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NEW APPROACHES TO THE TREATMENT OF HEPATIC MALIGNANCIES |
From The G. Pascale National Cancer Institute, Naples, Italy.
Correspondence: Address correspondence and reprint requests to: Francesco Izzo, MD, Via A Manzoni #52, Naples 80122, Italy; Fax: 39-081-5903-843; E-mail: izzo{at}connect.it
ABSTRACT
Background: Thermal ablation of hepatic malignancies is becoming a widespread treatment approach. In addition to radiofrequency ablation, microwave coagulation (MCT) and laser-induced interstitial thermotherapy (LITT) are being used clinically to treat patients with liver cancers.
Methods: The principles and clinical indications for MCT and LITT are described. Treatment approaches and results from published clinical studies are reviewed. The evolution of these thermal treatment modalities and limitations of currently available equipment is provided.
Results: The interstitial probes and equipment used for MCT and LITT for liver tumors are undergoing changes to improve treatment efficacy. Both MCT and LITT have been limited by the relatively small zone of coagulation produced with a single probe placement. Both techniques can be performed safely, and local recurrence and long-term survival rates are being established.
Conclusions: MCT and LITT are two alternative thermal ablation techniques being used to treat patients with primary and metastatic hepatic malignancies. The utility of these two treatments has been limited by the relatively small area of thermal necrosis produced around the interstitial probes, but design modifications and new equipment may improve these limitations.
Key Words: Microwave • Laser therapy • Liver cancer—Thermal ablation
MICROWAVE COAGULATION THERAPY FOR HEPATIC TUMORS
Background and Principles of Microwave Coagulation Therapy
Microwave coagulation was initially developed in the early 1980s to achieve hemostasis along the plane of transection during hepatic resection.1 Microwave coagulation of tissue surfaces was slower than electrocautery units and produced deeper areas of tissue necrosis. Although microwave coagulation has not been useful during hepatic resection, the extended area of tissue necrosis led to investigation of the use of microwave coagulation therapy (MCT) to treat unresectable hepatic malignancies.
The microwave generators developed for MCT produce microwaves with a frequency of 2450 MHz and a wavelength of 12 cm.2 Biologically, microwaves applied to living tissues produce dielectric heat by stimulation of water molecules within the tissue and cells. The rapid agitation of water molecules within cells and tissues with direct application of microwaves produces rapid frictional heating and coagulative necrosis. The microwave generators available for clinical use have an output of 70–90 watts. The microwave-emitting needle (14–22 gauge) is placed directly into the hepatic tumor to be treated, usually using ultrasonographic guidance. The microwave-emitting needle is attached to the microwave generator, the generator is activated, and each area of the tumor is treated for 30–60 seconds at 70–90 watts of power. The rapid generation of heat using MCT produces 10- to 25-mm zones of coagulative necrosis after only 30–60 seconds. The lesions can range from spherical to elliptical in shape. The rapid development of coagulative necrosis within the tissue around the MCT needle produces a tissue coagulum that inhibits further dissipation of heat into the tissue.
The small areas of coagulation produced by MCT require that the needle be advanced at 5- to 10-mm intervals throughout the area to be treated. For tumors larger than 2 cm in diameter, multiple MCT needle placements are required to produce overlapping zones of coagulative necrosis in the tumor and in a surrounding rim of hepatic parenchyma. Like radiofrequency ablation (RFA) and laser-induced interstitial thermotherapy (LITT), MCT can be performed percutaneously using ultrasound or computed tomography (CT) guidance for needle placement, or can be performed laparoscopically or during an open surgical procedure using intraoperative ultrasound guidance to place the MCT needle.
Results of MCT for Malignant Hepatic Tumors
The overwhelming majority of reports describing MCT to treat hepatic malignancies come from Japan, where this technique was first used in 1988. MCT has been used principally to treat cirrhotic hepatocellular carcinoma (HCC) patients. Most of the patients treated with MCT, even those with a solitary <3-cm tumor, were not candidates for resection because of the severity of their cirrhosis. A study of 19 patients with unresectable HCC reported that MCT was performed during laparotomy in 12, laparoscopically in 5, or using a thoracotomy approach in 2 patients with tumors at the dome of the liver.3 A solitary HCC tumor was treated in 13 patients, whereas the remaining 6 patients had between 2 and 5 HCC tumors treated with MCT. MCT was performed to palliate symptoms from a large tumor in 6 of the 19 patients who had additional intrahepatic or extrahepatic metastases. The mean size of the tumors treated with MCT was 21 mm (range, 5–90 mm) and the mean duration of operation was 4.7 hours (range, 1.8–7.0 hours). The reproducible and reliable zone of complete coagulative necrosis around the MCT needle electrode is only 10 mm, thus, the mean number of electrode insertions to treat the HCC tumors was 46 (range, 10–135). The authors report that the follow-up in these patients ranged from 4 to 64 months; there were 2 patients treated with curative intent who were alive 47 and 64 months, respectively, after MCT with no evidence of recurrent or new metastatic HCC. In the entire group of 19 patients, 6 had died of recurrent HCC or progressive liver failure, 10 were alive without radiographic evidence of recurrent HCC, and 3 were alive with evidence of new HCC metastases.3 The authors reported that there was no evidence of local recurrence in 28 of the 31 nodules (90.3%) treated with MCT. However, it is difficult to assess the true local recurrence rate because most of the patients were treated with hepatic arterial chemoembolization after MCT.
Small HCC nodules not visible on transcutaneous ultrasonography can be treated with percutaneous MCT using CT guidance.4 This technique is generally useful for tumors 30 mm in diameter or less. The requirement that the MCT needle be placed at multiple intervals within the tumor makes treatment of large lesions with percutaneous MCT problematic.
A recent report evaluated the risk factors for distant recurrence of HCC after treatment with MCT or RFA.5 A total of 92 patients with HCC tumors <3 cm in diameter were treated with MCT (68 patients) or RFA (16 patients). All patients were treated percutaneously or laparoscopically. This was a nonrandomized study so MCT or RFA was selected as a treatment option based on the preference of the treating surgeon. Eighty-four patients were followed for 12–44 months after treatment (median follow-up 22 months); the remaining 8 patients died before 12 months because of hepatic failure (5 patients), HCC progression (2 patients), or pneumonia (1 patient). In the 84 assessable patients, the 1-year survival rate was 99% and the 3-year survival rate was 78%. During follow-up distant recurrence of HCC was observed in 22 patients (26.1%). There is no comment on local recurrence rates after MCT or RFA in any of these patients. The only variables that were found to be significant in predicting a higher risk for the development of distant metastatic HCC after MCT or RFA was the treatment of more than one HCC nodule with MCT or RFA, or the presence of chronic hepatitis C virus infection as the underlying etiology of chronic liver disease.5
There is a striking paucity of data on local recurrence rates and complications following MCT to treat HCC or other malignant liver tumors. The production of very small zones of coagulative necrosis by the intratumoral microwave-emitting needle electrode necessitates moving the needle at 5- to 10-mm intervals within the tumor and the surrounding parenchyma to create multiple overlapping zones of coagulative necrosis. Some authors do mention that MCT should not be performed near the hepatic hilum where major bile ducts and blood vessels are located or near any major hepatic blood vessels, suggesting that there is experience with vascular and biliary complications related to treatment of tumors in these locations. It is unlikely that MCT will be widely applied to treat patients with unresectable malignant hepatic tumors unless modifications in equipment and treatment algorithms occur to produce larger zones of coagulative necrosis around the MCT needle. MCT may yet have a role during hepatic resection of malignant tumors as it has been demonstrated in an experimental model to produce a wider tumor-free margin following resection.6 This finding has not been confirmed in human trials.
INTERSTITIAL LASER HYPERTHERMIC ABLATION
Direct thermal destruction of hepatic tumors using laser energy is known by several acronyms: laser thermal ablation (LTA), interstitial laser thermotherapy (ILT), interstitial laser photocoagulation (ILP), and LITT. These acronyms and phrases all describe the same type of thermal treatment, and because LITT is the most common acronym that appears in the medical literature, it will be used through the remainder of this section.
Background and Principles of LITT
As described by the name of this thermal treatment modality, LITT requires placement of a laser fiber or fibers directly into the tumor or tissue to be treated. Thus, LITT is a type of contact mode laser therapy. Although the mechanism of action is different than RFA, LITT produces lethal thermal injury to tumor cells in an identical fashion. Prolonged heating of tumor cells to 45–55°C leads to cell death, whereas short exposure of cells to temperatures that exceed 60°C causes irreversible cell damage and death from protein denaturation, inhibition of protein synthesis, breaking of chemical bonds in DNA and RNA molecules, and loss of integrity in lipid bilayers. Application of LITT at low powers produces a progressively enlarging zone of radiant and conductive tissue heating around the laser fiber or fibers. Irreversible cytotoxic effects develop in cells that are heated above 55–60°C.
LITT produces local tissue heating when photons from low-intensity laser energy interact with molecular chromophores that are inherent to all mammalian cells. Photochemical effects may be accentuated by the exogenous administration of photosensitizing agents like photofrin, but the presence of natural cellular chromophores is sufficient to produce exothermic photochemical reactions. Naturally occurring chromophores that interact with laser light include hemoglobin, myoglobin, bilirubin, the cytochrome pigments in mitochondria, melanin, xantophyll, rhodopsin, and lipofuscin.7
Laser light in LITT is scattered, reflected, and absorbed to varying degrees depending on the wavelength of light, the applied laser energy, and the specific optical properties of the tissue. The tissue optical properties can vary markedly from area to area within a tumor or normal tissue depending on tissue composition, vascularity, fibrosis, and necrosis. Natural chromophores have strong dependence for wavelengths in the near infrared range for photochemical reactions to occur. This is fortunate because optical penetration depth increases with increasing wavelength of light. Thus, LITT uses diode lasers (wavelength 800–980 nm), or more frequently, Neodymium:Yttirum Aluminum Garnet lasers (wavelength 1064 nm).7,8 Laser light at 1064 nm generated by Neodymium:Yttirum Aluminum Garnet lasers has an optical tissue penetration depth of up to 10–12 mm.9 In contrast to other medical laser applications where high-energy laser light is applied briefly to achieve rapid photocoagulation, LITT uses low-energy (3–20 watts) laser light in the continuous mode applied over 2–20 minutes. Slow heating of tissue must be achieved by LITT to avoid carbonization and vaporization of tissue near the light-emitting portion of the laser fiber. Rapid production of a tissue coagulum from carbonization reduces optical penetration into the tissue and severely limits expansion of the zone of heated tissue with temperatures sufficient to produce lethal injury to tumor cells. In general, optical penetration of tumor tissue is greater than normal tissue by approximately 33% at 1064 nm wavelength, but rapid coagulative necrosis reduces optical penetration by up to 25% in both normal and tumor tissue.10
The laser fibers used for LITT range from 0.5 to 2.5 mm in diameter. The first type of fibers used for LITT was bare-tip quartz fibers. At high-power settings these bare quartz fibers produce elliptical lesions because of rapid tissue carbonization. Although temperature at the tip of a bare quartz fiber can reach 300–1000°C, rapid tissue coagulation severely impedes light penetration into tissue and heat propagation; the resultant area of tissue coagulation is often <1.0 cm in diameter.11 The application of lower-power settings using bare quartz fibers results in better diffusion of light through tissue and produces spherical lesions with diameters between 8 and 16 mm. Sapphire-tipped laser fibers were introduced to eliminate carbonization around the fiber tip and produce a more even and predictable thermal lesion.12 Use of sapphire-tipped laser fibers significantly reduces the occurrence of carbonization at the fiber tip, but the size of the thermal lesion was not significantly increased. The shape of the fiber tip can also influence the shape and size of the thermal lesion produced by LITT. Cylindrical quartz diffusers at the fiber tip also reduce tissue carbonization around the tip and can produce zones of thermal coagulative necrosis as large as 36 mm by 23 mm.13 A variety of other alterations in the fiber tip have been developed to create application systems intended to produce larger zones of thermal necrosis, and thus, allow treatment of larger hepatic malignant tumors. These modified LITT systems include ringmode applicators, scattering applicators, applicators with a prolonged active zone, and cooled-tip applicators. In contrast to bare quartz fibers, these special applicators tend to slightly increase the size of the zone of thermal necrosis while simultaneously lowering the power needed to produce thermal ablation, but the diameter of the applicator tip is larger than a bare quartz fiber.7
The development of multiple fiber systems with beam splitters was another technical advancement in the quest to produce larger zones of complete thermal coagulation using LITT. Most multifiber beam splitting LITT systems use four fibers at 1.5-cm separation. The simultaneous activation of the four laser fibers leads to enlargement of the inducible lesion volume around four fibers instead of one fiber, and it also produces an additional increase in the size of thermal necrosis by overlapping the coagulation zones.14 Studies performed ex vivo and in vivo have confirmed that four fiber beam splitting LITT systems produce a volume of heated tissue in the liver that exceeds hyperthermic levels (>45°C) 11 times greater in volume than a single fiber system and produces a volume of tissue exposed to coagulation temperatures (>55°C) 6 times greater. The beam splitting multiple fiber LITT systems have produced thermal lesions up to 4–7 cm in diameter, but these systems have not yet gained wide clinical application because they are more difficult to use for percutaneous or laparoscopic treatment. Thus, the principle limitation of current LITT systems is that they create lesions of reproducible thermal coagulation only 10–15 mm in diameter.
Similar to RFA, transient hepatic inflow occlusion during LITT can be used to double the volume of thermal injury using single fiber systems and can produce up to a 5-fold increase in the volume of thermal coagulation by using a four fiber system.15,16 Portal venous occlusion has been shown to be more important than hepatic arterial occlusion in producing this increase in the volume of thermal necrosis, suggesting that pretreatment transarterial hepatic arterial embolization associated with percutaneous LITT is less useful than laparoscopic or open surgical occlusion of both portal venous and hepatic arterial flow with a Pringle maneuver.
Imaging During and After LITT
With any technique that creates thermal ablation of malignant hepatic tumors, the availability of a radiologic imaging modality that accurately and reproducibly measures the region of thermal necrosis is an important issue. Ideally, the imaging modality should be noninvasive, inexpensive, and easily used and interpreted by all individuals using the technique. Unfortunately, there does not currently exist a modality that completely fulfills these criteria. Ultrasonography and magnetic resonance imaging (MRI) scanning are the imaging modalities most commonly used during and after LITT.
Ultrasonography has the advantages of relative low cost, widespread availability, and mobility. Laparoscopic or open hepatic ultrasonography increases the sensitivity and accuracy of this modality for detecting intrahepatic tumors and for guiding intratumoral placement of the thermal treatment device. Real-time ultrasonography can be used to detect initial tissue changes associated with any of the techniques that produce intratumoral heating. The first change detected by ultrasonography during LITT is a hyperechogenic area starting at the fiber tip that slowly expands outward from the tip as the expanding zone of tissue necrosis develops. Gas bubble production within the tissue and outgassing into vessels surrounding the area of thermal ablation is evident as the treatment proceeds.8 As with real-time ultrasonography during RFA, the expanding zone of hyperechogenicity produces significant shadowing, which makes monitoring of the deep tissue zones of ablation difficult, if not impossible. The area of tissue heating detected as a zone of hyperechogenicity by ultrasonography usually has an irregular shape and an indistinct outer margin. Furthermore, ultrasonography consistently overestimates the size of the area of complete thermal coagulation because it cannot distinguish between thermal gradients where temperatures are great enough to produce coagulation (>55°C) and zones of nonlethal tissue hyperthermia (45–55°C).17 Ultrasonography performed after LITT tends to underestimate the size of the thermal lesions, but this may be improved by using intravascular microbubble contrast agents and color power Doppler ultrasonography.
Dynamic MRI scanning has the advantage of being more sensitive than transcutaneous, but not intraoperative, ultrasonography in detecting malignant liver tumors and is much more accurate for measuring real-time and posttreatment laser-induced thermal tumor destruction. Its principle disadvantages include large size and relative immobility of the equipment, poor access to the patient during the LITT treatment, and high cost. The enclosed nature of conventional MRI systems makes access to a patient undergoing percutaneous LITT very difficult during the procedure. Patients will frequently undergo percutaneous placement of the laser fiber or fibers into the hepatic tumor under ultrasound or CT guidance. The patients are then transferred to the MRI scanner for treatment monitoring. Clearly, the fiber can be displaced from an optimal position in the tumor during transfer from a CT or ultrasound unit to an MRI scanner. Furthermore, the patient must be removed from within the bore of the magnet each time the laser fiber needs to be readjusted or if sedation of the patient is required. Many of these problems may be solved by routine use of an open configuration MRI system, which allows better access to the patient.18 However, the treatment time with the patient in the MRI scanner can be lengthy and associated with considerable expense.
Dynamic MRI can be modified for real-time monitoring of the laser-induced thermal lesion or for follow-up monitoring to assess for complete killing of the treated tumors. The various MRI sequences that have been evaluated for monitoring of LITT include rapid acquisition and relaxation enhancement, spin echo MRI, diffusion weighted imaging, and T1-weighted turbo fast low-angle shot sequence.19,20 MRI can be used to provide real-time thermal imaging maps because heating of the tissue results in a loss of the MR signal due to chemical and phase shift changes secondary to protein denaturation and rapid changes in tissue water distribution.18 The irreversible changes in protein molecular structure and loss of tissue water in tumors heated to temperatures >55°C results in a lengthening of the T1 relaxation times. These changes in the T1 appearance of tumor and tissue being treated with LITT has been shown to correlate accurately with the volume of tissue heated to a lethal temperature >55°C with an absolute error of ± 1°C.21 Real-time imaging processing software has been developed that converts the T1 signal loss during LITT from a gray-scale image to a color spectrum image ranging from blue to green and yellow to red. Tumor tissue and surrounding hepatic parenchyma that is heated to temperatures that exceed 55°C will undergo a green to yellow to red color change, whereas viable tissue that has not been heated above cytotoxic temperatures at the periphery of the lesion will maintain a blue color.
Results of LITT for Malignant Hepatic Tumors
The majority of reports describing LITT for liver malignancies describe a percutaneous approach for intratumoral placement of the laser fiber using ultrasonographic or MRI monitoring during the treatment. There are recent reports of laparoscopic or open laparotomy LITT, particularly using a multifiber beam splitting laser system, which also permits hepatic vascular inflow occlusion during the treatment. The disadvantage of a laparoscopic or open surgical approach is the need for general anesthesia and a longer recovery time from a more invasive procedure.7 However, these disadvantages may be outweighed in patients who are undergoing treatment of multiple tumors where the percutaneous treatment time in the MRI scanner is excessive or if tumors are located near key vascular or biliary structures where intraoperative ultrasonographic guidance to place the laser fiber is desirable. LITT suffers from the same problem inherent in the other recently developed thermal ablation techniques, a lack of long-term follow-up data to establish disease-free and overall patient survival rates. A study using an open MRI real-time monitoring system indicated that 27 hepatic tumors were treated with LITT in 12 patients.18 The mean diameter of the area of complete thermal necrosis was 3.0 cm, with a maximum thermal ablation diameter of 5.0 cm. However, only 2 of the 12 patients had complete ablation of the treated tumors as determined on gadolinium-enhanced fast breath hold MRI scans completed 4 and 10 weeks after the initial LITT. The remaining 10 patients required repeat LITT treatments to attempt complete local control of hepatic tumors through laser-induced thermal necrosis. The longest reported individual patient follow-up in this study was 32 weeks, making it impossible to determine local recurrence or patient survival rates.
A study of LITT to treat 55 patients with colorectal liver metastases had a mean follow-up of only 10 months.22 The mean number of LITT treatments required to complete percutaneous treatment of all detectable tumor was 2.2 sessions per patient. The mean survival rate at 12 months was 86%. An Italian study of 104 patients, 77 with HCC and 27 with hepatic metastases, treated with ultrasound-guided percutaneous LITT had a mean follow-up of <5 months.23 Complete destruction of tumor as assessed by triphasic contrast-enhanced CT scans was noted in 82.4% of the HCC tumors and 77.4% of the hepatic metastases. Three of the cirrhotic HCC patients developed liver failure after LITT, with one of these patients dying 2 months after the treatment. No data are provided on any repeat treatment sessions of the patients with incomplete destruction of the tumor after LITT, nor is there mention of local recurrence rates in lesions thought to be completely destroyed based on the results of the initial posttreatment imaging studies.
A small study of 8 patients with HCC and cirrhosis (Child-Turcotte class B in 3 and C in 5) reported the results following LITT of 1–4 tumors ranging from 2 to 7 cm in diameter.24 Despite multiple treatment episodes, all tumors >5 cm in diameter were incompletely treated by LITT. The survival time in these 8 patients ranged from 3 to 18 months with death caused by local and new tumor occurrence leading to liver failure.
A slightly larger cohort of 30 patients with HCC treated by LITT has recently been reported.25 Forty-five individual HCC tumors were treated with ultrasound-guided LITT. Thirty of these tumors had a mean diameter of 5.2 cm (range, 3.5–9.6 cm in diameter), whereas the remaining 15 tumors had a mean diameter of 1.9 cm (range, 0.8–3.0 cm in diameter). In all 30 patients, 30–90 days after LITT, transcatheter arterial chemoembolization using iodized oil and doxorubicin was performed. A total of 127 LITT sessions and 39 transcatheter arterial chemoembolization treatments were administered to the 30 patients. Complete tumor necrosis was noted in 27 of the 30 large HCC tumors (90%) and in all 15 (100%) of the small HCC tumors treated with LITT. The local recurrence rate in tumors treated with LITT was 7%. The 1-, 2-, and 3-year survival rates were 92%, 68%, and 40%, respectively.
The largest reported experience with LITT consists of 705 patients with 1981 metastatic liver tumors.26 A total of 1653 treatment sessions consisting of 7148 laser applications was required to treat the metastatic liver tumors in these patients. All treatments were performed with percutaneous insertion of the laser fiber using real-time MRI monitoring. The local tumor control rate was 97.9% based on MRI evaluation 6 months after completion of all LITT treatments in the individual patients. The mean survival time for patients with unresectable colorectal liver metastases treated by LITT was 41.8 months, with a 3-year actuarial survival rate of 50%. In a smaller subset of patients with breast cancer liver metastases, the mean survival was 4.3 years after LITT.26 The overall complication rate in the large series of 705 patients treated with percutaneous LITT was 7.5%, but the authors report that most of the complications were mild and were treated in the outpatient setting. The rate of more significant complications requiring hospitalization, interventional therapies, or prolonged treatment was 1.3%. This is consistent with other reports of complication rates of <2% in patients treated with LITT.8 Reported complications include pneumothorax, hemothorax, transient bile leaks, subcapsular hemorrhage or bleeding from the needle track, bradycardia, tachycardia, right upper quadrant abdominal pain, and transient hyperthermia.
Clearly, the major limitation of single fiber LITT is an inability to achieve large volumes of tumor necrosis. Another disadvantage is the need to perform multiple treatment sessions in most patients. It is possible that LITT may become a more clinically useful and widely applied treatment if improvements such as multiple fiber beam splitting systems, diffuser fiber tips, pharmacologic thermosensitization, and radiologic or direct surgical occlusion of hepatic inflow are able to overcome these problems. Presently, there are inadequate data on local tumor recurrence rates and long-term survival rates after LITT to perform a rigorous assessment of its future as a treatment modality for hepatic malignancies.
Footnotes
Microwave coagulation therapy and laser-induced interstitial thermotherapy are two alternative thermal ablation treatments being used in patients with hepatic malignancies. Like radiofrequency ablation, treatment-related morbidity rates are low. These treatments are limited by the relatively small zones of thermal necrosis produced, and long-term outcomes in patients treated with these modalities are not yet established.
Received for publication July 18, 2002. Accepted for publication August 15, 2002.
REFERENCES
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  D. Choi, H. K. Lim, H. Rhim, Y.-s. Kim, B. C. Yoo, S. W. Paik, J.-W. Joh, and C. K. Park Percutaneous Radiofrequency Ablation for Recurrent Hepatocellular Carcinoma After Hepatectomy: Long-term Results and Prognostic Factors Ann. Surg. Oncol., August 1, 2007; 14(8): 2319 - 2329. [Abstract] [Full Text] [PDF]
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