; Magnetic resonance; Monitoring INTRODUCTION Interstitial laser thermotherapy (ILT) involves the use of thermal energy, delivered by an optical fibre, to destroy tumours situated deep to the body surface. First described in 1983 [1], Correspondence to: Naomi Vaughan FRCS, Minimal Access Surgical Unit, 4th Floor Stanford Wing, St Mary s Hospital, Paddington, London W2 1NY, UK. there was initial enthusiasm and early reports of its use in tumours of the liver [2], breast [3] and pancreas [4]. Although the first reports used laser fibres placed within the tumour at open operation, with evolving fibre design it became possible to place the fibre into the tumour percutaneously using some form of imaging guidance. In theory this provides a minimally invasive means of tumour destruction that can be carried out under local anaesthesia and may have potential for the

2 Interstitial Laser Thermotherapy and Heat-sensitive Colour Subtraction MRI 251 palliation of metastatic and irresectable tumours, or even as a definitive treatment for small primary malignant lesions. However, a number of di$culties have prevented it from becoming an accepted widespread, clinically useful technique. The most important is the inability to accurately monitor the thermal destructive process within an organ in an interactive on-line fashion. This is vital to confirm complete destruction of the target lesion and prevent inadvertent thermal damage to any nearby important anatomical structures. The second limiting factor is the small lesions (generally no greater than cm diameter) produced with bare fibres. This situation has improved with the use of multiple bare fibre techniques [4,5] and the development of fibres fitted with various types of frosted-glass di#user tips [6]. The latter produce absorption of the thermal energy over a larger tissue volume, resulting in the ability to produce lesions up to 3.5 cm in diameter with a single fibre. A third di$culty is the problem encountered in placing the percutaneous fibres with su$cient accuracy into the lesion using some form of image guidance. Finally, many of the early studies in human patients were performed on irresectable lesions so that no histological confirmation of the e#ect of ILT was available. Largely because of these di$culties, no randomised controlled trials comparing this form of therapy with conventional treatments have been performed. However, there are a number of in vitro and animal studies that demonstrate the formation of reproducible and predictable lesions using these techniques [7,8]. If these problems can be successfully addressed ILT may develop into a clinically useful treatment modality. Image Guidance Computed tomography (CT) represents the e#ect of ILT on tumours as low attenuation, unenhancing areas but does not demonstrate tissue changes as they occur [7,8]. Ultrasound demonstrates lesions as they are formed but is spatially inaccurate [3,9]. Magnetic resonance imaging (MRI) has for some years been considered the ideal modality for monitoring this form of therapy [10 12]. This is because a number of factors, such as the temperature dependence of tissue T1 times, changes in tissue water distribution on heating, and alteration of protein molecule structure by thermal energy absorption, result in a predictable temperature-dependent MR signal loss using T1 weighted imaging techniques. In e#ect, MR acts as an in vivo thermometer. Also MR signal loss and the resulting histological e#ect in tissue have been closely correlated in several animal models [10,12 15]. MRI has been used to guide ILT in several clinical series, particularly to treat liver tumours [6,16 18]. The study by Vogl et al. [18] has shown some evidence of increased survival from hepatic colorectal carcinoma metastases treated in this manner when compared with historical survival data from untreated patients. However, there are a number of problems with current MR-guided ILT systems. The fibres are usually placed using some other means of image guidance, and this can result in their placement in suboptimal positions, even missing the tumour altogether [5]. This is because the tumour may be less clearly seen than with MR and there is the problem of transferring the patient with the laser fibre in place, with the risk of dislodgement. Signal loss is portrayed as a grey-scale change, and it may be di$cult to judge the exact degree of greyness that represents tissue necrosis. The degree of signal loss that signifies necrosis may vary from tissue to tissue in any case and the essentially arbitrary nature of the window and level settings used for MR imaging make the standardisation of images extremely di$cult. Finally, scan times that are fast enough to monitor heat-induced changes in real-time may not possess su$cient spatial accuracy for anatomical monitoring. The Signa SP10 Interventional MRI and Real-Time Image Processing (RTIP) Software The use of Interventional MR machines to monitor ILT, such as the General Electric SP10 0.5T Interventional MRI Unit (IMR) installed in our hospital, may o#set some of these di$culties. Its integral instrument guidance devices, open-access configuration and fast imaging (scan times <2 s) [19,20] allow laser fibres to be accurately placed in deep seated lesions under real-time MR control. We have successfully performed a number of realtime guided biopsies using this system to demonstrate its feasibility. The use of a colour overlay, heat-sensitive, subtraction sequence, known as real time image processing (RTIP)

3 252 S.W.T. Gould et al. based on a continuous subtraction technique allows monitoring of the temperature achieved within the tissue and of the lesion size obtained. A background image of the target (e.g. liver tumour) is obtained, and a region of interest (ROI) is drawn around it. ILT is then started while scanning in real-time continues. Each incoming image is subtracted from the background image and the signal loss in the ROI automatically calculated and given a numerical value, the larger values representing greater signal loss. This numerical value is represented on the overlay image as a colour in a spectrum. The spectrum runs from blue to red with increasing signal loss (and hence temperature) producing a thermal map of the region of interest. This technique has a number of theoretical advantages over previous MR monitoring methods. 1. It is easier to appreciate colour than greyscale changes. 2. The extent of irreversible necrosis and the surrounding reversible thermal e#ects should therefore be predictable with a greater degree of accuracy. 3. Since RTIP is a subtraction sequence, colour change is dependent only on the signal di#erence from the original image and should be independent of tissue type. 4. Window, level and threshold settings may be standardised between scans so that the system is reproducible. This system needs further investigation before it can become a useful clinical tool. This formed the objective of the present study. The first aim was to standardise RTIP software settings to allow reproducibility between treatment episodes, and then to calibrate the colour changes produced during an ILT lesion with absolute tissue temperature. The second was to determine the colour representing the temperature above which biological tissue would be expected to undergo necrosis. Having achieved this, the final aim was to use the resultant thermal map to predict the expected dimensions of the necrotic lesion from the images and to correlate this with the size measured by histological means. MATERIALS AND METHODS All procedures were performed in a General Electric Signa SPI0 Interventional MRI Unit (General Electric Corporation, Milwaukee, USA). Freshly excised whole porcine livers were placed in a plastic container at the isocentre of the magnet. A large loop flexible transmit/receive coil was positioned around the container such that the thickest part of the liver was at the centre of the imaging volume. An interstitial neodynium yttrium aluminium garnet (Nd:YAG) laser fibre (internal core diameter 600 µm) with a frosted glass di#user tip 2 cm in length and 1.9 mm in diameter (Cross Medical, London, UK) was placed within a 7 French gauge plastic thermostable sheath (Westcott Medical, Durham, UK). An MR compatible nickel/nickel copper thermocouple was attached to the outside of the sheath. This assembly was placed within the liver parenchyma to a depth of 5 cm. A cod liver oil capsule was positioned at its entry site to act as a fiducial marker for rapid identification of the correct scan plane. A template image was acquired using a Fast Gradient Recalled pulse sequence (FGR, flip angle 60, repetition time (TR) 19.4 ms, echo time (TE) 9.5 ms, field of view (FOV) cm, slice thickness 3 mm with no interslice gap, matrix , 1 excitation (NEX), acquisition time 4 s). The chosen image, in the sagittal plane, was that containing the tip of the thermocouple and fibre/ sheath assembly as identified by its artefact. A 3 cm elliptical region of interest (ROI) was drawn on the template image, centred over the tip of this artefact. The average pixel intensity value (API) in the ROI was measured using the in-built software device. The software settings for the result overlay images were standardised as follows: minimum pixel value 0, maximum 30% of API, window 30% of API, level 15% of API (Software support documentation and personal communication, Erik Penner, GE Medical Systems). At time zero the temperature recorded by the thermocouple, absolute pixel value and colour at the tip of the thermocouple artefact were recorded. The real-time subtraction sequence was then started (FGR, imaging parameters identical to the template scan). A laser lesion was produced using continuous mode power of 5 W for 20 min (total energy deposition 6000 J). Similar recordings of temperature, absolute pixel value and colour at the thermocouple were measured from the overlay images every minute during this time (Fig. 1). If an intermediate colour was present at the thermocouple tip at any given reading, it was

4 Interstitial Laser Thermotherapy and Heat-sensitive Colour Subtraction MRI 253 Fig. 1. RTIP colur subtraction: (a) 22 C; (b) 64 C; (c) 89 C. scale on the image canvas so that later measurements of lesion size corrected for magnification could be made. A total of 20 lesions were produced, four in each liver. The tissue was then examined by a histopathologist blinded to the MR monitoring results. The maximum macroscopic dimension of each burn in the same plane as the MR image was measured three times and the mean calculated. Analysis Fig. 2. Correlation between %API and tissue temperature. recorded as the colour further towards the red end of the spectrum. All procedures were recorded on S-VHS videotape, including the integral measuring The pixel intensity values recorded at the tip of the thermocouple during the burns were expressed as a percentage of the API (%API) to allow standardisation and comparison between lesions. The data were analysed to determine the nature of the relationship between Fig. 3. Individual colours versus temperature (mean+sem). *p<0.001 (Student Neuman Keuls) for all comparisons except between orange and yellow.

5 254 S.W.T. Gould et al. temperature and the change in standardised pixel intensity (%API). Colour and %API were compared to determine whether discrete colours could be assigned significantly di#erent ranges of standardised pixel change values. Temperature and colour measurements were compared to establish whether significantly di#erent temperature ranges could be assigned to each colour. This would allow the individual colours to predict the temperature and hence degree of thermal damage of the imaged tissue. The maximum dimensions of the lesions measured macroscopically were compared with those made from the images to determine whether the colour subtraction sequence could accurately predict tissue necrosis. The videotaped sequences were examined by an observer blinded to the results of the histological measurement. The maximum dimension of the extent of the colour change representing a temperature of greater than 45 C was measured using the internal scale. Each measurement was taken three times and a mean calculated. The two measurements were compared by statistical methods for di#erence and correlation. RESULTS The subtraction software functioned reliably and the full spectrum of colour change from blue to red was seen in each burn. Absolute temperature and %API measured at the tip of the thermocouple artefact were related in a linear fashion (r 2 =0.84, Pearson correlation coe$cient, 95% CI , Fig. 2). The colour and %API at the tip of the thermocouple/fibre assembly were compared by grouping individual %API changes by colour and calculating the mean %API for each group. In this way six discrete colours could be determined (blue, turquoise, green, yellow, orange and red) each having a mean %API significantly di#erent from the others (Table 1). This suggested that the individual colours, standardised using the software settings described above, could be used to predict significantly di#erent temperature ranges. The individual colours and the corresponding temperatures recorded at the tip of the thermocouple/fibre assembly were then compared in a similar manner, grouping the temperature readings for the discrete colours Table 1. Discrete colours and corresponding %API measurements Colour Blue 5.6 (0.46)* Turquoise 12.9 (1.1)* Green 19.7 (1.2)* Yellow 25.8 (0.7)* Orange 30.2 (0.9)* Red 43.1 (0.8)* together and calculating the mean temperature for each. Each mean temperature representing a distinct colour was significantly di#erent from the mean temperature for every other colour (p<0.001, Student Newman Keuls test) except when orange was compared to yellow (p=0.25) (Fig. 3). This probably represents the di$culty occasionally experienced in distinguishing these two colours during scanning. Since biological tissue can be expected to undergo irreversible necrosis above approximately C [10] the green colour (mean temperature C), was used to predict tissue necrosis from the images. There was a close correlation between lesion size predicted from the images in this way and those measured macroscopically by the histologist (Pearson correlation coe$cient r 2 =0.93, 95% CI , Fig. 4). DISCUSSION Mean %API (SEM) *p<0.05 Student Newman Keuls test for multiple comparisons. Magnetic resonance imaging has been shown to be the most sensitive radiological modality for monitoring the e#ects of energy deposition in interstitial thermotherapy. The use of thermal mapping in this way potentially addresses several of the limitations of existing techniques for monitoring this type of therapy. MR imaging can be used to guide the placement of fibres in a real-time, interactive fashion. Previous studies have relied on other radiological modalities such as ultrasound or CT to do this [5,6]. This may result in inaccurate placement of the fibres into the lesion, especially if they are not clearly seen using these other modalities [5] or dislodgement during transfer into the MR scanner. The instrument guidance devices integral to these

6 Interstitial Laser Thermotherapy and Heat-sensitive Colour Subtraction MRI 255 Fig. 4. Correlation between maximum dimensions (Max Dim) measured by histological assessment and predicted from analysis of RTIP image. machines should make this process quicker and more accurate. Interpretation of grey-scale changes on MR images during heat deposition may be di$cult. Due to the ability to alter image window and level parameters at will when the images are viewed, grey-scale levels in MR imaging are essentially arbitrary. This means that no standardised scale is available to determine the degree of signal change that signifies necrosis. No definite absolute temperature values can be given to these varying degrees of signal loss. Also the dependence of signal change generated on heating to tissue T1 times means that grey-scale changes representing a given signal loss in one type of tissue may not signify the same extent of heat deposition in any other tissue. Areas representing reversible heating e#ects may therefore be di$cult to distinguish from those where necrosis will definitely occur. The use of a standardised subtraction technique whereby only the signal change from an original image is measured may allow accurate prediction of the signal loss that represents necrosis, and may be independent of tissue type. The addition of a colour spectrum overlay will help the accurate recognition of areas of given signal loss even further. We have shown it is possible to standardise imaging and software parameters for RTIP and to calibrate individual colours observed with tissue temperature. From this, the colour representing a temperature above which tissue necrosis would be expected to occur can be determined. We have shown that this can be used to accurately predict the area of necrosis measured by histological techniques. Perhaps even more importantly, it will also be possible to monitor important anatomical structures adjacent to the target and halt the energy deposition if the colour change suggests that the structure is reaching a temperature where permanent damage may occur. It is possible to produce predictable lesions in vitro given a certain laser energy deposition [10,13]. However, these lesions are less predictable in the in vivo situation [5,14,15]. It has been suggested that this is due to factors such as the variability of tissue composition (and hence optical and thermal characteristics) and blood flow causing heat sink. This has previously been di$cult to monitor in an interactive fashion. Colour change monitoring by means of RTIP may allow easier visualisation of the thermal energy deposition in temporal and spatial senses allowing truly interactive direction of the therapy. We believe that the use of this technique may increase the accuracy and safety of ILT. It may also be useful to monitor interstitial therapy using other modalities, such as cryotherapy, radiofrequency ablation or focused ultrasound. Preliminary work in these areas has already been performed [21 23]. However, before these goals can be achieved further work is needed and some di$culties overcome. The technique must be validated in di#erent tissues. Also, its function must be studied in tissues that are perfused to mimic blood flow to determine its accuracy in the presence of the heat-sink e#ect. This will also allow calibration of the colour changes starting from a physiological temperature of 37 C. This needs to be followed by an in vivo study to determine whether RTIP can be validated in the presence of physiological peristaltic and respiratory movements. Finally, to be

7 256 S.W.T. Gould et al. clinically useful there is a need to be able to alternate rapidly between at least two imaging planes if accurate monitoring of the complete evolving lesion is to be achieved. CONCLUSION This study has demonstrated that it is possible to standardise the RTIP heat-sensitive software settings to allow comparison between acquisitions. It has also been shown that it is possible to calibrate the colour subtraction sequence with absolute tissue temperature with su$cient accuracy to allow prediction of the extent of tissue necrosis during ILT from the colour change alone. This technique may have enormous potential to increase the e$cacy and safety of image-guided ILT and may allow many of the existing di$culties to be overcome. This method should also be applicable to other modalities of interstitial thermotherapy, such as cryotherapy and focused ultrasound techniques. Despite the present limitations discussed above we believe that RTIP holds great promise for further development of ILT techniques and that this preliminary study represents an important starting point from which further refinement and development may proceed. REFERENCES 1. Bown SG. Phototherapy of tumours. World J Surg 1983;7: Steger AC, Lees WR, Walmsley K, Bown SG. Interstitial laser hyperthermia: a new approach to local destruction of tumours. B M J 1989;299: Harries SA, Amin Z, Smith M et al. Interstitial laser photocoagulation as a treatment for breast cancer. Br J Surg 1994;81: Masters S, Bown S. Interstitial laser hyperthermia. Semin Surg Oncol 1992;8: Mumtaz H, Hall-Craggs M, Wotherspoon A et al. Laser therapy for breast cancer: MR imaging and histological correlation. Radiology 1996;200: Vogl T, Mack M, Scholz W-R, Muller P, Weinhold N et al. MR imaging-guided laser-induced thermotherapy. Minimally Invasive Therapy and Allied Technologies 1996;5: Amin Z, Donald J, Masters A et al. Hepatic metastases: interstitial laser photocoagulation with real-time US monitoring and dynamic CT evaluation of treatment. Radiology 1993;187: Steger A, Lees W, Shorvon P, Walmsley K, Bown SG. Multiple-fibre low-power interstitial laser hyperthermia: studies in the normal liver. Br J Surg 1992; 81: Germer C-T, Ackrecht D, Roggan A, Isbert C, Buhr H. Experimental study of laparoscopic laser-induced thermotherapy for liver tumours. Br J Surg 1997; 84: Jolesz FA, Bleier A, Jakab P, Ruenzel P, Huttl K, Jako G. MR imaging of laser-tissue interactions. Magn Reson Imaging 1988;168: Laméris J, Matheijssen N, van Hillegersber R et al. Development of MR guided interstitial laser coagulation for solid tumours (abstract). Minimally Invasive Therapy and Allied Technologies 1996;5(Supp 1): Roberts H, Paley M, Sams V et al. Magnetic resonance imaging of interstitial laser photocoagulation of normal rat liver: imaging-histopathological correlation. Minimally Invasive Therapy and Allied Technologies 1997;6: Anzai Y, Lufkin R, Hirschowitz S, Farahani K, Castro D. MR imaging-histopathologic correlation of thermal injuries induced with interstitial Nd:YAG laser irradiation in the chronic model. J Magn Reson Imaging 1992;2: Jolesz FA, Matsumoto R, Selig AM, Colucci VM. Interstitial Nd:YAG laser ablation in normal rabbit liver: trial to maximize the size of laser-induced lesions. Lasers Surg Med 1992;12: Matsumoto R, Oshio K, Jolesz F. Monitoring of laser and freezing induced ablation in the liver with T1-weighted MR imaging. J Magn Reson Imaging 1992; 2: Vogl T, Muller P, Hammerstingl R, Weinhold N, Mack M. Malignant liver tumours treated with MR imagingguided laser-induced thermotherapy: technique and prospective results. Radiology 1995;196: Mack MG, Muller P, Vogl TJ et al. Recurrent nasopharyngeal tumors: preliminary clinical results with interventional MR imaging-controlled laser-induced thermotherapy. Radiology 1995;196: Vogl TJ, Mack M, Strank R, Roggan A, Felix R. Percutaneous MRI-guided laser-induced thermotherapy for hepatic metastases for colorectal carcinoma. Lancet 1997;350: Schenk JF, Jolesz FA, Roemer PB, Cline HE. Superconducting open configuration MR imaging system for image-guided therapy. Radiology 1995;195: Gould S, Darzi A. The magnetic resonance operating theatre. Br J Surg 1997;84: Anzai Y, Lufkin R, DeSalles A et al. Radiofrequency ablation of brain tumours using MR guidance. Minimally Invasive Therapy and Allied Technologies 1996; 5: Anzai Y, Lufkin R, DeSalles A, Hamilton DR, Farahani K, Black KL. Preliminary experience with MR-guided thermal ablation of brain tumours. Am J Neuroradiol 1995;16;1: Cline HE, Hynynen K, Watkins RD, Adams BS, Schenck JF, Ettinger RH. Focused US System For MR Imaging-guided Tumor Ablation. Magn Reson Imaging 1995;194: Paper received 16 September 1997; accepted after revision 18 March 1999.