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  2. Abstract

Salvage liver transplantation has been performed for recurrent hepatocellular carcinoma (HCC) or deterioration of liver function after primary liver resection. Because prior liver resection per se is an unfavorable condition for living donor liver transplantation (LDLT), we assessed the technical feasibility of LDLT after prior hepatectomy, and we compared the outcome of salvage LDLT with that of primary LDLT in HCC patients. Of 342 patients with HCC, 17 (5%) underwent salvage LDLT, with 5 having undergone prior major liver resection and 12 prior minor resection. During salvage LDLT, 12 patients received right lobe grafts, 3 received left lobe grafts, and 2 received dual grafts. There was 1 incident (5.9%) of perioperative mortality. Recipient operation time was not prolonged in patients undergoing salvage LDLT, but bleeding complications occurred more frequently than in patients undergoing primary LDLT. Overall survival rates after salvage LDLT were similar to those after primary LDLT, especially when the extent of recurrent tumor was within the Milan criteria. These results indicate that every combination of prior hepatectomy and living donor liver graft is feasible for patients undergoing salvage LDLT, and the acceptable extent of HCC for salvage LDLT is equivalent to that for primary LDLT. Liver Transpl 13:741–746, 2007. © 2007 AASLD.

Salvage liver transplantation (LT) has been performed for recurrence of hepatocellular carcinoma (HCC) or for deterioration of liver function after primary liver resection for HCC. Questions arise, however, regarding the technical feasibility of salvage LT in patients who have undergone prior liver surgery. Because initial liver resections in these patients are usually minor in extent, performing deceased donor whole liver graft implantation is not regarded as a contraindication. In contrast, prior performance of a major liver resection, such as right lobectomy, makes subsequent recipient hepatectomy technically difficult. To date, only a small number of salvage LT operations after major liver resection have been reported.1, 2 Living donor liver transplantation (LDLT) can also be performed for salvage. Although prior minor hepatectomy is acceptable for salvage LDLT, there have been no reports to date of salvage LDLT after major hepatectomy. Moreover, the extent of recurrent HCC eligible for salvage LT is not known.

To assess the technical feasibility and indication of salvage LDLT for recurrent HCC, we retrospectively assessed our experience performing these surgical procedures over 10 years. We especially analyzed the outcome of various combinations of prior major hepatectomy and graft types in patients undergoing LDLT for recurrent HCC after prior liver resection.


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  2. Abstract

Patient Selection

From February 1997 to March 2006, a total of 1,049 cases of adult LDLT have been performed in our institution,3, 4 with 342 recipients (32.6%) diagnosed as having HCC. Among the latter, 17 (5%) had undergone salvage LDLT after prior hepatectomy, including 5 who had undergone major liver resection (right or left lobectomy) and 12 who had undergone minor liver resection (sectionectomy, segmentectomy, or subsegmentectomy) (Tables 1 and 2).

Table 1. Clinical Profiles of Patients Who Underwent Salvage and Primary Living Donor LT for Hepatocellular Carcinoma
Profile characteristicTypes of LTTypes of prior liver resection before LT
Primary (n = 200)Salvage (n = 17)P-valueMajor resection (n = 5)Minor resection (n = 12)P-value
  • Abbreviations: LT, liver transplantation; MELD, Model for End-Stage Liver Disease; GRWR, graft-recipient weight ratio.

  • *

    Fifteen of 17 patients experienced recurrence of HCC; 4 underwent major resection and 11 underwent minor resection.

  • Including autotransfusions.

  • Requiring radiologic intervention or reoperation.

Patient profiles      
 Age (yr)51.2 ± 7.049.3 ± 8.60.29352.4 ± 6.148.0 ± 9.30.349
 Male sex158 (79%)12 (70.6%)0.4192 (40%)10 (83.3%)0.116
 Viral hepatitis B187 (93.5%)17 (100%)0.6065 (100%)12 (100%)-
 MELD score18.3 ± 8.313.6 ± 4.60.02611.6 ± 2.812.7 ± 7.00.749
 GRWR0.97 ± 0.191.05 ± 0.210.0991.06 ± 0.221.05 ± 0.210.941
 Within Milan criteria158 (79%)10 (66.7%)*0.4193 (75%)*7 (63.6%)*0.837
Liver graft      
 Right lobe graft113 (56.5%)12 (70.6%) 4 (80%)8 (66.7%) 
 Left lobe graft51 (25.5%)3 (17.6%) 1 (20%)2 (16.7%) 
 Dual grafts36 (18%)2 (11.8%) 0 (0%)2 (16.7%) 
Operation and surgical complication      
 Perioperative mortality14 (7%)1 (5.9%)0.8621 (20%)0 (0%)0.294
 Operation time (min)910 ± 203989 ± 2540.1331,034 ± 283970 ± 2450.645
 Packed red blood cell transfusion (units) 11.7 ± 6.512.7 ± 8.50.55413.2 ± 8.812.5 ± 9.40.888
 Bleeding complication20 (10%)5 (29.4%)0.0161 (20%)4 (33.3%)0.528
 Sepsis9 (4.5%)1 (5.9%)0.7940 (0%)1 (8.3%)0.706
 Vascular complication11 (5.5%)2 (11.8%)0.2710 (0%)2 (16.7%)0.884
 Biliary complication36 (18%)4 (23.5%)0.5251 (20%)3 (25%)0.685
Follow-up period      
 Mean ± standard deviation (mos)40.1 ± 22.430.7 ± 26.80.104   
 Median with range (mos)38 (0-110)27 (0-114)    
Table 2. Detailed Profiles of Salvage Living Donor Liver Transplant Recipients
Case No.Sex/Age (yr)Initial T stagePrior liver resectionRecurrence treatmentInterval to LT (mo)Cause of LTMELD scoreExplant T stageMaximal tumor size (cm)Tumor numberMicrovascular invasionMilan criteriaGraft typeSurvival period (mo)StateCause of death
  • Abbreviations: Subseg, subsegmentectomy; Seg, segmentectomy; Sect, sectionectomy; Left lobe, left lobectomy; Right lobe; right lobectomy; TACE, transarterial chemoembolization; RFA, radiofrequency ablation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; Recurrence, hepatocellular carcinoma recurrence; HCC, hepatocellular carcinoma; LL, left lobe graft; RL, right lobe graft; Dual, dual liver grafts.

  • *

    With combined intraoperative RFA.

  • modified pTNM (tumor, node, metastasis system) staging.7

  • Characteristics of the recurrent tumors.

1M/37pT2SegTACE + RFA41Recurrence8pT241AbsentWithinLL114Alive
2M/50pT1Left lobeTACE49Recurrence13pT20.42AbsentWithinLL0DeadSurgical complication
3M/46pT2SegTACE30Recurrence9pT4a4.85AbsentBeyondDual30DeadHCC recurrence
4F/57pT2SubsegTACE8Recurrence14pT22.61AbsentWithinLL6DeadChronic graft dysfunction
5M/42pT2SegTACE7Recurrence12pT4a3.512PresentBeyondRL15DeadHCC recurrence
7M/62pT2Left lobeTACE + RFA13Recurrence11pT4b42PresentBeyondRL18DeadHCC recurrence
9M/59pT3SegTACE25Recurrence12pT34.53PresentBeyondRL39DeadHCC recurrence
10M/33pT2Seg1Liver failure19No tumorDual42Alive
15F/54pT2Left lobeNone35Recurrence13pT21.32AbsentWithinRL16Alive
16F/50pT3Right lobeTACE42Recurrence7pT11.41AbsentWithinRL11Alive
17F/46pT3Right lobe81Liver failure14No tumorRL7Alive

In our institution, the criteria for salvage LDLT were basically similar to those for primary LDLT. In most patients, the extent of recurrent HCC was within the Milan criteria, but a few selected patients had more advanced recurrent tumors. The tumor staging at the time of initial hepatectomy was not taken into account. All patients underwent LDLT within 2 months after LT; this was considered a rescue treatment for recurrent HCC. After the decision was made to perform LDLT, the recurrent tumors were not further treated.

HCC workup routinely included positron emission tomography, radioisotope bone scan, magnetic resonance imaging, and chest computed tomography, with special attention to extrahepatic metastases.5 Recipient hepatic vascular structures were thoroughly evaluated through dynamic computed tomography with 3-dimensional reconstruction. During pretransplant evaluation, no patient was excluded as a result of prior liver resection per se.

When deciding on the type of partial liver graft to use for salvage LDLT, graft size-to-recipient matching was considered critically important, with the goal being a graft-recipient weight ratio of >0.8. The extent of prior liver resection did not change the type of liver graft selected, but dual-graft implantation was not attempted after major liver resection.

Surgical Techniques

Patients who had undergone prior minor liver resection underwent routine surgical procedures for adult LDLT without technical modifications. For patients who had undergone either right or left lobectomy, however, special attention was paid during mobilization of the native remnant liver for dissection of the previous liver cut surface. After fully severing the cut surface adhesions, the remaining mobilization procedures were the same as those for ordinary LDLT. Hepatic hilar adhesions were usually not severe because the hepatic hilum had not been dissected extensively during prior hepatectomy. To accommodate a sizable liver graft, either the right or left subphrenic space was extensively dissected, depending on the graft type. For secure hepatic venous reconstruction, the recipient inferior vena cava was fully isolated. Methods of graft vascular and biliary reconstructions were prudently selected, depending on the availability of recipient hepatic vein stump, portal vein, hepatic artery and bile duct, on a case-by-case basis.6

Tumor Staging and Statistical Analysis

The modified tumor, node, metastasis system (pTNM) classification was used to assess the extent of primary and recurrent HCC lesions.7, 8 As a control group for comparison of patient survival and HCC recurrence, we used clinical data of the first 200 patients who underwent primary LDLT for HCC (Table 1).

Mean values with standard deviation and median values with range were used for numeric data. The significance of differences was assessed by χ2, Fisher's exact test, and t test. Survival curves were estimated by the Kaplan-Meier method and compared by the log rank test. Statistical significance was set at P < 0.05.


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  2. Abstract

Patient Profiles

Patient profiles are summarized in Tables 1 and 2. In 15 of 17 patients, the main indication for salvage LDLT was treatment failure, either recurrent HCC or ineffective treatment of tumor recurrence. Two patients who had undergone prior left lobectomy received right lobe grafts, whereas of the 3 patients who had undergone prior right lobectomy, 2 received right lobe grafts and 1 received a left lobe graft. The mean interval between initial liver resection and LDLT surgery was 37 ± SD 26 months (range, 1-82 months).

Operation Profiles and Posttransplant Complications

Operation profiles and posttransplant complications are summarized in Table 1. Operation time was not greatly prolonged in the salvage compared with the primary LDLT group. The incidence rates of various posttransplant complications, other than bleeding, were similar in the salvage and primary LDLT groups. The incidence of bleeding complications was higher in the salvage than in the primary LDLT group (P = 0.016), but it did not differ between patients who had previously undergone major and minor liver resections (P = 0.528).

Patient Survival and HCC Recurrence

One patient (patient 2) with prior left lobectomy died of multiorgan failure that was initiated by postoperative bleeding, but there were no other cases of perioperative mortality. Overall survival did not differ significantly between the salvage and primary LDLT groups (P = 0.247, Fig. 1). After confining analysis to patients who met the Milan criteria, the survival rates between the salvage and primary LDLT groups became very close (P = 0.938, Fig. 2); in these patients, there was no incidence of HCC recurrence after salvage LDLT.

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Figure 1. Overall survival of patients who underwent salvage and primary LDLT. The 1-, 3-, and 5-year survival rates in the patients undergoing salvage LDLT were 88.2%, 64.8%, and 54%, respectively, whereas the respective survival rates in patients undergoing primary LDLT were 87.5%, 77.8% and 71.8%, respectively (P = .247).

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thumbnail image

Figure 2. Overall survival of patients who underwent salvage and primary LDLT, after excluding patients who did not meet the Milan criteria. The 1-, 3-, and 5-year survival rates in patients undergoing salvage LDLT were all 80% because there were only 2 early patient deaths, both unrelated to HCC recurrence (patients 2 and 4). The 1-, 3-, and 5-year survival rates in patients undergoing primary LDLT were 87.8%, 80.1%, and 74.8%, respectively (P = .938).

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  2. Abstract

In our institution, HCC was detected in about 30% of the explanted livers after adult LT, and 5% of these patients underwent salvage LT. Although HCC in patients with cirrhotic livers has been often managed by nonsurgical treatments, the number of HCC resections is gradually increasing in our program. The number of LDLTs for HCC patients is also increasing because LT has become widely accepted as a definite treatment to cure HCC and liver cirrhosis simultaneously. If a living donor is available, a nonnegligible proportion of HCC patients with advanced liver cirrhosis prefer LDLT as initial treatment or after failure of nonsurgical HCC treatments.9, 10 It is likely that the number of patients undergoing salvage LDLT will also increase.

Our results indicate that LDLT is technically feasible, even after prior major liver resection. Compared with patients undergoing primary LDLT, there was little additional perioperative risk from prior liver resection. Only 1 patient, the first who had undergone prior major liver resection and the 14th adult LDLT recipient in our institution, died from surgical complications. Our subsequent accumulation of experience in surgical techniques and postoperative management has reduced the surgical risk from prior liver resection such that the operation time and the volume of blood transfused do not remain serious drawbacks. Because the operation profiles and complication rates were similar in patients who had undergone prior major and minor liver resections, these 2 patient groups may have the same risks from surgery.

Two technical concerns arise when performing recipient hepatectomy, especially right hepatectomy, after prior liver resection. The first is in regard to recipient liver isolation with tolerable amount of bleeding. Heavy adhesions are often encountered after prior liver resection, and minute collaterals penetrate into such adhesions in patients with portal hypertension. Inattentive dissection of such perihepatic adhesions could result in many uncontrollable sites of pinpoint bleeding at the dissection surface. This technical difficulty may be one reason many transplant surgeons are unwilling to perform salvage LT after major hepatectomy. Similar difficulties have been encountered during late retransplantation after LDLT. Our experience with salvage LDLT and late retransplantation indicates that steady, meticulous sharp dissection is the only method to successfully determine the adequate dissection plane. Once the cut surface adhesions are fully severed, other mobilization procedures are similar to those for primary LDLT. The second technical concern is in regard to secure reconstruction of the hepatic vein outflow, which depends on the anatomical characteristics of the partial liver graft and hepatic vein stump at the recipient inferior vena cava. We have found that any method of hepatic vein reconstruction can be used after full dissection of the recipient inferior vena cava.6, 11, 12

We have shown here that various combinations of prior recipient hepatectomy and partial liver graft are possible in practice. Although we did not use one combination, left lobe graft implantation after right lobectomy, our results suggest that it may be technically feasible to use all 4 major combinations of salvage LDLT: right or left lobe graft and prior right or left lobectomy. We also found that HCC recurrence and patient survival after salvage LDLT were similar to those after primary LDLT, especially within the Milan criteria. No general consensus exists, however, regarding LT for recurrent HCC after liver resection. The outcome of salvage LT has been reported to be equivalent to that of primary LT, although primary resection and subsequent salvage LT has also been found to result in unfavorable outcomes compared with primary LT.1, 2 LDLT, however, differs from deceased donor LT in that the latter usually includes intervening waiting periods, with primary resection performed to avoid tumor progression. In situations in which there is an extreme shortage of deceased donors and limited availability of living donors, HCC resection is performed only for curative intent, without considering bridges to later salvage LT. Thus, indications for salvage LDLT may differ from those for salvage deceased donor LT.

Indications for salvage LT have been reported to differ, especially regarding the acceptable extent of recurrent HCC. Liver failure after liver resection can be an indication for LT, with even minor liver resection found to induce posthepatectomy hepatic failure in patients with advanced liver cirrhosis. Such early deterioration of liver function is vulnerable to infection. We do not regard superimposed infection as a contraindication for salvage LT unless it dramatically progresses to overt sepsis. Gradual progression of liver cirrhosis after liver resection is also an indication for salvage LT.

Recurrent HCC after liver resection is the main indication for salvage LT, but there is no consensus on its eligibility criteria. We used as the indication recurrent HCC meeting or slightly exceeding the Milan criteria. Although we had assessed the tumor extent at the time of prior liver resection and the response to the nonsurgical treatments, only the current extent of recurrent HCC per se was taken into account in practice. Because many patients in this series underwent repeated treatments of tumor recurrence, there may be some downstaging effect. Our results suggest that the survival outcome of salvage LDLT, based on explant tumor staging, was equivalent to that of primary LDLT. Thus, candidates for salvage LDLT can be selected without consideration of downstaging effects from preceding adjuvant therapies, and it may be reasonable that primary and salvage LDLT share HCC indication criteria.1, 2, 13–16 In our institution, the criteria for primary LDLT for HCC have been recently established as maximum tumor diameter of 5 cm or less, 6 or fewer tumors, and the absence of gross vascular invasion after detailed survival analyses.

For salvage LDLT, determination of the timing of surgery is of critical practical importance. We performed LDLT as early as the situation permitted in order to avoid tumor progression. In this series, the timing of LDLT was influenced by the timing of referral because 11 of the 15 patients with recurrent HCC had been referred from other institutions. Because most patients had undergone repeated episodes of transarterial chemoembolization or radiofrequency ablation therapy, the interval between initial recurrence after prior liver resection and LDLT operation was prolonged. For patients followed up at our institution, we usually recommend that LDLT be performed before the recurrent tumor exceeds the Milan criteria.

It is unclear whether patients who had early HCC recurrence after liver resection are candidates for salvage LDLT. If an early recurrence is associated with a well-advanced tumor or unfavorable pathology, the patient may not be indicated for salvage LT because there is a high probability of posttransplant HCC recurrence. In contrast, if early recurrence is related to incomplete local control of small HCC lesions, the patient may be indicated for salvage LT. Patients with a longer interval between prior liver resection and salvage LDLT showed more favorable survival than those with a shorter interval. A thorough pretransplant HCC workup should be performed because extrahepatic recurrence was not uncommon in patients with recurrent HCC after resection.5, 16

In conclusion, our results suggest that every combination of recipient prior hepatectomy and living donor liver graft is feasible for salvage LDLT and that the acceptable extent of HCC for salvage LDLT is equivalent to that for primary LDLT.


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  2. Abstract
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