Interstitial laser thermotherapy (ILT) of breast cancer.

AIM: To find out if ILT can be used as radical treatment of breast cancer. METHOD: Twenty-four patients, aged 39-84 (mean 61), with invasive breast cancer were treated with ILT. All underwent mammography, ultrasound and core biopsy before treatment. The tumour was an invasive ductal carcinoma in 15 patients, a lobular carcinoma in eight and lobular-ductal cancer in one. Average tumour diameter was 14 mm on ultrasound (5-35). Patients were treated in the outpatient clinics under local anaesthesia. Probes were placed under ultrasound guidance, in 19 patients, and ILT was performed with a diode laser at a steady-state temperature of 48 degrees C for 30 min using temperature feedback control. Standard surgical excision was performed 12 (4-23) days after ILT and was preceded by Doppler ultrasound. RESULTS: Treatment-induced necrosis of invasive cancer was 33% (range 0-100) and was complete in three patients. At follow-up before surgery, the extent of laser damage could not be judged with ultrasound, although abolished tumour blood flow was demonstrated after treatment resulting in large necroses. Efficacy of treatment varied negatively with tumour size. The inefficacy of ILT was mainly due to the underestimation of tumour size by mammography and ultrasound and the shortcomings of these methods to demonstrate tumour borders, tumour irregularity and carcinoma in situ (CIS). ILT was well tolerated. Five patients had breast tenderness, and three patients had pain, during the first day after treatment. Small skin necroses were observed in two patients. CONCLUSION: Small breast cancers can be treated radically with ILT. The method may become useful in the treatment of breast cancer but needs further refinement, even for small well-defined breast cancers, if it is going to be employed for radical treatment.

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response.

Previous studies in our laboratory have shown that interstitial laser thermotherapy (ILT) of an experimental liver tumour is superior to surgical excision, at least partly due to a laser-induced immunological effect. The aim of the present study was to investigate the time-response relationship of the ILT-induced immunisation and the cellular response of macrophages and lymphocytes. A dimethylhydrazine-induced adenocarcinoma was transplanted into the liver of syngeneic rats. Rats with tumour were treated 6-8 days later (tumour size 0.25-0.40 cm(3)) with ILT of tumour or resection of the tumour-bearing lobe. Two groups of rats without tumour were treated with resection of a normal liver lobe or ILT of normal liver. A challenging tumour was implanted into the liver of each rat 2, 5 or 10 weeks after primary treatment. Rats were killed 6, 12 and 48 days (or earlier due to their condition) after challenge (n = 8 in all groups). Immunohistochemical techniques were used to determine lymphocytes (CD8, CD4) and macrophages (ED1, ED2) in rats having had treatment of a primary tumour. Interstitial laser thermotherapy of the first tumour was followed by eradication of challenging tumour and absence of tumour spread. This contrasted with rapid growth and spread of challenging tumour in the other groups. In the challenging vital tumour tissue and in the interface between the tumour and surroundings, the number of ED1 macrophages and CD8 lymphocytes was higher in rats having been treated with the ILT of tumour than in those having undergone resection of the tumour-bearing lobe. The number of ED2 macrophages and CD4 lymphocytes was low and did not vary between these two groups. Interstitial laser thermotherapy elicited an immune response that eradicated a challenging tumour and was associated with increased numbers of tumour-infiltrating macrophages and CD8 lymphocytes.

Percutaneous ablation of liver tumours.

The goal of local ablation treatment of hepatic disease is to prolong survival for patients with unresectable tumours. Presently, influence on survival is difficult to estimate because of the heterogeneity of indications and treatments and short follow-up. This chapter therefore focuses on potential benefits and limitations, complications and solutions for improvement. The main problems with in situ ablation are the lack of good imaging techniques to determine the extent of disease and the lack of a method for real-time monitoring of irreversible tissue effect. With one exception, there are no prospective, randomized studies comparing local destruction methods. It appears that percutaneous ethanol injection and cryotherapy should be replaced by radiofrequency ablation (RFA) or interstitial laser thermotherapy (ILT) and that there is little difference in outcome between RFA and ILT. Intraoperative RFA or ILT is valuable as an adjunct to hepatic resection in order to increase the rate of resectability. The percutaneous approach needs further development. It might be valuable in a few truly unresectable or inoperable patients or in selected patients with neuroendocrine liver metastases. In the large majority of unresectable patients it should, however, presently be used and evaluated only in prospective, randomized studies.

Interstitial laser thermotherapy of a rat liver adenocarcinoma.

The aim of this study was to compare interstitial laser thermotherapy with excision of a liver tumour. A dimethylhydrazine-induced adenocarcinoma was implanted into the left lateral lobe of the rat liver, and treatment was performed 8 days later. Rats were treated with resection of the tumour-bearing lobe or underwent interstitial laser thermotherapy, which was performed at a steady-state temperature of 46°C for 30 min, 3 mm from the tumour margin. The incidence and extent of intraperitoneal spread was smaller after laser thermotherapy than after resection, with no difference in local control. Using inoculation of tumour cell suspensions into the lateral and the median lobes of the liver simultaneously and treating the lateral lobe tumour only, we found that laser thermotherapy reduced take and growth of the untreated tumour in the median lobe indicating that laser thermotherapy may induce immunologic effects. It is concluded that interstitial laser thermotherapy reduces spread of liver tumour as compared to resection. It is suggested that this can be at least partly explained by a laser-induced immunologic effect.

Electrically mediated drug delivery for treatment of an adenocarcinoma transplanted into rat liver.

BACKGROUND: In this study, electrochemotherapy (ECT), i.e. tumour treatment based on local augmentation of intracellular drug delivery from short, intense electric pulses, was evaluated in rats with an adenocarcinoma implanted into the liver. Tumour response and concentrations of macrophages and T-lymphocytes (CD4 and CD8) in and around the tumour were measured. MATERIALS AND METHODS: Rats were treated with permeabilizing electric pulses, bleomycin, or both, eight days after implantation of the tumour, while one group received sham treatment. RESULTS: Treatment with electric pulses and bleomycin resulted in a significantly reduced lesion volume and 92% cure rate (12 out of 13, p<0.0002 compared to the other treatment groups). The highest concentration of CD8 lymphocytes was found in tumours treated with electric pulses and bleomycin. Macrophages were found mainly in tumours treated with electric pulses, with or without bleomycin. CONCLUSION: Electrochemotherapy using millisecond exponential pulses and bleomycin is efficient in a rat liver tumour model and appears to stimulate the host's immune system.

Simplified treatment planning for interstitial laser thermotherapy by disregarding light transport: a numerical study.

BACKGROUND AND OBJECTIVE: The objective was to investigate the effect of light transport on the temperature distribution and the coagulated volume under conditions relevant to interstitial laser thermotherapy (ILT) of tumors in the human liver. STUDY DESIGN/MATERIALS AND METHODS: Temperature distributions and coagulated volumes produced with a diffusing laser fiber or a conductive heat source, at equal output power, were numerically calculated for tissue with different optical penetration depths. Four irradiation times (5, 10, 20, and 30 min) were studied. A three-dimensional finite-element model was used to calculate the temperature distribution during heating with four conductive heat sources (no light emission). Results were compared with measured temperature distributions during laser irradiation in a gel phantom with known optical properties. RESULTS: Numerical calculations showed that the influence of light transport on the coagulated volume was negligible in tissue with optical penetration depths below 3-4 mm at all studied irradiation times. The phantom experiment indicated good agreement with the calculated temperature distribution, both with a single diffusing laser fiber and with four fibers. CONCLUSION: Light transport influences coagulated volumes only slightly under conditions presented in this work, which is relevant to ILT of tumors in the human liver.

Changes in local hepatic blood perfusion during interstitial laser-induced thermotherapy of normal rat liver measured by interstitial laser Doppler flowmetry.

Interstitial laser Doppler flowmetry was used to measure the effect of interstitial laser-induced thermotherapy on local blood perfusion in normal rat liver in the peripheral treatment region elevated to hyperthermic temperatures. The Nd:YAG laser emitting at 1064 nm was utilised as heat generation source. The plane-cut tip of an optical fibre was placed in the middle of the exteriorised left liver lobe. Blood perfusion and temperature were measured in the liver parenchyma 4 mm from the laser fibre. The temperature at the location of the liver temperature sensor was maintained at 41 or 44°C during 30 min by regulating the power of the heating laser. The laser Doppler signal was recorded during and after heat treatment, for a total time of 60 min. At 41°C, a significant increase in perfusion up to 1.3 times the initial value was observed 2-16 min after start of treatment. At 44°C, perfusion decreased continuously during and after treatment, and was significantly different from control 40 min after start of treatment. The results may be valuable in assessing the thermal response of tissues surrounding the target in interstitial laser-induced thermotherapy of liver tumours during conditions of normal blood flow.

MRI thermometry in phantoms by use of the proton resonance frequency shift method: application to interstitial laser thermotherapy.

In this work the temperature dependence of the proton resonance frequency was assessed in agarose gel with a high melting temperature (95 degrees C) and in porcine liver in vitro at temperatures relevant to thermotherapy (25-80 degrees C). Furthermore, an optically tissue-like agarose gel phantom was developed and evaluated for use in MRI. The phantom was used to visualize temperature distributions from a diffusing laser fibre by means of the proton resonance frequency shift method. An approximately linear relationship (0.0085 ppm degrees C(-1)) between proton resonance frequency shift and temperature change was found for agarose gel, whereas deviations from a linear relationship were observed for porcine liver. The optically tissue-like agarose gel allowed reliable MRI temperature monitoring, and the MR relaxation times (T1 and T2) and the optical properties were found to be independently alterable. Temperature distributions around a diffusing laser fibre, during irradiation and subsequent cooling, were assessed with high spatial resolution (voxel size = 4.3 mm3) and with random uncertainties ranging from 0.3 degrees C to 1.4 degrees C (1 SD) with a 40 s scan time.

Comparison between interstitial laser thermotherapy and excision of an adenocarcinoma transplanted into rat liver.

The aim of this study was to compare interstitial laser thermotherapy with excision of a liver tumour. A dimethylhydrazine-induced adenocarcinoma was transplanted (implanted if not stated otherwise) into the left lateral lobe of the rat liver, and treatment was performed 8 days later. In the main experiment, rats were treated with resection of the tumour-bearing lobe or underwent interstitial laser thermotherapy, which was performed at a steady-state temperature of 46 degrees C for 30 min, 3 mm from the tumour margin. The incidence and extent of intraperitoneal spread was smaller after laser thermotherapy than after resection of the tumour-bearing lobe, with no difference in local control. Metastatic spread after resection of the median liver lobe was similar to that observed after sham procedures for thermotherapy or resection, suggesting that the advantage of thermotherapy was not due to a difference in surgical trauma. Additional studies showed that laser thermotherapy reduced intraperitoneal spread when treatment was suboptimal or in a tumour inoculation model and suggested that immunological mechanisms might be involved. It is concluded that interstitial laser thermotherapy reduces spread of liver tumour compared with resection.

Feedback interstitial diode laser (805 nm) thermotherapy system: ex vivo evaluation and mathematical modeling with one and four-fibers.

BACKGROUND AND OBJECTIVE: In this study a newly developed microprocessor controlled power regulation and thermometry system integrated with a diode laser (805 nm wavelength) was evaluated with respect to temperature distribution, effectiveness of regulation, and ability to predict temperature distributions by computer simulation. STUDY DESIGN/MATERIALS AND METHODS: Experiments were performed in ground bovine muscle using either a single laser fiber or four-fibers. The target temperature at one (feedback) thermistor, placed 5 mm from one of the laser fibers, was set to 50 degrees C and was maintained by means of stepwise power regulation. The temperature distribution was monitored using multiple thermistor probes. A numerical model based on the bioheat equation was used to calculate the temperature distributions. RESULTS: Temperature regulation was excellent with a tendency towards better regulation in the four-fiber than in the single-fiber experiments. Agreement between calculated and measured temperatures was good. The coagulated (> 55 degrees C) and hyperthermic (> 45 degrees C) volumes were 6 and 10-11 times larger, respectively, with four-fibers than with a single fiber. CONCLUSION: It is concluded that the stepwise power regulation system was efficient in maintaining a stable target temperature. The results indicate that the system can produce lesion volumes adequate for treating a relatively large tumor in a single session and that computer simulation may be useful for predicting temperature distribution.

Interstitial laser thermotherapy of adenocarcinoma transplanted into rat liver.

OBJECTIVE: To examine the effect of different temperatures and exposure times in interstitial laser thermotherapy. DESIGN: Controlled laboratory study. SETTING: University hospital, Sweden. MATERIAL: 48 male Wistar FU rats with dimethylhydrazine-induced adenocarcinoma transplanted into the liver. INTERVENTION: Treatment was given with an Nd:YAG laser and a feedback system for temperature regulation. Light was delivered into the centre of the tumour and the feedback thermistor probe was placed 3 mm from the tumour margin. Rats were treated at steady-state temperatures at the feedback thermistor of 43, 46, or 50 degrees C for 30 minutes, and at a steady-state temperature of 46 degrees C at the feedback thermistor also for 10 and 20 minutes. MAIN OUTCOME MEASUREMENT: Tumour control as assessed 6 days after treatment using light microscopical examination including immunohistochemical determination of bromodeoxyuridine (BrdU) incorporation into DNA as a measure of cell viability. RESULTS: Complete tumour necrosis was achieved in all rats treated for 30 minutes, in 6/8 rats treated for 10 minutes and in 6/8 rats treated for 20 minutes at 46 degrees C. During steady-state thermotherapy, temperatures at the tumour margin were about 11 degrees higher than at the feedback thermistor (range 54-61 degrees C). The surrounding liver tissue also became necrotic so that the total necrosis volume exceeded the pretreatment tumour volume. CONCLUSION: Interstitial laser thermotherapy at temperatures ranging from 54-61 degrees C at the tumour margin ensures total necrosis of a transplanted rat liver carcinoma provided that treatment is given for 30 minutes.

Interstitial laser thermotherapy in pig liver: effect of inflow occlusion on extent of necrosis and ultrasound image.

BACKGROUND/AIMS: The aim was to investigate the effect of blood inflow occlusion on lesion size and ultrasonographic findings during interstitial laser thermotherapy of normal liver. METHODOLOGY: Pigs were treated with or without hepatic inflow occlusion at a laser power of 3W or without inflow occlusion at 5 W (target temperature 43 degrees C). The thermotherapy system consisted of an Nd:YAG laser and a temperature feedback circuit. Ultrasonography was performed immediately after treatment. Lesion size was determined using light microscopy including immunohistochemistry with bromodeoxyuridine. RESULTS: Hyperechoic ultrasonographic changes were observed after treatment with inflow occlusion or when there was carbonization. If carbonization did not occur, unoccluded blood flow was associated with hypoechoic lesions. Following inflow occlusion, maximum lesion width 2 and 6 days after thermotherapy averaged 21.9 +/- 1.3 and 20.2 +/- 0.8 (means +/- SEM) mm, respectively. This was larger than the corresponding values of 10.8 +/- 0.8 and 11.1 +/- 2.0 observed after treatment without inflow occlusion at 3W (p < 0.01). Increase in laser power from 3 to 5W in experiments without inflow occlusion produced early carbonization and a slight increase in lesion size that did not match that produced by inflow occlusion. Ultrasound gave a correct prediction of necrosis size after treatment with inflow occlusion but overestimated the necrosis when inflow occlusion was not used. Ultrasound was furthermore unable to predict size of necrosis in individual experiments. CONCLUSION: Blood flow has a major influence on lesion size in interstitial laser thermotherapy of the liver and affects ultrasonographic images. Also, it appears that intraoperative ultrasonography cannot monitor lesion size with an accuracy that is sufficient for clinical use.

Temperature control and light penetration in a feedback interstitial laser thermotherapy system.

The aim of this study was to describe the performance of a closed loop interstitial laser thermotherapy system in processed liver and to demonstrate its suitability for treating a vascularized tumour in vivo. The thermotherapy system consisted of an Nd: YAG laser and a temperature feedback circuit including an automatic thermometry system and thermistor probes. Experiments in processed liver were performed with a sapphire probe and temperature control at a distance of 10 mm. In most experiments at 1-2 W, and in half of the experiments at 3 W, there was no carbonization, a moderate change in the light penetration and excellent control of the temperature. In experiments with output powers of 4-5 W there was carbonization with rapid deterioration of light penetration and impaired control of the temperature. Carbonization affected the distribution of temperatures, which were lower below, and higher above, the laser tip in experiments with carbonization as compared to experiments without carbonization. Treatment of an adenocarcinoma implanted into rat liver was performed at 2 W with a bare fibre and without blood inflow occlusion. The feedback thermistor probe was placed 3 mm outside the margin of the tumour (largest diameter 9.5 +/- 0.3 mm (mean +/- SEM)). Temperature control and light penetration characteristics were similar to those found in vitro. No tumour could be demonstrated at sacrifice 6 days later. It is concluded that a closed loop feedback system can produce stable and reproducible local hyperthermia, that it performs better when carbonization is avoided and light penetration is preserved and that it has a great potential for interstitial thermotherapy of malignant tumours.