Outcome after hepatectomy versus percutaneous radiofrequency ablation for treatment of solitary hepatocellular carcinoma in Childs A cirrhotic patients

Outcome after hepatectomy versus percutaneous radiofrequency ablation for treatment of solitary hepatocellular carcinoma in Childs A cirrhotic patients

Gamal Saleh,a MD; Mostafa  El-Sayed,a MD; George A. Nashed,c MD Magdy Gad,b MD; Mohamed S.Abdelbary,d MD

a) Department of General Surgery, Benha University Hospital, Egypt.

b) Department of Tropical Medicine, Benha University Hospital, Egypt. c) Department of General Surgery, Cairo University Hospital, Egypt.

d) Department of Tropical Medicine, Cairo University Hospital, Egypt.

Abstract

Aim: Is to compare the short-term outcome of hepatic resection and radiofrequency ablation (RFA) in two groups of patients with a solitary hepatocellular carcinoma (HCC) less than 5 em in Childs A cirrhotic patients.

Patients and methods: The study comprised 60 patients; 52 (86.7%) males and 8 (13.3%)

females,  with  mean  age  45.2±9.6,  range  26-67  years.  The  patients  were randomized  into

2 groups: Resection group (n=28 patients) assigned to undergo hepatic resection and radiofrequency group (n= 32 patients) assigned to undergo RFA. The morbidity; hospital stay; overall survival; disease-free survival; psychological and physical welfare of the patients were assessed during the follow up period.

Results:  There  was  non-significant  difference  (P >0.05)  in  both  groups  as  regards  the

morbidity (21.4% in resection group versus 15.6% in RFA group).The mean hospital stay was

7±2.9 in resection group and 1±1.2 in RFA group; with a significant shorter stay (P<0.001) in  RFA group.  Patients  included  in  RFA group  showed  significantly  increased  scores  of psychological and physical welfare compared to resection group (P<0.001). Subgroup analysis showed non significant difference between both groups as regards the 2 years overall survival

&  recurrence-free  survival in tumours  less than 3cm.On  the other  hand,  surgical resection

was superior to RFA for 2 years overall survival & the recurrence-free survival in subgroup analyses for lesions > 3cm, <5cm.

Conclusion: In patients with ChildA cirrhosis with solitaryHCC  >3cm, RFAprovided results with non-significant difference to surgical resection with the advantages of being less invasive, shorter hospital stay, and better quality of life. While in tumours between 3 and 5 em, surgical resection was superior to RFA having better overall survival and tumour-free recurrence.

Key words: Radiofrequency  ablation, hepatic resection, hepatocellular carcinoma.

Introduction:

Hepatocellular  carcinoma  (HCC)   is  the fifth most common cancer in the world, with an estimated 500,000 deaths per year.l Advances in diagnostic imaging  and widespread application of  screening programs in  high­ risk  populations have  allowed  detection of small HCC, which can be curable by partial hepatic  resection  (HR),  liver transplantation, or local ablation  therapies. Out of these,  liver

transplantation,  which   offers  the   potential to both  resect  the  entire  potentially tumour­ bearing liver and to eliminate the cirrhosis, achieves  the  best  results  but  can  be offered only to a minority  of patients  because  of the shortage  of donors and high cost.2

Therefore, HR has generally been accepted as the  first  treatment of  choice  for  HCC  in many  centres.  Nevertheless, the associated cirrhosis  carries  a high risk of intraoperative

hemorrhage  and limits the extent of surgery thus   increases   the   risk   of   postoperative liver failure. So, many nonsurgical ablative methods  have  been  developed  for  patients with  small  HCC  not  eligible  for  surgery, such as cryoablation,  percutaneous ethanol injection, acetic acid injection, radiofrequency ablation (RFA), microwave coagulation and transcatheter arterial chemoembolization.3-8

Among these therapies, RFA is a promising and recently developed ablation technique. It induces deep thermal injury in hepatic tissue while  sparing  the  normal  parenchyma.   Its basic principle includes generation of high­ frequency alternating current which causes ionic agitation and conversion to heat, with subsequent evaporation of intracellular water which  leads to irreversible cellular changes, including intracellular protein denaturation, melting of membrane lipid bilayers, and coagulative necrosis of individual tumour cells.9

Cohort studies have shown RFA to g1ve encouraging results in terms of tumor control, with complete tumor ablation rates of90% to

95%, and low local recurrence rate of 5% to

10%. The treatment  has also been shown to be safe, with a 3-year survival rate of 62% to

68%.10-14

More recently, RFA has been also successfully  offered  in  patients  eligible  for liver  resection  or  transplantation_l5,16 Few studies in literature evaluate the outcomes of percutaneous treatments in comparison with surgical treatment.17-19

The aim of this study is to compare the short-term outcome of hepatic resection and radiofrequency  ablation in two groups of patients with a single HCC less than 5 em in Childs A cirrhotic patients.

Patients and methods:

This  prospective   study   was   conducted in General  Surgery & Tropical Medicine Departments, Benha and Cairo University Hospitals from April 2007 to May 2011 on

60 patients.

Patients  were  diagnosed  to  have  HCC based on histopathological examination (via percutaneous   ultrasound   guided   18  gauge

needle biopsy) with typical radiological features of HCC by two imaging techniques (US  and  spiral  contrast-enhanced   CT)  plus or minus alpha fetoprotein  level higher than

400ng/ml.

Inclusion criteria:

• Solitary HCC smaller than 5 em m diameter.

• No extra-hepatic metastasis.

• No radiological evidence of invasion into the major portal/ hepatic vein branches.

•  Good  liver  function   with  Child  Class

A, with no history of encephalopathy, ascites refractory to diuretics, or variceal bleeding.

•  Platelet   count   of   >50,000/mm3   and

prothrombin activity higher than 60%.

• No previous treatment ofHCC.

• Patient generally fit for either surgical resection   or     local     radiofrequency ablation therapy.

Patients were randomized into 2 groups:

• Resection group (n=28 patients) assigned to undergo hepatic resection.

•   Radiofrequency    group   (n=32patients)

assigned to undergo radiofrequency thermal ablation.

Written informed consent was obtained before surgery from all patients after explanation  & discussion  of  the  procedure and its possible complications.

All patients were subjected to:

• History taking.

• Thorough clinical examination including hepatomegaly, splenomegaly or ascites.

• Laboratory investigations including: hepatitis  viral  markers,  complete  blood count, liver function tests and serum alpha fetoprotein.

• Imaging studies including

- Abdominal ultrasound for assessment of hepatic focal lesion: site, size, number, echopattem, and detection of splenomegaly or ascites.

-Colour-Doppler detection of intralesional arterial signal (before, during and after treatment).

- Spiral contrast-enhanced  CT to detect hepatic lesion with contrast uptake in early

arterial  phase and rapid wash-out  in late venous (portal) phase.

• Liver biopsy under ultrasound guidance

was done using a true cut needle 18 gauge.

Resection Group:

During the study period, 28 patients were submitted to surgical resection of HCC. Resection  aiming at a free resection  margin of at least 1em over the tumour by visual estimation  was  performed   intraoperatively. All surgical resections had negative resection margms confirmed with histopathology. Surgical   specimen   examination   confirmed the    presence    of   liver    cirrhosis    in    all patients. Non anatomic resections were performed  in 17 cases, in the other 11 cases anatomic  resections   were  performed:   four left lateral lobectomy (segments 2,3), five bisegmentectomies (segments  5,6), and two segmentectomies   (segment 5).

Anatomic  resection  was  defined  as resection   of  the   lesion  together   with  the portal vein branch  related to the  lesion and the corresponding hepatic territory. Non anatomic  resection  was defined as resection of a lesion without regard to segmental, sectional, or lobar anatomy.20

Surgery was carried out under general anaesthesia  using  a  bilateral  subcostal inclSlon.   Formal    abdominal    exploration was done to exclude other intra-abdominal pathology.

After mobilization of the lobe with the lesion,   attention   was  then   turned   to   the porta-hepatis  which was dissected, followed by extra-hepatic pedicle occlusion of the respective portal and hepatic artery branch in anatomic resections.

In non anatomic resections, hilar dissection

was  omitted  and  direct  parenchymal transection was done along an estimated plane

1 em over the tumour using scalpel or cutting current diathermy after application ofbipolar radiofrequency   device21 (which  consists  of

2x2 array of needles arranged in a rectangle, introduced perpendicular into the liver along the intended transection line producing coagulative necrosis of liver parenchyma and sealing  biliary  radicles  and  blood  vessels);

or using ultrasonic activated scalpel with application of hemostatic sponge over the raw liver surface to assure haemostasis.  Ligation of the Intra-parenchymatous  pedicles was routinely  done  in all cases..  Suction  drains were left after hepatic resection, Figures(l-6).

RFAGroup:

During   the   study   period,   32   patients were submitted to RFA with a percutaneous approach under ultrasound guidance in an operative room setting under conscious sedation  or  general  anaesthesia.  Both subcostal  and  intercostal  approaches   were used while the patient was in an anti­ Trendelenburg position.

Either 3 or Scm expandable electrode needles,  according to tumour  size, with multiple    retractable     lateral-exit    J-hooks on the  tip  were  introduced  into  the  centre of the tumour enabling a substantial and reproducible enlargement of the volume of thermal necrosis produced with single needle insertion  and  offer  the  potential  of  large volume coagulation necrosis. RF thermal ablation  was performed  with  a gradual increase in power until either the power roll off was achieved or 15 minutes of treatment time    had   elapsed.    Thermal    coagulation of the track was performed during needle withdrawal.

Immediately  after  the  procedure,  sterile

dressings were applied on the site of puncture; the  patients were  asked to  lie down  on the site of puncture for at least 2 hours with observation of vital signs every half an hour.

Assessment of patients after treatment and

follow up:

HCC treatment was ended when the entire tumour appeared echogenic with ultrasound and disappearance of intralesional arterial colour-Doppler signals with the next strategy offollow up:

•  Abdominal   ultrasound   to   detect   the

change  of echopattem  of hepatic focal lesion,   one week after treatment,  1 and

3 months later then every 6 months.

•  Needle  biopsy  one  week  after the  end of treatment, response was considered complete                   when    specimens    revealed

necrotic tissue with no viable cells.

• Spiral CT one month after treatment, response   was  considered   complete   if there was no contrast enhancement of hepatic  lesions   in  arterial   phase  and partial ifthere were areas of enhancement within the original lesion.

• Serum  alpha-fetoprotein  3 months  later

and every 6 months.

The   morbidity,    hospital    stay,   overall survival,  and  disease-free  survival  for  both groups  were  accounted.  Psychological  and physical welfare of the patients were assessed on a 4-point (4: normal, 3: partially disturbed,

2: disturbed and 1: distressing) questionnaire of three subscales including: physical well­ being; relational life and psychological well­ being; and total psychological and physical welfare.

Statistical analysis:

The collected data were tabulated and analyzed   using  t-test   Chi-square   test  and Z-test.   Statistical   analysis   was   conducted using the SPSS (Version 16) for Windows statistical package. Values of P<0.05 were considered significant.

Results:

The study comprised 60 patients;  52 (86.7%)  males and 8 (13.3%)  females, with mean age 45.2±9.6, range 26-67 years. There was a non-significant  difference (P>0.05) between patients enrolled in both groups as regards the age and sex presentation,  with a significant   (P<0.001)   male   predominance in either group. The characteristics of the patients  submitted to the study  are reported in Table(l).

In the early post-operative period; transient liver failure was reported in 4 patients, 2 (7.1%)inresectiongroup and 2 (6.2%) in RFA group, they  were responded  to conservative

treatment; mild pleural effusion in 3 patients,

1 (3.6%) in resection group and 2 (6.2%) in RFA group; bile leak in 1 (3.6%) patient in resection group; hepatic abscess in 1(3.1%) case in RFA group; and wound infection in 2 (7.1%) patients in resection group. There was non-significant difference (P>0.05) in both groups as regards the morbidity (21.4% in resection group versus 15.6% in RFAgroup), Table(2).

The mean hospital stay was 7±2.9 in resection group and 1±1.2 in RFAgroup; with a significant shorter stay (P<0.001) in RFA group, Table(3).

Patients included in RFA group showed significantly increased scores of psychological and physical welfare compared to resection group (P<0.001), Table(4).

The  2  years  overall  survival  rates  were

82.1%  (85%  in  patients  with  HCC  < 3cm

& 75%  in patients  with  HCC>3,  <Scm) in resection group; and 68.7% (77.7% & 57.1% in those who had HCC of <3cm & >3, <Scm respectively) in RFA group; with a significant longer survival  (P<0.05)  in resection  group. Also the recurrence-free  survival rates at the end of follow up period were 71.4% (75% &

62.5% in cases with HCC< 3cm & >3,<Scm respectively) in resection group; and 59.3% (72.2% &42.8% in those who had HCC of <

3cm & >3, <Scm respectively) in RFA group; with a significant higher recurrence (P<0.05) in RFAgroup.

Subgroup analysis showed non significant

difference   (P>0.05)   between   both   groups as regard the 2 years overall survival & recurrence-free  survival in tumours less than

3cm.  On the  other  hand, surgical  resection

was significant superior (P<0.05) to RFA for

2  years  overall  survival  & the  recurrence­

free survival in subgroup analyses for lesions

>3cm, <Scm, Table(5&6).

Figure (1): HCC in right lobe ofthe liver.

Figure (3): Cutting  through  the liver parenchyma using current diathermy

Figure (5): Cut surface  of the liver after resection.

Figuer  (2): Radiofrequency device used,

1em away from the margin of the tumour, for haemostasis.

Figure (4): The dissected  tumour  with  ]em safety margin before complete  excision.

Figure (6): Resected specimen.

Table (1): Patients' demographic characteristics.

Mean (X-) ±SD *

Table (2): Complications for each method

Table (3): Early outcome.

Mean (X-) ±SD *

Table (4): Psychological and physical welfare  scores among  studied groups.

Data are shown as mean ±SD

Table (5): Overall patients' survival rates during the follow up period

Table (6): Recurrence-free survival rates during the follow up period.

Discussion:

The management of hepatocellular carcinoma on cirrhosis involves  nowadays many   treatment  options   in  relation   to  the tumour  stage  and the severity of underlying chronic  liver disease. 22,23 Among  these, liver transplantation has the  best  results  in terms of overall  survival and  disease-free survival, but only few patients  can be submitted to this treatment because of organ shortage. 24,25

Currently, liver  resection  is the  gold standard  treatment  for  resectable  liver tumours  whenever functional hepatic  reserve allows  it; however  it is not possible  or appropriate in up  to  80%  of cases  due to  a low predicted hepatic reserve in cirrhosis, significant co-morbidity or technical issues related  to the location, number  or size of the lesions,  subsequently other  modalities must be fully examined.26-28

RFA presents  a valid alternative to hepatic resection on many levels,  especially by improving  the   overall   survival    compared to standard chemotherapy or palliative treatments. Despite  this,  overall  survivals at

5 years still do not match those of hepatic resection and these  outcome  differences have been attributed to the factthat hepatic resection patients had resectable lesions  while those treated  by  RFA were  unresectable. It is this explanation, which has been taken by some authors  to  imply  that  in  matched   patients, results with hepatic  resection  and RFA would

be similar, that has resulted in some units advocating a randomized prospective trial for resectable lesions.  If proven, the advantage of a minimal invasive technique, with the greater preservation of liver,  reduced  complications and shorter hospital stays would expand the indications considerably.27,29,30

In  the  current  study,  only  patients submitted to  surgical   or  ablative   treatment with curative intent were included because the strong prognostic  value of complete  response oftreatment both in surgical  therapies  and in RFA has been clearly  demonstrated.31,32

Both  treatments in  this  series  were confirmed  to be safe, with no death occurring in either  group.  The current  study  showed  a lower incidence of complications in the RFA group.  In addition  the length  of hospital  stay was  significantly shorter  in the  RFA  group. These  results  were  likely  explained by  the less invasive  nature of RFA compared with surgical  resection.  Similar  figures  were reported by other authors.33-36

In the current study, no patient had postoperative haemorrhage in resection group and the rate ofbiliary leak was also1ow (3.5%), this could  be attributed to effective  biliary control as well as blood vessel occlusion with either  the  bipolar  radiofrequency device   or the ultrasonic activated scalpel.  Also,  all our resections were  performed without  applying Pringle's  manoeuvre and  therefore the  rate of  postoperative  liver  failure   in  our  series

was low; since avoidance of hepatic pedicle clamping  prevents  ischemia-reperfusion injury to the liver, which is known to predispose to postoperative liver failure.37-41

Apart from achieving a low rate of resection specific complications, the rate of overall postoperative complications in this series was

21.4% and is consistent with that reported in

other series ranging from 16 to 4S%.42-47

In this study, RFA provided better quality of life-adjusted  survival  than  that  observed with resection group. On the other hand Molinari  and Helton48 reported  that hepatic resection had better quality of life-adjusted survival as ablation therapy.

There was superior survival benefit for patients undergoing surgical resection as compared with  RFA. However, in subgroup analysis of lesions less than 3 em, there was no significant difference in recurrence-free survival between RFA and surgical resection. This corresponds with the findings of other studies_l8,19,34 Viral hepatitis could contribute to the HCC recurrences and it could influence the overall outcome. According to the results ofthis study, recurrence was the main reason of death which directly affected the overall survival   analyses   (68.7%   in   RFA  group and   82.1%   in   surgical   resection   group). The difference of local tumour clearance between the two modalities might be the essential   factor   that   affected   recurrence. HCC mainly disseminates through portal and hepatic  veins.  The  tumour  embolus  could shed in the neighbouring  branches of vessels and  form  the  microsatellite.49-52 Partial hepatectomy especially anatomic resection removed at least one em rim of normal liver parenchyma together with the original lesion macroscopically, and thus theoretically eliminated both the primary tumour and possible  venous  tumour  thrombi.53,54  This was   impossible   to   be   achieved   by   any local    ablation     modalities.     Furthermore, in  the   RFA  procedure,  repeated   insertion and overlapping the ablation areas were necessary when encountering tumours larger than one single session ablative area. Via the guidance  of  two-dimensional  ultrasound,  a

in the actual  lesion area which existed  in a three-dimensional  formation  during  the process of overlaying the ablation sessions. This  hypothesis  had  actually  been  proved by  Toyosaka  et  a1.,53 In  cases  of  solitary HCC less than 3cm, overlaying ablation was usually  not  necessary  because  the  necrosis area produced by one session of a single­ needle electrode was closed to a sphere with a diameter of three em.55 The viable tumour nest was consequently hard to survival due to homogeneously heat effect. This might at least in part explain why no significant  difference in recurrence-free survival between RFA and surgical  resection  for  HCC  less  than  3  em was found.

The results in this study were comparable with other series, Chagnon56 study on solitary HCC  measuring   less  than   Scm  observed similar overall   survival with HR and RFA. In the  retrospective  study  of  Hasegawa  et al.,57 although  for  HCC  higher  recurrence rates  were  found  for  RFA,  overall  survival was similar to HR for tumours less than 3cm. Vivarelli et al.,17 showed that  percutaneous radiofrequency had a higher recurrence rate than liver resection and a high number of recurrences,  31.6%,  developed at the site of the treated tumour.

It could be concluded that in patients with Child  A  cirrhosis  with  solitary  HCC  less than  3cm,  RFA provided  results  with  non­ significant   difference  to  surgical  resection with the advantages of being less invasive, shorter hospital stay, and better quality of life. While in tumours between 3 and Scm, surgical resection was superior to RFA having better overall survival and tumour-free recurrence rate.

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