Goldberg Sn

Combination radiofrequency thermal ablation and adjuvant IV liposomal doxorubicin increases tissue coagulation and intratumoural drug accumulation.

There has been marked interest in minimally-invasive, image-guided radiofrequency (RF) tumour ablation (i.e. coagulating tumour using short duration heating (<15 min) by directly applying temperatures >50°C via needle electrodes) to treat focal liver, renal, breast, bone and lung tumours. In spite of advances in RF technology and improved understanding of tumour biophysiology that now enable experimental treatment of tumours up to 5 cm, investigators have been unable to achieve complete ablation in many cases, particularly at the tumour margins and adjacent to blood vessels. One strategy for overcoming these limitations has been to take advantage of complementary interactions between RF thermal ablation and chemotherapy, particularly liposomal doxorubicin preparations, to attempt more complete tumour destruction. This paper will review published laboratory investigations demonstrating that this combined treatment paradigm has the unique potential both to potentiate preferential delivery of cytotoxic agents in liposome vehicles and to maximize the completeness of ablation of a treated tumour. New confirmatory data describing increased tumour destruction with RF ablation combined with different liposome preparations, documenting increased lipid peroxidation and expanding on previously published tumour growth studies is presented. Additionally, early clinical data including a randomized, pilot clinical study on 10 patients with primary and metastatic liver tumours, in which a non-optimized combination of RF ablation and IV liposomal doxorubicin (Doxil) increased the volume of tumour destruction 25–30% compared to RF alone, will also be described in detail.

Introduction: thermal ablation therapy.

The diseases which medicines cannot cure, excision cures: those which excision cannot cure, are cured by the cautery; but those which the cautery cannot cure, may be deemed incurable (Hippocrates Aphorisms, 400 BCE).

Computer modeling of the effect of perfusion on heating patterns in radiofrequency tumor ablation

Purpose: To use an established computer simulation model of radiofrequency (RF) ablation to further characterize the effect of varied perfusion on RF heating for commonly used RF durations and electrode types, and different tumor sizes. Methods: Computer simulation of RF heating using 2-D and 3-D finite element analysis (Etherm) was performed. Simulated RF application was systematically modeled on clinically relevant application parameters for a range of inner tumor perfusion (0–5 kg/m3-s) and outer normal surrounding tissue perfusion (0–5 kg/m3-s) for internally cooled 3-cm single and 2.5-cm cluster electrodes over a range of tumor diameters (2–5 cm), and RF application times (5–60 min; n = 4618 simulations). Tissue heating patterns and the time required to heat the entire tumor ± a 5-mm margin to >50°C were assessed. Three-dimensional surface response contours were generated, and linear and higher order curve-fitting was performed. Results: For both electrodes, increasing overall tissue perfusion exponentially decreased the overall distance of the 50°C isotherm (R2 = 0.94). Simultaneously, increasing overall perfusion exponentially decreased the time required to achieve thermal equilibrium (R2 = 0.94). Furthermore, the relative effect of inner and outer perfusion varied with increasing tumor size. For smaller tumors (2 cm diameter, 3-cm single; 2–3 cm diameter, cluster), the ability and time to achieve tumor ablation was largely determined by the outer tissue perfusion value. However, for larger tumors (4–5 cm diameter single; 5 cm diameter cluster), inner tumor perfusion had the predominant effect. Conclusion: Computer modeling demonstrates that perfusion reduces both RF coagulation and the time to achieve thermal equilibrium. These results further show the importance of considering not only tumor perfusion, but also size (in addition to background tissue perfusion) when attempting to predict the effect of perfusion on RF heating and ablation times.

Radiofrequency Ablation: Inflammatory Changes in the Periablative Zone Can Induce Global Organ Effects, including Liver Regeneration

PURPOSE To determine the kinetics of innate immune and hepatic response to the coagulation necrosis area that remains in situ after radiofrequency (RF) ablation, the cytokine profile of this response, and its local and global effect on the whole organ in a small-animal model. MATERIALS AND METHODS A standardized RF ablation dose (70°C for 5 minutes) was used to ablate more than 7% of the liver in 91 C57BL6 mice (wild type) according to a protocol approved by the animal care committee. The dynamic cellular response in the border zone surrounding ablation-induced coagulation and in the ablated lobe and an untreated lobe were characterized with immunohistochemistry 24 hours, 72 hours, 7 days, and 14 days after ablation (the time points at which cells migrate to necrotic tissues). After characterization of the cellular populations that reacted to the RF treatment, cytokines secreted by these cells were blocked, either by using interleukin-6 knockout mice (n = 24) or c-met inhibitor PHA 665752 (n = 15), to elucidate the key factors facilitating the wound healing response to RF ablation. Statistical significance was assessed with nonparametric analysis of variance. RESULTS RF ablation induces a strong time-dependent immunologic response at the perimeter of the necrotic zone. This includes massive accumulation of neutrophils, activated myofibroblasts, and macrophages peaking at 24 hours, 7 days, and 14 days after ablation, respectively. In correlation with myofibroblast accumulation, RF ablation induced hepatocyte proliferation in both the ablated lobe and an untreated lobe (mean, 165.15 and 230.4 cyclin-dependent kinase 47-positive cells per ×20 field, respectively, at day 7; P < .02). Blockade of either IL-6 or c-met significantly reduced global hepatocyte proliferation (P < .05 for both), with the former reducing the accumulation of both macrophages and myofibroblasts surrounding the coagulation necrosis area (42.9 and 113.6 vs 7.3 and 46.6 macrophages and activated myofibroblasts per ×20 field, respectively; P < .036 for both). CONCLUSION Hepatic RF ablation induces not only a local periablational inflammatory zone but also more global proliferative effects on the liver. These IL-6- and/or c-met-mediated changes could potentially account for some of the local and distant tumor recurrence observed after treatment.

Hepatic Radiofrequency Ablation-induced Stimulation of Distant Tumor Growth Is Suppressed by c-Met Inhibition

PURPOSE To elucidate how hepatic radiofrequency (RF) ablation affects distant extrahepatic tumor growth by means of two key molecular pathways. MATERIALS AND METHODS Rats were used in this institutional animal care and use committee-approved study. First, the effect of hepatic RF ablation on distant subcutaneous in situ R3230 and MATBIII breast tumors was evaluated. Animals were randomly assigned to standardized RF ablation, sham procedure, or no treatment. Tumor growth rate was measured for 3½ to 7 days. Then, tissue was harvested for Ki-67 proliferative indexes and CD34 microvascular density. Second, hepatic RF ablation was performed for hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and c-Met receptor expression measurement in periablational rim, serum, and distant tumor 24 hours to 7 days after ablation. Third, hepatic RF ablation was combined with either a c-Met inhibitor (PHA-665752) or VEGF receptor inhibitor (semaxanib) and compared with sham or drug alone arms to assess distant tumor growth and growth factor levels. Finally, hepatic RF ablation was performed in rats with c-Met-negative R3230 tumors for comparison with the native c-Met-positive line. Tumor size and immunohistochemical quantification at day 0 and at sacrifice were compared with analysis of variance and the two-tailed Student t test. Tumor growth curves before and after treatment were analyzed with linear regression analysis to determine mean slopes of pre- and posttreatment growth curves on a per-tumor basis and were compared with analysis of variance and paired two-tailed t tests. RESULTS After RF ablation of normal liver, distant R3230 tumors were substantially larger at 7 days compared with tumors treated with the sham procedure and untreated tumors, with higher growth rates and tumor cell proliferation. Similar findings were observed in MATBIII tumors. Hepatic RF ablation predominantly increased periablational and serum HGF and downstream distant tumor VEGF levels. Compared with RF ablation alone, RF ablation combined with adjuvant PHA-665752 or semaxanib reduced distant tumor growth, proliferation, and microvascular density. For c-Met-negative tumors, hepatic RF ablation did not increase distant tumor growth, proliferation, or microvascular density compared with sham treatment. CONCLUSION RF ablation of normal liver can stimulate distant subcutaneous tumor growth mediated by HGF/c-Met pathway and VEGF activation. This effect was not observed in c-Met-negative tumors and can be blocked with adjuvant c-Met and VEGF inhibitors.

Non-invasive temperature monitoring and hyperthermic injury onset detection using X-ray CT during HIFU thermal treatment in ex vivo fatty tissue.

Abstract Purpose: This paper examines X-ray CT, to serve as an image-guiding thermal monitoring modality for high intensity focused ultrasound (HIFU) treatment of fatty tissues. Materials and methods: Six ex vivo porcine fat tissue specimens were scanned by X-ray CT simultaneously with the application of HIFU. Images were acquired during both heating and post-ablation stages. The temperature at the focal zone was measured simultaneously using a thermocouple. The mean values of the Hounsfield units (HU) at the focal zone were registered and plotted as a function of temperature. Results: In all specimens studied, the HU versus temperature curves measured during the heating stage depicted a characteristic non-linear parabolic trajectory (R2 > 0.87). The HU-temperature trajectory initially decreased to a minimum value at about 44.5 °C and then increased substantially as the heating progressed. The occurrence of this nadir point during the heating stage was clearly detectable. During post-ablation cooling, on the other hand, the HU increased monotonically with the decreasing temperature and depicted a clearly linear trajectory (R2 ≥ 0.9). Conclusions: Our results demonstrate that the HU-temperature curve during HIFU treatment has a characteristic parabolic trajectory for fat tissue that might potentially be utilised for thermal monitoring during HIFU ablation treatments. The clear detection of 44.5 °C, presumably marking the onset of hyperthermic injury, can be detected non-invasively as an occurrence of a minimum on the HU-time curve without any need to relate the HU directly to temperature. Such features may be helpful in monitoring and optimising HIFU thermal treatment for clinically applicable indications such as in the breast by providing a non-invasive monitoring of tissue damage.

Clinical application of hepatic wedge ablation for treating liver malignancies of the inferior margin: a new ablation technique

Abstract Purpose: To determine the efficacy and safety of percutaneous hepatic wedge ablation in treating hepatic malignancies of the inferior margin. Materials and methods: Seventy-seven patients with hepatic malignancies at the inferior margin underwent percutaneous radiofrequency ablation (RFA). Thirty-two patients underwent hepatic wedge ablation and 45 patients underwent conventional tumour ablation. Comparative analysis of the two groups was performed including gender, age, tumour size, number of ablation cycles, ablation duration and injected hydrodissection volume. The rate of technical success, local tumour progression, intrahepatic distant recurrence, major complications and overall survival were assessed and compared. Survival analysis was analysed using the Kaplan–Meier method. Differences in the survival rates were compared with log-rank test. Results: The mean number of ablation cycles and ablation duration were significantly higher in the hepatic wedge ablation group than conventional tumour ablation (1.6 ± 0.9 vs. 1.2 ± 0.4, p = .042, and 30.2 ± 18.5 vs. 22.5 ± 8.5 min, p = .031, respectively). The local tumour progression rate was significantly lower in hepatic wedge ablation group (0% vs. 17.78%, p = .038) at median follow-up of 21 months. The rate of technical success, intrahepatic distant recurrence, major complications and overall survival did not differ between the two groups. Conclusion: Hepatic wedge ablation appears to be a highly effective treatment for hepatic malignancies in the inferior margin and provides a better local control than conventional tumour ablation.