Introduction

Follow-up and monitoring program and progress in imaging have made notable contributions to early and accurate diagnosis of primitive and metastatic neoplastic nodules of the liver. Today, the indications for surgical resection of patients suffering from hepatocar-cinoma and metastases (colorectal and non-colorectal) are well codified.

The refinement of image-based diagnostic methods and thin-needle biopsy techniques have permitted the development of guided therapeutic systems, in which the therapeutic agent is introduced directly into the lesion (interstitial therapies), with the aim of destroying the neoplastic tissue, leaving the healthy surrounding parenchyma. Cellular death can be caused by cytotoxic damage (ethanol, acetic acid) or by heat damage (laser, cryotherapy, microwaves, radiofrequency). Percutaneous ethanol injection has acquired proven efficacy in the treatment of HCC [1].

Thermoablation by means of radiofrequencies (RFA), described initially for the treatment of small intracranial lesions, osteoid osteomas, rhizotomies, and cordotomies, was successively experimented on animal and then human liver in the treatment of small HCC [2]. It consists of the destruction of the neoplastic tissue by means of the action of heat generated by an active needle electrode introduced into the neoplastic tissue itself, high-frequency alternating current flowing from an electrode into the surrounding tissue. Frictional heating is caused when the ions in the tissue attempt to follow the changing directions of the alternating current. In the mononopolar mode, current flows from the electrode to a round pad applied externally to the skin. In the bipolar mode, current passes between two electrodes inserted at opposite poles of the tumor.

The needle electrode can be positioned percutane-ously (under ultrasound or TC guidance), by lapa-roscopy or open laparotomy. It is connected to an appropriate generator and is insulated, except for the terminal part (active). The active electrode has a thermocouple on the point to constantly monitor the temperature. The energy emitted inside the tissue is converted into heat that causes cell death by means of coagulative necrosis. At 43°C in 30-60 s apoptosis already is seen. Cellular death occurs in a few minutes at 50°C; in a few seconds at 55°C, and almost instantaneously at temperatures above 60°C.

The destruction of a limited volume of tissue is thus realizable in a controlled and reproducible manner. Heating of the tissue decreases in proportion to the fourth power of the distance from the electrodes. Charring causes sudden rise in impedance adjacent to the electrode.

Many strategies exist for increasing the size of ablation volume (enlarge the zone of ablation):

• Cooling the electrode to avoid charring and increase of impedance

• Cluster cooled electrode

• Expandable jack hook needles

There are various types of electrodes commercially available: cooled tip, single and triple (cluster) and expandable needles [3-5].

The diameter of the volume of necrosis must be greater than that of the neoplastic nodule by at least 5-10 mm. Imaging techniques are important to localize the tumor and to monitor the ablation process. Typically, the electrode is placed under ultrasound or CT.

During ablation, ultrasound monitoring shows a round hyperechoic area.

This phenomenon depends, according to some writers, on the vaporization of the interstitial liquid and to others on the out-gassing of dissolved nitrogen in the tissue that is roughly proportionate to the volume of necrosis (Fig. 14.1).

To verify destruction of the tumor after RFA we recommend high-resolution, good-quality contrast enhanced CT or MR to evaluate completeness and recurrence rates [6] (Fig. 14.2).

Published studies are principally directed at criteria of feasibility, efficacy, safety, and survival (even if the follow-ups are still short) [6-8].

RFA is currently directed at those patients for whom resection is not suitable. As part of a mandatory mul-tidisciplinary approach, RFA must be seen within the

Fig. 14.1 RFA of HCC. US monitoring: hyperechoic area that gradually covers the entire nodule (a-d). Bubbles eventually run in hepatic vein (e)

Fig. 14.2 CT pre and posttreatment in 55-year-old patient subjected to anterior rectal resection and RFA of two synchronous liver metastases (a, b). Complete necrosis occurred (c, d)

therapeutic algorithm of primitive and metastatic tumors of the liver.

The advantages of RFA are the saving of healthy liver, the mini-invasiveness of the method itself, the repeatability, the limited costs, the feasibility also in patients for whom resection is not suitable with reduced morbidity, and almost nil mortality.

The laparoscopic approach has been proposed as an alternative to the percutaneous approach in selected patients; it permits better staging (24% lesions not diagnosed by TC) and a safer approach for lesions that are not safely treatable percutaneously (subcapsular, near the hollow viscera etc.) [9].

Analogously, the laparotomic approach permits better staging; access to segments I, VII, and VIII; the protection of surrounding viscera; vascular control maneuvers (Pringle); and, further, association with the resective surgery itself.

Orthotopic liver transplant (OLT) permits treatment of both hepatocarcinoma and cirrhosis. It is indicated in patients with early HCC (single nodule <5 cm, or <3 nodules <3 cm). However, because of the limited number of organs, average waiting time is over 1 year. Surgical resection therefore remains the fundamental therapeutic option.

Transarterial chemoembolization (TACE) is used for patients with hypervascularized multiple nodules. Alcoholization (percutaneous ethanol injection [PEI]) is indicated in nodules of small dimensions.

RFA initially used as an alternative to PEI [1, 10, 11] has rapidly gained ground and is currently included in the HCC therapeutic algorithm both as curative therapy (European Consensus Conference, Barcelona) and as a bridge to OLT [12-14].

Histological investigations on removed livers have validated RFA as an efficacious treatment in small HCCs (<3 cm) [15]. Further, interstitial therapies such as PEI or RFA can be integrated with TACE.

Hepatic metastases can be divided into colorectal and non-colorectal. Twenty to 30% of patients with colorectal carcinoma develop hepatic metastases; only 10-20% are respectable, and hepatic resection is the therapeutic gold standard [16-18].

Regarding those from non-colorectal tumors, indication for resective surgery is straightforward for tes-ticular, renal, and neuroendocrine tumors (NET) [19].

Hepatectomy for metastases from other primitive tumors appears to be appropriate for metastases from some sarcomas, mammary carcinomas and the gynecological sphere, and lastly from melanoma, but the selection criteria are still little defined.

The criterion of nonresectability must be expressed by a surgeon expert in the field of hepatic surgery. For patients for whom resection is not available, ablative techniques can provide a therapeutic alternative.

Further, RFA has gained growing application in association with hepatic resection itself.

In general, in connection with colorectal carcinoma metastases, RFA can be indicated in patients not suitable for resection for general reasons; for anesthe-siological reasons; for location, number, and vascular relationships of the lesions; for patient refusal; in association with resection of the primitive tumor; in association with hepatic resection of other nodules; and finally, in local recurrences following surgery.

Elias [20] reports his clinical experience with intraoperative RFA associated with hepatectomy to treat otherwise unresectable liver metastases with curative intent. The same author states [21] that well-used RFA is at least as efficient as wedge resections to treat liver metastases smaller than 3 cm.

At the same time, it is clear that RFA is better tolerated than is wedge resection, is less invasive, is less hemorrhagic, and does not necessitate vascular clamping. It could thus be currently considered a valid tool in the arsenal of intraoperative procedures to treat liver metastases. The combination of anatomical segmental and wedge resections, RFA, and optimal chemotherapy in patients with technically unresectable LM results in median survival of 36 months [22].

Analogically, Oshowo and Gillams report that RFA used in conjunction with surgery, in patients who were regarded as "nonsurgical" due to the extent and distribution of their disease, gives results similar to those reported for patients undergoing resection for operable liver metastases. They concluded that RFA extend the scope of surgical treatment in patients previously thought to be unsuitable for surgical resection [23].

Tepel [24], in 26 patients with 88 hepatic lesions, concluded that intraoperative RFA alone, or in combination with liver resection, extends the spectrum of liver surgery in cases where complete resection is not possible.

Our case experience consists of 37 patients with 65 HCC nodules, 5 patients affected with cholangiocar-cinoma, and 63 patients with 115 metastatic lesions originating from various primitive tumors (40 patients with colorectal carcinoma; 10 patients with breast carcinoma; 6 patients with gastric neoplasia, 4 of which with carcinoma, 1 with gastrointestinal stromal tumor [GIST] and 1 with NET; 2 patients with renal carcinoma; 2 with oesophageal carcinoma; 2 with pancreatic cancer; and 1 with anal cancer.

Regarding HCC, there were 55 procedures, of which 52 were carried out percutaneously, 2 by laparotomy, and 1 by laparoscopic approach.

In the field of metastatic lesions, there were 85 procedures, of which 58 were percutaneous and 27 lapa-rotomic.

Fig. 14.3 A 71-year-old patient, subjected to left colectomy and RFA of two synchronous metastases. a, b CT preoperative scan. c-e Intraoperative RFA by cluster; e shows the hyperechoic ring around necrotic area. f, g CT scan shows complete necrosis

All the procedures were performed with a Radionics generator and cooled-tip electrodes, single or cluster (triple).

Complete necrosis, evaluated through TC with vascular contrast medium, analogically to the data in the literature, was obtained in almost all of the nodules <3 cm.

In addition, with a view to evaluating the feasibility of RFA in synchronous metastases from colorectal carcinoma, 10 patients with 36 nodules (range: 1-10) were treated.

Intestinal resection was always effected prior to ablation (Fig. 14.3).

The necrosis obtained was complete in all nodules except for one with diameter >6 cm.

In our experience, open RFA is effective and safe, the use of the cluster is facilitated, numerous nodules can be treated, vascular control maneuvers can be car ried out, and it is easier to evaluate intraoperatively the completeness of the necrosis [25-29].

As stated earlier, given the present state of knowledge, RFA can be considered as a curative treatment of HCC. Its impact in terms of survival in connection with hepatic metastases remains to be determined.

Gillams [30] studied the impact on survival by image-guided thermal ablation, using interstitial laser photocoagulation in patients with metastases from colorectal metastases not suitable for surgical resection. This therapy improved survival both when compared with systemic and regional chemotherapy results.

Oshowo compared outcome in patients with solitary colorectal liver metastases treated by surgery or RFA [31]. The contraindications at surgery were lesion close to or involving a major vessel (nine patients, comorbidity [nine], and stable extrahepatic disease [seven]). Patients who had liver resection had truly solitary metastases with no evidence of extrahepatic disease. Preliminary survival curves between the two groups were similar.

Abdalla examined recurrence and survival rates in patient treated with hepatic resection only, RFA plus resection, or RFA only for colorectal liver metastases. He concluded that the RFA alone or in combination with resection for unresectable patients does not provide survival comparable to resection and is only slightly superior to nonsurgical treatment [32].

Positive results in terms of survival are given by Berber with respect to systemic chemotherapy alone [33].

Poston [34], however, posed crucial questions in this field:

• Is destructive therapy equal in curability to surgery for resectable colorectal liver metastases?

• What additional survival benefit does destructive therapy have over modern systemic chemotherapy (oxaliplatin and irinotecan) in the treatment of unre-sectable disease?

Trials to attempt to answer these questions are ongoing.

After the initial phase centered on the feasibility and efficacy of the method, important multicentric investigations were carried out, from which on the one hand precise data regarding complications and mortality emerged, and on the other opportune guidelines.

Mulier reports a mortality rate of 0.5%, with complications of 8.9% [35].

Livraghi reports a mortality rate of 0.25%, with major complications of 2.1% and minor of 4.7% [36].

Even if it is widely recognized that the mechanism of cell destruction induced by RFA is sustained by necrosis and apoptosis mechanisms, the effective biological processes that result from this are not clear. RFA induces an inflammatory response in the site of application, thus modulating the cellular components of the immune system. Moreover RFA application seems to enhance antitumor immunity. In collaboration with our colleagues of the University of Rome La Sapienza, we have shown that leukocyte subsets differently respond to RFA application; in particular CD3/ CD4 cells and CD19+ cells decrease following RFA in metastatic liver patients, while no such modulation is observed in HCC patients. Moreover an antigen specific antitumor immune response mediated by interferon (IFN)-y production can be augmented following RFA [37].

With a view to obtaining greater volumes of necrosis, compared with monopolar RFA, from January to June 2003 at the Department of Biology, Animal Facility Centre (STA) University of Rome Tor Vergata, we started a series of experimentations on ex vivo pig liver, adopting multiple needle electrodes in bipolar mode. The preliminary results obtained from this experimentation led us to realize that multiple electrode needles arranged comb fashion would realize slices of paren-chymal coagulation with closure of the blood and biliary vessels in a reasonable time, avoiding multiple applications of a single monopolar needle.

In these procedures RF electrosurgical apparatus in bipolar mode was used to produce a sinusoidal pure wave of 660-kHz frequency, 140-V output, and maximum power of 30 W, with 100-Q impedance that fed two electrodes.

The entire system was originally composed of three RF generators and six electrodes. Finally, we fashioned a single generator that was modified to deliver 60 W, through six electrodes with 500-Q impedance, and forced cooling. The apparatus was modified in order to supply controlled power simultaneously to five bipolar circuits through the six electrodes that constituted the application tool, fed from an output transformer with six terminals. The following parameters were evaluated: distance between electrodes, energy delivered, width and thickness of necrosis, and needle diameter. After the approval of the Animal Ethics Committee, 18 liver resections on six pigs (Landrace pig) were performed from September 2003 to December 2004. All procedures were performed under general anesthesia, with tracheal intubation and continuous cardiac monitoring, with midline laparotomy and without vascular control. Nine atypical liver resections were performed in three animals sacrificed at the end of the experiments. Nine atypical liver resections were performed in three animals, at two different times. The animals were kept alive after primary operation to evaluate the principal complications (bleeding, biliary leakage). Blood sampling was performed before the first operation, and at the fourth postoperative day to assess bleeding.

During the second operation, we carefully evaluated the entire abdominal cavity and the liver edge, performing biopsy of the necrotic tissue (for histologi-

Fig. 14.4 a Single line coagulation in left lateral lobe in pig's liver. b Section with scalpel along the necrotic line. c Liver edge after resection

Fig. 14.4 a Single line coagulation in left lateral lobe in pig's liver. b Section with scalpel along the necrotic line. c Liver edge after resection

Fig. 14.5 Bipolar automatic generator and comb

cal control), and carried out another two resections on each animal.

The resections were performed with a normal scalpel after multiple application of the multielectrode probe along the established line (Fig. 14.4).

In order to obtain optimal coagulation of the slice of liver parenchyma, and to facilitate the cutting of the tissue, we decided to perform a double parallel line of application of the probe.

During this phase we used a generator with 475 kHz, 160 V, and 150 W (SURTRON SB) (Fig. 14.5).

Finally, to access the tolerability and safety of the system on human beings, after IRB approval, we designed and implemented a clinical pilot study in our institution. In connection with the feasibility, we looked at the coagulative panel and intra- and postoperative echo color Doppler blood flow results. With regard to the efficacy, we studied the extent of the coagulative necrosis, blood loss, and the healing of the transected liver as well as the handling of the probes.

We obtained the approval of the Hospital Ethical Committee and the informed consent of each patient. The preoperative work up was standard for surgery of hepatic tumors. Postoperative controls involved evaluation of the blood count, liver enzymes, and coagulation panels. Ultrasound examination allowed us to evaluate collection and hepatic vessel flow. Finally, the CT scan gave us evaluation of the liver edge (Fig. 14.6).

The study included the enrolment of six patients with primary and metastatic tumors suitable for liver resection according to the usual surgical criteria for these cases. Four patients had colorectal metastases, one patient suspected gallbladder carcinoma, and one patient suspected intrahepatic cholangiocarci-noma.

Altogether, the following procedures were carried out: three left lobectomies, one left hepatectomy, one gallbladder bed resection, and four wedge resections. Associated surgery was RFA in two unresectable tumors, one total colectomy, and one ileocoloanastomo-sis. Whenever possible, ligation, and division of the inflow vessels was performed before transection, allowing rapid coagulation of the liver plane.

In the case of the left hepatectomy, we proceeded prudently, as it was our first patient and so performed control of portal left pedicle and left hepatic vein; in contrast, in last left lobectomy we performed resection without vascular control.

No vascular control was needed for the wedge resection. In the other patients only portal inflow control was obtained.

After the double line of tissue coagulation, we cut the liver parenchyma with a normal scalpel. Successive application of the probe allows transection close to the hepatic vein. Blood loss is minimal. The probe can be used also in an anteroposterior direction.

Fig. 14.6 A 68-year-old patient with metachronous metastases from colonic cancer subjected to left hepatectomy. Left to right a Preoperative CT scan, b intraoperative coagulation of the liver resection plane, c postoperative CT scan after 1 month that shows necrotic tissue at liver edge

Fig. 14.6 A 68-year-old patient with metachronous metastases from colonic cancer subjected to left hepatectomy. Left to right a Preoperative CT scan, b intraoperative coagulation of the liver resection plane, c postoperative CT scan after 1 month that shows necrotic tissue at liver edge

Close to the hepatic vein, coagulation is not prudent and so we transect the tissue in a traditional way.

The hepatic vein was divided by a stapler.

We observed only one complication in Patient 2, whose drainage was removed with output still at 100 ml. However, normalization came about after 45 days.

Recently, another three patients with colorectal liver metastases underwent liver resection using this device: two right hepatectomy and one right lateral segmen-tectomy plus RFA of nodule in the fourth segment.

In conclusion, the coagulation with multielectrode bipolar radiofrequency device allows a liver bloodless resection. Liver resection assisted by this device is feasible, easy, and safe. This method for liver resection is absolutely tolerable by the patient with no systemic complication or adverse reaction. This new technique offers a method for a blood less hepatic transection [38-42].

Currently, the generator is able to check the tissue impedance and thereby automatically choose the power. Further, still automatically, it can operate the switching out of each electrode as soon as necrosis is reached. The comb is relatively manageable; a special device has been realized in order to facilitate both the insertion and the protection of the hands of the surgeon, together with the surrounding organs. Thanks to the tissue necrosis, we can hypothesize a low level of recurrence at the level of the resected liver edge over the long term.

not suitable for surgical resection, and for low morbidity and mortality related to the ablation technique itself.

Information from experience and literature data gave us a lot of information in the field of tolerability, safety, efficacy, complications, and the possibility of specifying opportune guidelines.

Nevertheless many questions as to biological and therapeutic issues are still unsolved:

• Impact on long-term survival

• Relation to systemic inflammatory and immunologic response

• Imbrications with systemic or intra-arterial chemotherapy

• Immunotherapy

• Relation to other kind of interstitial therapy

• Relation to, or substitution of, surgical resection

• Benefits of debulking in conjunction with chemotherapy or other systemic therapy

RFA is actually the most versatile and most used form of interstitial therapy. It has found defined utilization in HCC treatments. Its role in the field of liver metastasis is still evolving, above all due to notable results with recent aggressive chemotherapy.

In the multidisciplinary approach to the solid liver tumor, RFA is a further important tool in the ongoing battle against cancer.

Definitive data should emerge from controlled clinical trials.

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