Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P30 pptx

Microwave energy is an effective local thermal ablation technique for the treatment of hepatocellular carci-noma which exhibits many of the advantages over alternative ablation and resec

Microwave Ablation and Hepatocellular

Carcinoma

Robert C.G Martin

Keywords Microwave ablation· Hepatocellular cancer

Introduction

Hepatocellular carcinoma remains one of the most common malignant neoplasms and is responsible for greater than one million deaths per year [1] Prognosis of HCC is exceedingly poor because of the high malignancy biology, high recurrence, and overall resistance to current therapies [2] Partial hepatectomy remains the first option for the treatment of HCC; however, it is only suitable for 9–27% of all patients diagnosed [3] The reasons for this are the severe underlying cirrhosis and the multifocality of the hepatic disease, which often precludes liver resection in most patients with hepatocellular carcinoma Moreover, tumor recurrence is common after curative resection, and thus, few patients are candidates for further hepatec-tomy after undergoing their initial curative hepatechepatec-tomy [4] Therefore, minimally invasive yet effective therapeutic options are essential to improve the overall qual-ity of lifetime in patients with hepatocellular carcinoma Microwave energy is an effective local thermal ablation technique for the treatment of hepatocellular carci-noma which exhibits many of the advantages over alternative ablation and resection techniques [5 8] In recent years microwave ablation technology has undergone tremendous progress due to the better understanding of the energy delivery and technological advances that are currently now commercially available

R.C.G Martin (B)

Division of Surgical Oncology, Department of Surgery, University of Louisville School of Medicine, Louisville, KY, USA

275

K.M McMasters, J.-N Vauthey (eds.), Hepatocellular Carcinoma,

DOI 10.1007/978-1-60327-522-4_17,  C Springer Science+Business Media, LLC 2011

276 R.C.G Martin

Mechanism and Theoretical Benefits

Microwave ablation refers to the electromagnetic method of inducing tumor destruc-tion by using devices with frequency greater than or equal to a 900 MHz [9] The rotation of the dipole molecules accounts for the efficient amount of heat generated during microwave ablation [10] One or more molecules are dipoles with unequal electrical charge distribution and as they attempt to continuously re-orient at the same rate in the microwave’s oscillating electric field As a result of the microwave transmission the water molecules flip back and forth at a billion times per second, leading to this vigorous movement to produce friction and heat which leads to cel-lular death via coagulation necrosis An additional mechanism responsible for heat generation in microwave ablation is ionic polarization which occurs when ions move

in response to the applied electric field of the microwave The displaced ions cause collisions with other ions converting this kinetic energy into heat However, this is the lesser of the two mechanisms that generate the efficient heat from microwave ablation

The current frequencies of the commercially available microwave ablation devices are at either 915 or 2450 MHz (Fig.17.1) The 2450 MHz is the most commonly adopted microwave ablation device which is the frequency used in the conventional microwave ovens giving the reported most optimal heating pro-files The benefit of the 915 MHz microwave is that it can penetrate deeper than the 2450 MHz microwave which may theoretically yield larger ablation zones However, the energy deposition is also influenced by the dielectric properties of the antenna design; thus, there are specific antenna design limitations that do not necessarily translate into the 915 MHz generator leading to larger ablations (Fig.17.2)

The theoretical advantage of microwave ablation over the more established and more published radiofrequency ablation is predominantly that microwave ablation

Fig 17.1 Current frequencies of the two types of microwave ablation devices and corresponding

frequencies

Fig 17.2 Dielectric properties of the antenna design and the feed point of energy deposition

heating is primarily active while RFA heating is primarily passive Microwave, thus, has a much broader zone of active heating and does not rely on the conduction of electricity into the tissue, and thus, the transmission of this energy is not limited

by tissue desiccation and charring [11] Therefore, intratumoral temperatures can consistently be driven higher leading to theoretically a larger zone of ablation over

a more efficient treatment time and a more complete coagulative necrosis and tumor kill [12] Second is the resistance of the heat sink effect, that being the cooling effect

of blood flow from the tumor during this heating Given the fact that microwave ablation is an active heating process, it is less affected by this perfusion-mediated effect which may allow for more uniform tumor necrosis within the target zone as well as in proximity to large vessels Third, the simultaneous application of multiple microwave energy sources is allowed since there is no need to create a circuit as in RFA Thus, multiple microwave ablations can be performed simultaneously leading

to a more efficient ablation time when dealing with multiple tumors as well as the capability of ablating larger tumors in conjunction with multiple probes [13] Microwave ablation therapy was initially developed in the 1980s to achieve hemostasis along the plane of transection during hepatic resection [14] At that time, microwave coagulation was slower than electric cautery units and produced a much deeper area of necrosis and thus was not widely utilized for hemostasis during hep-atic transection This area of extended necrosis, however, did lead to an investigation

of microwave coagulation therapy (MCT) to be another form of ablative technique

278 R.C.G Martin

Table 17.1 The Current Microwave Generator Systems that have been used and reported in Peer

Review Literature

MW

companies Covidien Microsulis Microtaze

UMC-I (Institute 207 of Aerospace Industry – Beijing, China) Generator

frequency

915 MHz 2450 MHz 2450 MHz 2450 MHz

Antennas 3.7 cm active

length

3 lengths, 12, 17,

and 22 cm

13 gauge

diameter

5.7 mm active diameter

15 and 25 cm length, 1.6–2 mm active diameter

24.7 cm length, 1.6 mm

in diameter, 2.7 cm exposed antenna

Information: – A single probe

45 W for

10 min

produces 4 cm

– 3 probes

spaced 1.5 cm

45 W for

10 min

produces 6 cm

– A single

100 W probe application for

8 min resulted

in lesions consistently

>5 cm – Unlike RF energy, microwave energy does not appear to

be limited by charring and tissue desiccation

– Has been uniquely employed in liver surgery for more than

20 years.

– Local recurrence rates were 11.8% for MWA

vs 20.9% for RFA, without significant differences rates between the two

groups (P= 0.12).

The initial microwave generators developed produced a microwave frequency of

2450 MHz and a wavelength of 12 cm (Table17.1)

Equipment

The current microwave generators available have an output between 30 and 100 W All of the commercially available reported microwave systems are composed of the three basic elements of generating microwave energy: microwave generator, low-loss flexible coaxial cable, and microwave antenna The microwave energy is generated by a magnetron which contains spaces called resonance cavities which act as tuned circuits to generate an electrical field The microwave output frequency

is also determined by these cavities, which are connected to the antenna via a low-loss coaxial cable to transmit the microwaves from the magnetron to the tissue The design of the antenna is crucial for the ability to deliver effective and efficient energy to create therapeutic efficacy [15] This is one of its greatest advantages and limitations in that the length and diameter of the antenna is limited based on

the energy available and low-loss flexible coaxial cables Effective antennas have

to be specifically tuned to the dielectric properties of the tissue and, thus, opti-mized for each solid organ that is to be ablative keeping the power of feedback

to a minimum to ensure localized power deposition around the feed point and active tip of the antenna To adequately destroy an entire tumor, the tumor abla-tion zone should extend at least 1.0–3.0 cm beyond the tumor Therefore, antennas with larger coagulation diameter have the potential advantage over sources of energy deposition

Microwave ablation for unresectable hepatocellular carcinoma was first reported

in Japan with the use of the microwave coagulator developed by Tabuse in 1979 to achieve hemostasis during hepatic transaction [14] Using the same device, Saitsu reported intraoperative and laparoscopic microwave ablation for small hepatocellu-lar carcinomas in 1991 [16] This first microwave system was used for percutaneous microwave and was the Microtaze system which had a needle antenna of 1.6 mm

in diameter and a 2450 MHz generator with ablation performed at 60 W for 120 s demonstrating a coagulation zone of 2.4× 1.6 cm in normal liver [17] Since the coagulation diameters were not large enough, it was predominantly used to treat tumors less than 2.0 cm in size A competing microwave generator system, the UMC-I microwave system, has been mainstay of microwave generators in China (Table17.1) [18] This antenna has a diameter of 1.4 mm, an active tip of 27.0 mm which also operates at 2450 MHz It relies on a 14 gauge needle to facilitate antenna insertion and after 60 W of generator power for 300 s a 3.7× 2.6 cm

coagula-tion zone was obtained in the porcine livers [18] Because of the ability to obtain larger zones of ablation, this antenna has been utilized to treat larger hepatocel-lular carcinomas and has so far been reported to obtain satisfactory therapeutic outcomes [7,8] However, this system has been plagued by higher power feedback enabling the temperature of the antenna shaft to rise very quickly and has led to severe adverse events including skin burns and potentially extrahepatic damage to surrounding tissues Consequently, a protective cooling of the skin has to be per-formed during percutaneous ablation when the application of the energy is utilized for a certain duration of time A third system in 2003 was released in the United States by Vivant Medical, capable of producing 60 W of power at a lower 915 MHz generator [19] It was subsequently purchased by Covidien and is now called the EvidentTM Microwave Ablation System This antenna initially was a 13 gauge in diameter, 15.0 cm in length, and a 3.6 cm active tip with specific dielectric proper-ties tuned for liver tumors thus reducing power feedback and increasing the amount

of energy deposited to the tissue In vivo experiments with a porcine liver using a triple antenna produced synergistically larger ablation lesions than used with a sin-gle antenna ablation After initial animal experiments and recently reported phase

II data, it currently is one of the two microwave ablation systems that are approved for use in the United States [19] A maximum mean ablation diameter of 5.5 cm has been reported with the use of utilizing three antennas spaced at 2.0 cm apart The fourth system that has been reported in the literature which is currently in use in Europe is the Microsulis system

280 R.C.G Martin

Indications

In general, similar to radiofrequency ablation the indication for microwave abla-tion should be applied to patients who are not candidates for the more definitive and effective surgical resection The definition of resectability for hepatocellular carcinoma is quite complex, because in addition to taking into consideration the underlying tumor biology (multiplicity of tumors) The treating physician must take into consideration the health of the non-tumorous liver to ensure that a potential curative resection may be an option Unfortunately, given the fact that a majority of patients with hepatocellular carcinoma have underlying cirrhosis from either hepati-tis B or C, alcohol, or other sources, most patients who have potentially resectable lesions based on the number and location are not surgical resectable candidates based on the lack of health of the non-tumorous liver and the ability of that liver

to withstand that type of resection Given those limitations, microwave ablation is indicated currently to treat lesions approximately 5.0–7.0 cm in maximum size or less [7,8,19] Most treating physicians would agree that microwave ablation should

be utilized in a “curative” indication These indications or criteria are predominantly defined as a single hepatocellular carcinoma lesion of 6.0 cm or smaller, three or fewer hepatocellular carcinoma lesions with a maximum diameter of 4.0 cm or less and the absence of significant extrahepatic disease, and an expected life expectancy greater than 6 months of survival Patients in consideration for hepatic ablation must undergo these same extensive pre-evaluations as would patients undergoing hemi-hepatectomy which should include high-quality dynamic cross-sectional imaging of the liver as well as abdomen and chest, both for ablation planning and for staging of the patients

Choice of Approach

Microwave ablation has been reported to be effectively delivered through an open laparotomy [19,20], laparoscopically [21], percutaneously [8], and even thoraco-scopically [22] in the appropriate patients Each approach offers its advantages and disadvantages The current advantages of the percutaneous approach are that it is less invasive and does not require an operation theater to perform the ablation The potential disadvantage of percutaneous ablation is the inability to evaluate the sur-face of the liver and inability to evaluate the abdomen for extrahepatic disease As has been demonstrated in metastatic colorectal cancer, percutaneous ablation has the limitation of understaging patients when relying just on cross-sectional imaging The potential advantages of laparoscopic approach are the ability to truly evalu-ate the hepatic parenchyma, surface of the liver, as well as the intra-abdominal peritoneum for more precise staging The limitation is that this requires general endotracheal anesthesia as well as an intra-abdominal access which has the potential

to be a greater risk for patients with marginal hepatic function Microwave ablation through an open technique has been reported to be effective also with the ability to

combine that technique with radical resection Use of a combined hepatic resection and ablation technique has been found to be effective and safe in the management

of patients with multifocal hepatocellular carcinoma The ablation technique for microwave ablation is a complex technique requiring the treating physician to have extensive knowledge of the hepatic anatomy, knowledge of the histology of the tumor being treated, extensive knowledge of intra-ablation imaging, and appropri-ate knowledge for adequappropri-ate follow-up Ultrasound is currently the most commonly employed imaging technique because of its convenience and ability to continually allow for real-time evaluation of the ablation However, ultrasound of the liver is a learned technique that must be optimized in order to appropriately and effectively treat patients utilizing microwave energy Even with the advantages of microwave energy in comparison to radiofrequency ablation, microwave energy will not make a treating physician a better ablator of hepatocellular carcinoma if that treating physi-cian does not have extensive knowledge in imaging guidance and image acquisition during the ablation process Accurate pre-ablation imaging with ultrasound using either B-mode or combination B-mode and harmonic contrast-enhanced ultrasound leads to precise lesion size estimation as well as defining potential moderate-to-large heat sink vessels from either inflow or outflow structures This then allows for a more precise antenna placement strategy leading to a greater incidence of overall ablation success and significantly reduced ablation recurrence Given the rapidity of the heat generated using microwave ablation, the size of the ablation zone can be more precisely judged by the expanding hyperechoic area during the ablation especially in the first 3–5 min Thermocoupling evaluation has also been reported to be utilized Placed at 0.5 cm outside of the tumor margin, and once target temperature of 60◦C is reached or 54◦C for at least 3 min is reached, then suc-cessful ablation has occurred [23] Post-ablation contrast-enhanced ultrasound has also been found to further enhance the accuracy of ablation using microwave and if there is any residual tumor, then focal ablations can be performed in those certain areas

Assessing the efficacy of microwave ablation is of utmost importance and needs

to be further standardized in order to avoid the wide ranging results that have plagued radiofrequency ablation It has been recommended that an immediate follow-up CT (defined as within 1 month of ablation) be performed in order to accu-rately determine ablation success Repeat imaging at 3-month intervals for the first year and then at 6-month intervals following is needed to accurately define ablation recurrence (recurrent disease within 1.0 cm of the ablation defect) as well as non-ablation hepatic recurrence and, lastly, extrahepatic recurrence Defining non-ablation success utilizing these four criteria is of utmost importance

Clinical Use

The initial result of MCT has come from Japan where the technique was first utilized

in 1988 MCT in Japan has primarily been utilized to treat the cirrhotic hepatocel-lular carcinoma patient The majority of these patients had small, less than 3 cm

282 R.C.G Martin tumors and were not candidates for resection because of the underlying severe hepatic cirrhosis [17] The initial MCT technology produced a reproducible and reliable zone of complete coagulation necrosis; however, because of the rapid devel-opment of this necrosis, the heat is quickly dissipated producing ablations of only

10 mm at maximum diameter More recent evaluation of MCT therapy is based on a similar principle but improvements in probe, shape, and conduction have allowed for significantly greater size of ablation

Currently, the overwhelming majority of reports utilizing microwave ablation in hepatocellular carcinoma have come from Japan and China The initial report from Seki et al of 18 patients with solitary, small hepatocellular carcinoma (less than

or equal to 2.0 cm) demonstrated 100% complete ablation but very short follow-up following the ablation [17] The smaller report from Murakami used the similar sys-tem as Seki et al in evaluation of nine patients with hepatocellular carcinoma greater than 3.0 in size, which again demonstrated 100% complete ablation; however, local recurrence occurred in four of these nine tumors within 6 months of treatment [24] When you compare these results using the UMC-1 system to the Microtaze system, the current UMC-1 system appears to yield larger ablations and potentially longer term durable control The largest reported system using the UMC-1 microwave abla-tion system for HCC in a single instituabla-tion evaluated 288 patients with 477 tumors [25] The UMC-1 microwave system used in this study yielded 1-, 2-, 3-, 4-, and 5-year cumulative survival of 93, 82, 72, 63, and 51%, respectively with local tumor recurrence or ablation site recurrence in 8% of patients [23] They demonstrated that single tumors measuring 4.0 cm and less had a far better overall predictor of ablation control Izumi analyzed the risk factors for distal recurrence after complete percuta-neous microwave ablation in 92 patients with three tumors or less, less than 3.0 cm

in size [26] His report found that two HCC nodules and a hepatitis C infection were associated with a higher incidence of recurrence

Similar results have been reported in the use of microwave ablation for hepatocel-lular carcinoma through a laparoscopic as well as open technique Yamanaka et al evaluated the therapeutic effects of microwave ablation in 27 patients with that of

23 patients undergoing hepatectomy [27] They demonstrated that microwave abla-tion achieved long-term survivals equivalent to that obtained with hepatectomy with significantly lower complications rates Abe et al also reported on 43 hepatocellular carcinoma patients treated with microwave ablation and demonstrated a complete ablation rate of 93% for tumors measuring 4.0 cm or less, but only 38.5% ablation success for tumors larger than 4.0 cm [21]

The complications of microwave ablation mirror those reported with radiofre-quency ablation, similar to the fact that both energy systems generate significant amounts of heat Because of that, bile duct stenosis, colon perforation, and skin burn have also been reported with microwave ablation [8,25] Similarly, liver abscess and tumor seeding have also been reported based on the type of technique utilized

in performing ablation [28]

Side effects of microwave ablation do include postoperative pain as well as potential asymptomatic pleural effusions when ablating lesions high in the dome

of the liver [19] Similarly, the degree of postoperative pain and underlying fatigue

is directly related to the volume of necrosis induced by the microwave ablation therapy [29] There has also been an evaluation of combining therapies, especially

in trying to manage hepatocellular carcinoma lesions greater than 5.0 cm in size [30] The most common combined technique that has been evaluated is the use of transarterial chemoembolization prior to ablation Transarterial chemoembolization

is an effective method of reducing blood supply to the hepatocellular carcinoma and, thus, reducing any type of heat sink effect that could occur potentially improv-ing the microwave ablation efficacy for lesions that are larger than 5.0 cm in size Seki et al has reported the use of microwave ablation 1–2 days after transar-terial chemoembolization with good results as well as good long-term ablation control [31]

The use of microwave ablation in hepatocellular carcinoma has been reported

in two US centers, predominantly using the Valley Lab Evident-based system The initial report from Martin et al demonstrated the use of the 915 MHz system on five patients with HCC with median lesion size of 3.3 cm (range 2.7–3.6 cm) They demonstrated 100% ablation success with ablation times ranging from 15 to

20 min in total, with initial 12-month follow-up demonstrating no evidence of abla-tion recurrence and a 50% hepatic non-ablaabla-tion recurrence These data have been further strengthened by a collaborative report from Iannitti et al with a report of

23 HCC tumors ablated ranging in size from 3.6 to 5.5 cm [29] All ablations were again performed using the Covidien Evident 915 MHz system

Our current experience now includes the treatment of 20 hepatocellular carci-noma patients with a majority of them men, all but one of Caucasian descent with

a median age of 66 years (range 45–83) The median number of tumors ablated was one with the median largest lesion being 4.0 cm (range 2.0–5.9 cm) Median ablation time was 15 min and the median OR time of 100 min, with an even distri-bution of access through either a laparoscopic incision or an open incision since a small minority of these patients underwent a concomitant hepatectomy at the time

as microwave ablation Four patients sustained six complications with the median highest grade being II, and the length of stay in these patients was 3 days (range 1–10 days) Post-ablation median volumes were 125.75 cm3 (range 21.2–243.6) Median disease-free survival of 18 months and overall survival of 41 months has been seen in this patient cohort

Despite its encouraging experimental and clinical results, microwave ablation, like other ablative techniques, is still in its evolutionary phase and needs to be standardized The utility of microwave ablation, as with radiofrequency abla-tion, is strongly influenced by appropriate patient selecabla-tion, anatomic location of the tumor(s), physician experience and training, and standardization of ablation techniques There still remains a demand for minimum standards for defining abla-tion success, ablaabla-tion recurrence, non-ablaabla-tion site hepatic recurrence, as well as extrahepatic recurrence in order to establish true quality control in this technology With ever-increasing treatment options available now in the management of hep-atocellular carcinoma, microwave ablation needs to be held to the highest standards

in order to demonstrate where it is most effective in the treatment algorithm of patients with unresectable hepatocellular carcinoma

284 R.C.G Martin

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