15018752330
发表时间:2015-11-10 浏览次数:486次
Introduction
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths and the fifth most common form of cancer worldwide. Due to the nature of HCC, tumor stage, liver function, and performance status are the main prognostic variables and treatment allocation is based on the Barcelona-Clinic Liver Cancer (BCLC) staging system Liver transplantation and surgical resection are considered the optimal curative strategy, but only one-third of patients with HCC are suitable candidates for surgery. Radiofrequency ablation (RFA) is considered the most effective local ablative therapy for patients who cannot undergo surgery due to the number and distribution of the nodules and/or the liver impairment, and can be performed percutaneously, by laparotomy or by laparoscopy. Laparoscopic RFA is an interesting alternative when percutaneous RFA (perRFA) cannot be performed due to the tumor location (e.g., in the case of subcapsular lesions, nodules adjacent to diaphragm without a therapeutic window, proximity to adjacent structures, and lesions in deep locations) or because of the impossibility of visualizing the tumor by percutaneous ultrasound. It has been reported that intra-operative laparoscopic ultrasound (IOLUS) permits detection of 25% of new HCC nodules and allows much more accurate staging.
In this paper, we present our experience in laparoscopic RFA, analyzing the outcomes to show the safety and utility of this technique as a valid therapeutic alternative in the selected patients with HCC.
Methods
Patients and methods
Between March 2009 and December
2014, all patients with HCC attended at the Hospital Son Llàtzer in
Palma de Mallorca were entered in a prospective database. A complete
medical report was obtained in each patient. Age, gender, etiology,
patient characteristics such as comorbidities and liver function, size
and location of the tumors, main and associated procedures,
post-operative complications, treatment effectiveness and long-term
results were recorded. In all, 149 patients were included in the
database, with a mean of 24.83 new cases/year. Thirty-seven percent of
the patients were suitable for curative treatments such as liver
transplantation (which is not performed in our center), liver resection,
alcoholization, and radiofrequency.
A retrospective study was
carried out of patients undergoing laparoscopic RFA for HCC. The
procedure was performed in: patients with a single lesion or a maximum
of three lesions smaller than 5 cm who, due to medical problems or their
age, were not candidates for liver transplantation; patients not
suitable for liver resection in whom perRFA was contraindicated for the
following reasons: (1) lesions in proximity to the viscera; (2)
subcapsular lesions with a high risk of tumoral seeding; (3) lesions not
visible by perRFA; and selected patients as a bridging therapy in order
to meet the Milan criteria.
The follow-up period of each patient
was recorded as the time from the surgical procedure until last
clinical evaluation, loss to follow-up or death.
Post-operative complications were recorded and classified by the modified Clavien-Dindo Classification System.
Surgical procedures
Procedures were performed with the patient under general anesthesia and in the supine position. The pneumoperitoneum was performed with insufflation of CO 2 through a Veress needle inserted through a small 2-3 cm incision above the umbilicus. Patients with nodules in segments VI and VII were positioned in left decubitis position and an 11-mm port was placed in the anterior axillary line. In all cases, the abdominal pressure was maintained under 12 mmHg. In our procedures we used a 30° camera (Karl Storz GrubH and Co KG, Tuttlingen, Germany) and a first complete inspection of the intraperitoneal organs were performed to rule out any extrahepatic disease. A second 5-mm trocar was placed in the epigastric area on the left side of the falciform ligament to introduce the ultrasound device. When lesions were located in the upper part of segment VIII, a hole was made through the falciform ligament in order to provide better access for the ultrasound transducer. Usually an auxiliary 5-mm trocar was placed on the right side. More trocars were used if it was necessary to mobilize the liver, perform adhesiolysis between the liver and other adjacent organs or release an associated procedure like cholecystectomy.
Intra-operative laparoscopic ultrasound of the entire liver parenchyma was performed to confirm location of the tumor to be treated and to rule out the presence of new nodules. In cases of lesions that were not visible by ultrasound, a piece of a 1-cm (22G) needle was inserted preoperatively into the tumor guided by computed tomography (CT) or ultrasound with a signal enhancer. We did not perform an intra-operative biopsy of the tumor prior to the RFA. Interventional radiologists came to the operating room to perform the RFA procedure and the IOLUS.
The RFA was carried out using the Cool-Tip RFA system (Covidien, Boulder, CO, USA), which uses internally cooled electrodes (ICEs) for ablation. This system circulates chilled saline to the tip of the needle electrode, thus lowering the temperature of the tissue immediately adjacent to it, minimizing tissue charring, and improving the delivery of energy to surrounding tissues.
The RFA electrode was inserted through a separate percutaneous puncture and the needle was placed as parallel as possible to the plane of the ultrasound so that its entire path could be seen on the ultrasound image as it traversed the liver parenchyma. A single needle 20-cm long and with a 2-cm tip exposure was used for tumors < 3 cm, and for tumors ≥ 3 cm a cluster was used to achieve an adequate tissue margin. A 12-min RFA cycle was performed as per the manufacturer's recommendations
The ICEs have sensors in their tips which measure tissue temperature and impedance at the end of the ablation procedure. [13] The ablation was considered satisfactory if the end-tissue temperature after 12 min of RFA was ≥ 60 °C, which is enough to cause instantaneous cellular necrosis. [13] If the end-tissue temperature was < 60 °C, another RFA cycle lasting 6-10 min was performed.
After finishing the nodule ablation, the intrahepatic needle track was treated with thermocoagulation to avoid track seeding.
Follow-up and definition of clinical outcome
Treatment outcome was evaluated with an enhanced CT scan 2 months after laparoscopic RF. [14] The inflammatory reaction makes the proper assessment of the treated nodule difficult during the 1st month. Thereafter, patients were followed with CT or magnetic resonance imaging and with the α-fetoprotein every 3 months during the 1st year and every 6 months in the 2nd year.
Initial incomplete ablation was determined as the presence of enhanced areas within the treated nodule in the first follow-up imaging. Sustained complete ablation was defined as the absence of enhanced areas within the treated area at the end of the follow-up period.
Local tumor recurrence was defined as the presence of a growing tumor in the ablation zone after complete ablation had been determined in the first follow-up CT. Distant recurrence or new tumor progression was determined as a growing nodule occurring away from the ablation zone.
Statistical analysis
Data for all patients with HCC
were recorded prospectively and introduced into a Microsoft ACCESS
database. Data from patients undergoing laparoscopic RFA were analyzed
retrospectively using the statistical software SPSS version 18 (SPSS
Inc., Chicago, IL, USA). Continuous data were described as means and
analyzed with Student's t-test if the distribution was normal or with Mann-Whitney U-test
otherwise. Discontinuous data were presented as percentages and were
analyzed by the Chi-square of Fisher's exact test. Overall survival
curves and cumulative recurrence curves were analyzed by the
Kaplan-Meier method. P < 0.05 was considered statistically significant.
Results
Patient and tumor characteristics
Between March 2009 and December 2014, 149 new cases of HCC were recorded. Eight perRFA and 40 surgical RFA were performed during this period. Only 3 lesions with radiological features of HCC from the 40 surgical RFA were treated by an open approach, while 37 lesions from 32 different patients were treated with laparoscopic RFA. We recorded the age of all patients, gender, liver function (Child-Pugh Classification), etiology [hepatitis C virus (HCV + ) or non-HCV + ], and previous treatment. For tumors we recorded the number of nodules (uninodular or binodular), size, and location (subcapsular, intrahepatic or adjacent to viscera).
All patient and tumor characteristics of the laparoscopic RFA procedures are shown in .The main reasons for preferring laparoscopy to the percutaneous approach were: subcapsular location in 26 cases, intrahepatic location in eight cases which were difficult to define by perRFA, and location very close to adjacent viscera in three cases.
Although according to BCLC guidelines patients with liver function Child C are not initially candidates for RFA, one patient with Child C finally underwent RFA as palliative treatment after discussion with the Hepatobiliary Committee.
Two patients had a simultaneous surgical procedure associated with the laparoscopic RFA. One of them had a cholecystectomy due to the proximity of one of the tumors to the gallbladder, which was performed prior to the RFA. The specimen was removed by using an endobag and no tumoral seeding was reported. The other simultaneous procedure was a hysteroscopy for a uterine biopsy.
Radiofrequency ablation results
An initial complete ablation was achieved in 35 of the 37 lesions that underwent laparoscopic RFA (94.6%). In one patient without initial complete ablation the lesion was subsequently treated by laparoscopic alcoholization and in the other transarterial chemoembolization (TACE) was performed.
Morbidity
No complications were reported during any
of the laparoscopic RFA procedures nor in relation to other simultaneous
techniques. Conversion to open surgery was not needed in any patient.
The mean post-operative hospital stay was 4.9 days (1-30). All
complications are detailed in [Table 2] following the modified Clavien-Dindo Classification System. [12]
Eight patients presented some kind of complication: only one of them
required emergency reintervention, following a hemoperitoneum (Clavien
IIIb). One patient presented liver decompensation with mild ascites and
was successfully treated with diuretics (Clavien I).
Recurrence
The median follow-up period was 28.3 ± 2.3
months. After achieving initial complete ablation (35 procedures), local
recurrence was seen in 13 cases, after a median delay of 8.38 months
(range 3-30). Six recurrent lesions were treated by TACE, 5 by new
laparoscopic RFA, 1 by perRFA, 1 by sorafenib, and 1 underwent
symptomatic treatment only.
Cumulative recurrence rates at 6, 12,
and 36 months were 22.85%, 34.28%, and 37.18%, respectively. A higher
local recurrence rate was observed in cirrhotic patients, HCV +
, with subcapsular tumors, although the differences were not
statistically significant. Twenty-two lesions of the 35, which achieved
initial complete response did not present local recurrence at the end of
the follow-up period, representing a rate of sustained complete
ablation of 62.85%. Mean follow-up was 18.72 months (range 3-44).
Distant recurrence was observed in 15 patients after a mean delay of
16.66 months of follow-up (range 4-39).
Mortality and survival
One patient was lost to follow-up
and 16 had died by the end of the follow-up period. No mortality related
to the main procedure was reported. One death was reported 30 days
after the surgical procedure in a patient with Child-Pugh C cirrhosis
who, after RFA, also had complications related to acute vascular ulcers
following severe sepsis and multi-organ failure. Only 3 deaths were
related to HCC progression.
Overall survival rates at 1, 2, and 3 years were 89%, 67.5%, and 40%, respectively [Figure 3]. There was no association between local or distant recurrence and survival.
Discussion
Patients with HCC have very poor prognosis. Most have poor liver function or
major comorbidities at the time of diagnosis that rule out major resections; in
fact, liver resection can only be performed in one third of the patients with
the disease. Modern techniques such as RFA are not only potentially curative,
with results similar to those achieved with liver resection, but are also
minimally invasive. Laparoscopic RFA was introduced by Jung et al. in 2002 as an alternative technique in cases in which the
percutaneous approach was not feasible. Another indication for the procedure is
as a bridging therapy to liver transplantation for patients with HCC and
terminal liver disease awaiting liver transplantation.
Compared to
perRFA, the laparoscopic approach allows a complete vision of the entire
intervention, especially when associated with ultrasound, which has demonstrated
its utility in reporting new malignant lesions intra-operatively, and offers the
possibility of treating other tumors simultaneously. Some groups have shown
better oncological outcomes and less tumoral spread with laparoscopic RFA than
with the percutaneous procedure. Moreover, simultaneous procedures can be
performed together in laparoscopic RFA such as cholecystectomy or liver
resection if needed. However, de la Serna et al reported that
laparoscopic RFA for HCC adjacent to the gallbladder seems to be associated with
a decreased ablation efficacy in terms of both initial and long-term complete
tumor response. The complications associated with perRFA reported in the
literature include intraperitoneal hemorrhage, hepatic infarction, hepatic
abscess formation, intestinal perforation, bile peritonitis, and carcinoma
seeding. Laparoscopic RFA of HCC is associated with a low rate of major
complications, most of them related to bleeding from hepatic puncture sites or
trocar accesses and to iatrogenic malignant seeding. We reported only one case
of major bleeding requiring reintervention, and no tumor spread was observed.
There were no treatment-related deaths in our series.
In the literature,
few reviews of minimally invasive RFA are available, since most surgical RFA
procedures are still performed by laparotomy. Today the advantages that the
laparoscopic approach can offer, in terms of creating fewer adhesions and
achieving earlier recovery, are well known. The procedure also appears to
minimize the surgical insult, with less post-operative morbidity in cirrhotic
patients, ] so laparoscopic RFA seems preferable to open RFA in these
patients as well. The laparoscopic approach has also shown lower morbidity,
lesser hepatic decompensation, and blood loss, and fewer pulmonary
complications. Moreover, the increased intraperitoneal pressure necessary to
perform laparoscopy reduces the portal venous flow, thus improving thermal
conduction, enhancing ablation efficacy, and enlarging the ablation zone.
The rates of initial complete ablation, sustained complete ablation,
local recurrence, and survival in the present report are similar to those in
previously published reviews, despite the limitation of our study in terms of
its retrospective nature and its small sample size. de la Serna et al reported an initial complete ablation rate of 94% in a study including
51 treated lesions, with a sustained complete ablation rate of 70%, slightly
higher than our rate of 62.85%. Our 1-year cumulative recurrence of 34.28% is an
improvement on the rates of 47.4% published by Lee et al. and of
39% published by de la Serna et al
Some authors have
reported that pre-treatment α-fetoprotein and poorly differentiated HCC were
independent predictors of local tumor recurrence. This suggests that performing
an intra-operatively biopsy prior to laparoscopic RFA, as some groups do
systematically, may help to predict long-term results, although it has also been
reported to contribute to malignant seeding.
Patients with HCC have a
dismal prognosis, with a moderate rate of local recurrence and low long-term
survival. Moreover, most of the patients who are treated with laparoscopic RFA
are elderly, have severe comorbidities or have impaired liver function which may
make prognosis even worse. Further prospective randomized controlled trials with
larger sample sizes should focus on combining RFA with therapies like TACE in
order to decrease local tumor progression.
As a conclusion, laparoscopic
RFA of HCC is a safe and effective curative strategy in selected patients with
unresectable disease, especially when the percutaneous approach is very
difficult. In combination with ultrasound, this technique offers clear
advantages over other approaches. The incidence of major complications within 30
days after the procedure is very low and the long-term outcomes are similar to
those achieved with liver resection. Further trials are needed to assess
long-term results in terms of local recurrence and survival.
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