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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

In patients with hepatocellular carcinoma (HCC) exceeding conventional (T2) criteria for orthotopic liver transplantation (OLT), the feasibility and outcome following loco-regional therapy intended for tumor downstaging to meet T2 criteria for OLT are unknown. In this first prospective study on downstaging of HCC prior to OLT, the eligibility criteria for enrollment into a downstaging protocol included 1 lesion >5 cm and ≤8 cm, 2 or 3 lesions at least 1 >3 cm but ≤5 cm with total tumor diameter of ≤8 cm, or 4 or 5 nodules all ≤3 cm with total tumor diameter ≤8 cm. Patients were eligible for living-donor liver transplantation (LDLT) if tumors were downstaged to within proposed University of California, San Francisco (UCSF) criteria.13 A minimum follow-up period of 3 months after downstaging was required before cadaveric OLT or LDLT, with imaging studies meeting criteria for successful downstaging. Among the 30 patients enrolled, 21 (70%) met criteria for successful downstaging, including 16 (53%) who had subsequently received OLT (2 with LDLT), and 9 patients (30%) were classified as treatment failures. In the explant of 16 patients who underwent OLT, 7 had complete tumor necrosis, 7 met T2 criteria, but 2 exceeded T2 criteria. No HCC recurrence was observed after a median follow-up of 16 months after OLT. The Kaplan-Meier intention-to-treat survival was 89.3 and 81.8% at 1 and 2 yr, respectively. In conclusion, successful tumor downstaging can be achieved in the majority of carefully selected patients, but longer follow-up is needed to further access the risk of HCC recurrence after OLT. (Liver Transpl 2005;11:1505–1514.)

Following the seminal publication by the group from Milan, Italy,1 using a restrictive set of criteria for orthotopic liver transplantation (OLT) in patients with hepatocellular carcinoma (HCC) to limit the risk for tumor recurrence, excellent 5-yr patient survival of greater than 70% after OLT has been reported from at least 4 other centers using criteria similar to or slightly exceeding the Milan criteria.2 The United Network for Organ Sharing (UNOS) has incorporated the Milan criteria into stage T1 (single lesion, <2 cm) and T2 (single lesion, 2-5 cm; 2 or 3 lesions, all within 3 cm) in a modified HCC staging system.3 The Model for End-Stage Liver Disease (MELD) system of organ allocation in the United States, implemented in February 2002, also included a priority scheme for patients with T1 and T2 HCC.3, 4 This has resulted in a significantly shorter waiting time for OLT and a lower risk of dropout from the waiting list due to tumor progression among these patients with early-stage HCC.4–6 After the latest modification of the HCC-adjusted MELD scheme, only patients with T2 HCC are currently eligible to receive priority listing for OLT.3, 4 While OLT is now widely accepted as the best treatment for early-stage HCC, the demand for OLT to treat HCC is also increasing as a result of the rising incidence of HCC, largely due to the hepatitis C epidemic, which will likely continue for at least another decade.7

Patients who present with HCC initially exceeding T2 criteria are generally excluded for cadaveric OLT, especially in light of the current UNOS guidelines for priority listing under MELD. The idea of tumor downstaging to within currently acceptable criteria for OLT in these patients has generated considerable interests and controversies in recent years. Some groups have reported their limited experience using transarterial chemoembolization (TACE) to reduce the size of the tumor, thereby facilitating resection or OLT.8, 9 However, there has been no published study designed specifically to evaluate the feasibility and outcome of HCC downstaging to within conventional criteria for OLT.

The experience accumulated with loco-regional therapy as bridging procedures to OLT,8–12 along with the reduced waiting time under the HCC-adjusted MELD system for organ allocation, enabled us to embark on a prospective study on tumor downstaging for OLT. This study was designed to address 2 key questions. First, what is the likelihood of successfully bridging these patients to OLT with downstaging procedures under the HCC-adjusted MELD scheme of organ allocation, and the risk of further tumor progression or dissemination during the treatment phase and subsequent waiting period for OLT (dropout)? Second, even if tumor downstaging were considered successful, would the risk for tumor recurrence following OLT in these patients be the same or significantly higher than those with T2 HCC from the outset at the time of diagnosis to OLT?

In this first prospective clinical study on HCC downstaging before OLT, we present the initial results based on an intention-to-treat analysis, focusing on the probability of successful downstaging to meet T2 HCC criteria for OLT. We also examined the short-term risk for HCC recurrence after OLT.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

Downstaging Protocol

The downstaging protocol was initiated in June 2002. All potential candidates for downstaging of HCC required approval by the institutional liver transplant committee before entry into the downstaging protocol. The eligibility criteria for downstaging based on HCC size and number are summarized in Table 1. We used 8 cm as the upper limit for the diameter of a solitary lesion and as the maximum total tumor diameter for multifocal HCC, based on a previous study from our institution showing a total tumor diameter beyond this limit to be an independent predictor of worse survival in multivariate analysis.13 The criteria for patients with 4 or 5 lesions were modified from the criteria proposed by Marsh et al.14 from the University of Pittsburgh and by Bruix and Llovet2 from the University of Barcelona. Criteria for successful downstaging included a decrease in the size of a single or multiple lesions to within T2 criteria, or complete tumor necrosis without contrast enhancement based on either computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen (Table 1).15 For patients with 4 lesions, for example, successful downstaging required complete tumor necrosis (equivalent to tumor obliteration) of at least 1 of these lesions, so that there would be no more than 3 lesions with viable tumor, all within 3 cm in diameter to meet T2 criteria. In all patients, treatment was intended to achieve complete tumor necrosis of all the lesions.

Table 1. Downstaging Protocol for Patients with Hepatocellular Carcinoma Initially Exceeding UNOS T2 Criteria for Liver Transplantation
  1. Abbreviations: HCC, hepatocellular carcinoma; UNOS, United Network for Organ Sharing; OLT, orthotopic liver transplantation; LDLT, Living-donor liver transplantation; UCSF, University of California, San Francisco.

Eligibility criteria for downstaging based on HCC characteristics
 a) 1 lesion > 5 cm and ≤ 8 cm.
 b) 2 or 3 lesions, at least one > 3cm but ≤ 5 cm + total tumor diameter ≤ 8 cm.
 c) 4 or 5 lesions, all ≤ 3cm + total tumor diameter ≤ 8 cm.
 d) No vascular invasion by imaging studies.
Criteria for successful downstaging by imaging studies
 1) Tumor size and number meeting UNOS T2 criteria.3
 2) Complete tumor necrosis without contrast enhancement to suggest residual tumor, equivalent to obliteration of the tumor irrespective of the tumor size.15
Additional guidelines
 1) A minimum follow-up period of 3 months after downstaging is required before cadaveric OLT or LDLT, along with imaging studies meeting the above defined criteria for successful downstaging.
 2) Approval for a petition to the regional UNOS review board for priority listing is needed for priority listing for cadaveric OLT after successful downstaging.
 3) Patients can undergo LDLT if a donor is available, and if imaging studies meet proposed UCSF expanded criteria.13
 4) Those with acute hepatic decompensation after downstaging procedures are not eligible for OLT unless they meet the above criteria.

Additional guidelines to be met prior to cadaveric OLT or right hepatic lobe living-donor liver transplantation (LDLT) are summarized in Table 1. A minimum follow-up period of 3 months after downstaging was required before cadaveric OLT or LDLT, along with CT or MRI, meeting the above-defined criteria for successful downstaging. Patients undergoing cadaveric OLT received approval by the regional UNOS review board of a petition for priority listing for OLT following successful downstaging of HCC. Among patients who were initially listed for OLT with T2 HCC under MELD and then developed tumor progression to beyond T2 criteria, but within downstaging criteria, these patients were temporarily removed from the waiting list for OLT while undergoing HCC downstaging. Upon successful downstaging based on the same set of criteria, a petition was sent to the regional UNOS review board for these patients to be given an extension of the previous MELD priority score for OLT. Patients were eligible for LDLT if the tumors were downstaged to within the proposed University of California, San Francisco (UCSF) criteria (a single lesion not greater than 6.5 cm, or no more than 3 lesions, none of which exceed 4.5 cm and whose total tumor diameter does not exceed 8 cm).13 Should a patient develop hepatic failure as a result of tumor downstaging, the option of salvage OLT was not available unless the above-defined criteria for successful downstaging and all other guidelines were met. The downstaging algorithm is also summarized in Figure 1.

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Figure 1. Summary of the downstaging algorithm at UCSF. The eligibility criteria for downstaging according to HCC characteristics are summarized in Table 1. The proposed UCSF criteria are based on data from Yao et al.13 *, A minimum follow-up period of 3 months after downstaging is required before cadaveric OLT or LDLT, along with imaging studies meeting the above-defined criteria for successful downstaging. CLT, cadaveric liver transplantation.

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In terms of loco-regional therapies used for downstaging (Fig. 2), laparoscopic radiofrequency ablation (RFA) was the preferred treatment modality for patients with multifocal HCC and a Child-Turcotte-Pugh (CTP)16 score of <10, taking advantage of the fact that laparoscopic RFA could effectively treat all the lesions in a single session. For patients with a single lesion of >5 cm and ≤8 cm, TACE and laparoscopic RFA, either alone or in combination, were the mainstays of downstaging treatment. Selected patients with adequate hepatic reserve, especially if the tumor was located in the left lateral segment, were also considered for hepatic resection as a downstaging procedure prior to OLT, rather than as a primary treatment. If histopathologic examination of the resection specimen revealed microvascular invasion, these patients were no longer considered for OLT. Percutaneous RFA or ethanol injection was used mainly in conjunction with TACE for residual or satellite lesions ≤4 cm, in accord with published data showing lower efficacy of these treatments for tumors beyond 4 cm in maximal diameter.11, 17–19 The choice of treatment was ultimately determined based on tumor size, number, location, and hypervascularity according to CT or MRI, as well as the hepatic reserve of the individual patient, upon thorough review of the clinical and radiologic information in a multidisciplinary tumor conference.

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Figure 2. Loco-regional treatment protocol for downstaging. Laparoscopic RFA was the preferred treatment modality for patients with multifocal HCC and a CTP of <10. For patients will a single lesion, TACE and laparoscopic RFA, either alone or in combination, was the mainstay of downstaging treatment.

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All patients undergo CT or MRI of the abdomen every 3 months during the treatment phase and after they were placed on the waiting list for OLT following successful downstaging. Chest CT was performed at baseline and every 3 months to exclude metastatic disease. Bone scan was performed at baseline and if bone metastasis was suspected during follow-up. Exclusion criteria for OLT included evidence of gross vascular invasion, further progression of tumor beyond entry criteria for HCC, and extrahepatic or lymph node metastases.

Histopathologic Analysis

Among patients who underwent OLT after successful downstaging, explant tumor staging in this study was based on the size and number of only the viable tumors. For example, if there was a 4-cm nodule with viable tumor and a 3-cm completely necrotic nodule in the explant, the tumor was staged as T2 based on a single 4-cm lesion. The grade of differentiation was based on the Edmondson and Steiner criteria (grade 1, well differentiated; grade 2, moderately differentiated; and grade 3, poorly differentiated).20 The presence of microvascular or macrovascular invasion was also recorded.

Outcome Analysis

The Kaplan-Meier method was used to estimate the intention-to-treat survival and the probabilities of treatment failure. Time 0 was defined as the date of the first downstaging treatment. Treatment failure was defined as death from any cause without OLT, dropout from the waiting list due to tumor progression using criteria as defined earlier (tumor size and/or number exceeding entry criteria, macrovascular invasion, or extrahepatic metastasis), or HCC recurrence after OLT.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

Baseline Patient Characteristics

The baseline clinical characteristics of the 30 patients undergoing downstaging in this study are summarized in Table 2. Among them, 28 patients had initial tumor stage already exceeding T2 criteria but meeting eligibility criteria for the downstaging protocol (Table 1) at the time of presentation at our center. The other 2 patients presented initially with HCC stage within T2 criteria but had tumor progression to beyond T2 criteria while on the waiting list for OLT, requiring downstaging of HCC to be reconsidered for OLT. The majority of the cohort (70%) had chronic hepatitis C as the etiology of liver disease. Three patients had diagnoses other than chronic hepatitis B or C, which included cryptogenic cirrhosis, autoimmune hepatitis, and hemochromatosis. The majority of patients (87%) had Child's class A or B cirrhosis (CTP < 10) before tumor downstaging. The median alpha-fetoprotein level before HCC downstaging was 66 ng/mL (range = 3-6539). The single patient with an alpha-fetoprotein level of >1000 ng/mL (6539 ng/mL) underwent resection as the downstaging procedure. Seventeen of 30 patients (57%) had histologic confirmation of HCC at or before downstaging treatments. All patients had CT or MRI characteristics strongly supporting the diagnosis of HCC.

Table 2. Baseline Characteristics of 30 Patients Undergoing Downstaging
Median Age (yr, range)57 (47-73)
Gender (M/F)25/5
Asian number (%)9 (30%)
Child-Turcotte-Pugh class cirrhosis (A/B/C)*12/14/4
Etiology of liver diseaseNumber (%)
HCV21 (70%)
HBV6 (20%)
Others3 (10%)
Alpha-fetoprotein (ng/mL) (median, range)66 (3-6,539)
HCC characteristics before downstaging
Number of lesionsNumber of patients (median and range of maximal tumor diameter)
  • *

    Child-Turcotte-Pugh class A, B, and C correspond to Child-Turcotte-Pugh (CTP) scores of 5-6, 7-9, and 10-15, respectively.

  • Baseline alpha-fetoprotein before downstaging treatment was missed in 1 patient.

114 (6.5 cm, 5.3-8 cm)
28 (4.3 cm, 3.3-5 cm)
36 (4.6 cm, 4.2-5 cm)
42 (2.6 cm, 2.2-3 cm)
Histologic confirmation of HCC at or before downstaging17 (57%)

Loco-regional Therapy for Tumor Downstaging

Loco-regional treatments used for downstaging in this cohort are summarized in Table 3. Laparoscopic or open RFA and TACE were the primary treatment modalities in 26 of 30 patients. Seven patients received a combination of laparoscopic RFA and TACE. Among them, TACE was used as the initial treatment to facilitate subsequent laparoscopic RFA in 5 patients, and for residual or recurrent HCC after laparoscopic RFA in 2 patients. Four patients underwent resection as a bridge to OLT. One of these patients underwent resection despite a high preoperative CTP score of 11. The decision for resection in this patient was based on the location of a 5.3-cm lesion very close to the liver surface, which precluded TACE or laparoscopic RFA because of the risk for tumor rupture, and was too large for percutaneous ablation to be effective. This patient did well after resection without developing further hepatic decompensation.

Table 3. Downstaging Treatments Received by the 30 Patients
 Number of patients (Number of treatments)
  • Abbreviations: RFA, radiofrequency ablation; TACE, trans-arterial chemoembolization; PEA, percutaneous ethanol ablation; CTP, Child-Turcotte-Pugh.

  • *

    Two had open RFA and the other 7 received laparoscopic RFA.

  • TACE was used as the initial treatment to facilitate subsequent laparoscopic RFA in 5 patients, and for residual or recurrent HCC after laparoscopic RFA in 2 patients.

  • One of these patients underwent resection despite a high preoperative CTP score of 11. This patient had a 5.3-cm lesion very close to the liver surface, which precluded TACE or laparoscopic RFA because of the risk for tumor rupture, and was too large in size for percutaneous ablation to be effective. The other 3 patients had a CTP score of ≤ 7 before resection.

Laparoscopic/open RFA only*9 (9)
Laparoscopic RFA + TACE7 (15)
TACE only5 (9)
TACE + percutaneous ablation5 (16)
 TACE + PEI3 (12)
 TACE + percutaneous RFA2 (4)
Resection4

Intention-to-Treat Outcome

The intention-to-treat outcome for the 30 patients undergoing tumor downstaging is summarized in Figure 3. Downstaging was considered successful in 21 of 30 patients (70%) based on the criteria as defined earlier. Among these 21 patients, 16 had received OLT subsequent to successful downstaging, including 2 who underwent LDLT, and 4 patients were still awaiting OLT after successful downstaging. The other patient had an initial response, with complete necrosis of the tumor by serial imaging studies, following downstaging of a 5.7-cm well-differentiated HCC by open RFA. However, this patient was subsequently excluded for OLT at 300 days after downstaging due to psychosocial reasons. Follow-up was censored at the time of exclusion from OLT. The median time was 6.0 months (range = 3-25 months) from the first downstaging procedure to OLT, and 4.6 months (range = 3-25 months) from the last downstaging treatment to OLT. Seven of 16 patients who underwent OLT received a single downstaging treatment. After a median follow-up of 16 months (range = 5-27) after OLT, 1 patient died 14 months after OLT with poor graft function and biliary complications. The other 15 patients were alive and free of HCC recurrence at the time of last follow-up.

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Figure 3. Summary of the intention-to-treat outcome of 30 patients undergoing downstaging of HCC. *, Follow-up in 1 patient was censored at the time of exclusion from OLT due to psychosocial reasons. This patient had an initial radiologic response, with complete necrosis of a 5.7-cm HCC treated with open RFA. CLT, cadaveric liver transplantation.

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The HCC characteristics and outcome of the 9 patients classified as treatment failures are summarized in Table 4. They included 7 dropouts related to HCC (1 subsequently died) and 2 deaths without OLT unrelated to HCC progression but due to liver failure. Five of the 7 dropouts were found to have either metastases or macrovascular tumor invasion after laparoscopic RFA as the main downstaging treatment (Table 4). One patient developed multiple satellite lesions in the liver after achieving complete necrosis by 4 sessions of TACE. The remaining patient underwent segmental resection of a 6.5-cm lesion in the left lobe, but was excluded for OLT due to the presence of microvascular tumor invasion in the resection specimen. This patient was considered a treatment failure based on an intention-to-treat principle.

Table 4. Characteristics of the 9 Patients with Treatment Failure
Initial HCC featuresTreatmentOutcome
  1. Abbreviations: L-RFA, laparoscopic radiofrequency ablation; LN, lymph node; TACE, transarterial chemoembolization; IVC, inferior vena cava.

1) Dropout due to HCC (N = 7)  
 3 lesions up to 4.3 cm (poorly differentiated)L-RFA × 1Cervical and intraabdominal LN metastases at 79 days; alive
 4 lesions up to 2.2 cm (poorly differentiated)L-RFA × 1Invasion of portal vein at 105 days; alive
 3 lesions up to 4.2 cm (moderately differentiated)L-RFA × 1Invasion of portal vein at 152 days; alive
 2 lesions; 4.8 cm and 3 cmL-RFA × 1, TACE × 1Bone metastases at 150 days; died
 1 lesion; 6.5 cm (moderately differentiated)ResectionMicrovascular invasion in resection specimen, excluded for OLT per protocol; alive
 1 lesion; 6.4 cm (moderately differentiated)TACE × 1, L-RFA × 1Invasion of IVC at 210 days; alive
 1 lesion; 8 cm (well differentiated)TACE × 4Multiple satellite lesions developed after complete necrosis of the main nodule, alive
2) Death without OLT unrelated to HCC progression (N = 2)  
 2 lesions; 5 and 2 cm (moderately differentiated)Resection + open RFADied of multiorgan failure 23 days after resection.
 2 lesions; 3.3 and 1.6 cmL-RFA × 1Hepatic decompensation, died of multiorgan failure 29 days after L-RFA.

Among the 2 deaths due to liver failure without OLT (Table 4), 1 patient had a 5-cm lesion in the left lateral segment and a 2-cm lesion in the right hepatic lobe by CT of the abdomen. This patient had a CTP score of 7 before undergoing resection of the left lateral segment in combination with open RFA of the other lesion. This patient then developed respiratory failure in the early postoperative period and subsequently died of multiorgan failure 23 days after surgery. Pathology of the resection specimen in this patient showed a moderately differentiated HCC measuring 6.2 cm, with 3 other satellite tumor nodules, which would have also precluded further consideration of OLT. The other patient had a CTP score of 7 before treatment with laparoscopic RFA for 2 tumors measuring 3.3 and 1.6 cm, respectively. This patient then developed severe hepatic decompensation following this procedure and succumbed to multiorgan failure on the 29th postoperative day.

The Kaplan-Meier intention-to-treat survival rates at 1 and 2 yr after initiation of downstaging were 89.3 and 81.8%, respectively (Fig. 4). The Kaplan-Meier probabilities of treatment failure, defined as death without OLT, dropout due to tumor progression, or HCC recurrence after OLT, were 27.1 and 31.1% at 1 and 2 yr, respectively (Fig. 4).

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Figure 4. The Kaplan-Meier intention-to-treat survival function and probabilities of treatment failure. Time 0 is the date downstaging treatment was initiated. Treatment failure was defined as death from any cause without OLT, dropout from the waiting list due to tumor progression (tumor size and/or number exceeding entry criteria, macrovascular invasion, or extrahepatic metastasis), or HCC recurrence after OLT. The number of patients at risk at each time point is shown below the horizontal axis.

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Explant Tumor Characteristics following Downstaging

Individual tumor characteristics before downstaging and in the liver explant are summarized in Table 5. Downstaging treatments achieved complete tumor necrosis without residual HCC found in the liver explant in 7 patients (44%). Among them, 4 of 7 had biopsy-proven HCC prior to OLT, 2 had presumably false negative biopsies, and 1 had no preoperative biopsy done. The histologic grade of the tumors based on preoperative biopsies was also shown in Table 5. Among the other 9 patients, 7 met T2 criteria (including the 2 patients who underwent LDLT) and 2 exceeded T2 criteria according to explant pathologic staging. One of these 2 patients had 4 tumor nodules (T4a), and the other had a 3-cm tumor thrombus within a large branch of the portal vein (T4b) despite extensive necrosis (>90%) of the 2 tumor nodules.

Table 5. The Explant Histopathologic HCC Characteristics in 16 patients
 HCC before downstagingDownstaging treatments
  • Abbreviations: L-RFA, laparoscopic radiofrequency ablation; TACE, transarterial chemoembolization; Perc-RFA, percutaneous radiofrequency ablation; PEA, percutaneous ethanol ablation.

  • *

    This patient underwent resection of a 5.3-cm lesion and 2 small residual lesions were found in the explant.

  • These 2 patients underwent living-donor liver transplantation.

Complete necrosis in explant (n = 7)  
 1 lesion; 7.3 cm (poorly differentiated)L-RFA × 1
 3 lesions; 4.3, 1.3, and 1.2 cmL-RFA × 1
 2 lesions; 4.5 and 2.2 cmTACE × 2, PEI × 1
 3 lesions; 5, 2, and 1 cmTACE × 1, L-RFA × 1
 1 lesion; 7.5 cm (moderately differentiated)TACE × 1, L-RFA × 1
 1 lesion; 7 cm (well differentiated)TACE × 1
 1 lesion; 6 cm (well differentiated)Open RFA × 1
Meeting T2 criteria in explant (n = 7)  
 1 lesion; 4.5 cm (moderately differentiated)2 lesions; 5 and 2 cmTACE × 2
 1 lesion; 3.6 cm (well differentiated)1 lesion; 5.5 cmL-RFA × 1
 1 lesion; 2 cm + 3 necrotic nodules (moderately differentiated)4 lesions; up to 3 cmL-RFA × 1
 2 lesions; 0.9 and 0.3 cm* (well differentiated)1 lesion; 5.3 cmResection
 3 lesions; 2.3, 2.2 and 1.6 cm (well differentiated)2 lesions; 3.7 and 3.2 cmPerc-RFA × 1, TACE × 1
 1 lesion; 5 cm + 2 necrotic nodules (well differentiated)3 lesions; 4.8, 2, and 1.1 cmTACE × 3
 2 lesions; 1.9 cm and 1.2 cm (moderately differentiated)3 lesions 5, 1 and 1 cmTACE × 1, PEI × 3
Exceeding T2 criteria in explant (n = 2)  
 4 lesions up to 3.3 cm (T4a) (moderately differentiated)2 lesions; 3.5 and 1.7 cmPerc-RFA × 1, TACE × 1
 2 necrotic lesions; 4.5 and 3.5 cm; tumor thrombus (T4b) (moderately differentiated)2 lesions; 4 and 4 cmTACE × 2

The grade of tumor differentiation could not be determined in the 7 patients with complete tumor necrosis and was moderately differentiated in 5 patients and well differentiated in the remaining 4 patients. None had poorly differentiated tumor grade. Except for the single patient with macrovascular invasion, none of the other 14 patients had microvascular invasion.

Correlation between Radiologic and Pathologic Response

Among 26 patients who received loco-regional therapies and not resection, 12 patients (44%) had complete radiologic response, with no residual contrast enhancement of the tumors, at the time of OLT or last follow-up. Sixteen responders underwent OLT, of whom 10 were considered complete responders to loco-regional therapies by radiologic assessment, 1 had undergone resection, and the remaining 5 patients had partial response by radiologic criteria with tumor stage within T2 criteria. Complete response with no residual tumor was verified in the liver explant in 7 of the 10 patients (Table 5). In the other 3 patients, 1 had 2 residual tumors within T2 criteria in the liver explant, 1 had a single 2-cm HCC with 3 other completely necrotic nodules, and the third patient had 2 almost completely necrotic tumor nodules, but also a tumor thrombus in a large branch of the portal vein (T4b). Among 5 patients with partial response by radiologic criteria, 4 had pathologic tumor stage within T2 criteria and 1 had pathologic tumor stage exceeding T2 criteria with 4 lesions (T4a).

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

Extending the HCC criteria for OLT remains a controversial issue in light of the shortage of donors and that the diagnostic criteria for HCC and the selection of candidates with HCC for OLT under the current MELD system for organ allocation have not yet been optimally defined.21 Nevertheless, there is increasing evidence that the tumor size limits may be modestly expanded, without significantly compromising posttransplant survival.13, 22, 24–26 A recent multicenter study also suggested that preoperative loco-regional therapy decreased the risk for tumor recurrence in a subgroup of patients with pathologic T2 and T3 HCC.12 Furthermore, a subgroup of patients who achieved >60% of necrosis of the largest tumor in the liver explant due to preoperative loco-regional treatments, even if their pathologic tumor stage exceeded the proposed UCSF criteria, had significantly better survival than those who achieved a lesser degree of tumor necrosis.26 These observations support the potential benefit of OLT in some patients with advanced HCC within certain upper limits in tumor size and number, if these lesions can be treated to induce a high degree of tumor necrosis and successfully downstaged before OLT. Another critical factor in determining the feasibility of tumor downstaging is the significantly reduced waiting time for OLT under the HCC-adjusted MELD organ allocation system.4–6 In the pre-MELD era, the rate of dropout from the transplant waiting list ranged from 10 to 40% at 1 yr of listing among patients with early-stage HCC.27–29 According to the study by Roayaie et al.,30 the dropout rate was almost 50% in the pre-MELD era among 80 patients presenting initially with a single lesion of >5cm who were enrolled in a protocol combining adjuvant chemotherapy with TACE before OLT.

In this first prospective study on tumor downstaging prior to OLT based on a protocol with well-defined criteria for patient selection and treatment response, the treatment failure rate was about 30% based on an intention-to-treat principle. Considering the advanced nature of tumor at the time of presentation, this treatment failure rate should be considered acceptably low. If the 2 patients with explant pathologic tumor stage exceeding T2 criteria were included as treatment failures, the failure rate would have increased to just greater than 1/3. The minimal observation period of 3 months between downstaging treatment and OLT was arbitrarily determined in our protocol. Only 1 patient in this study had rapid tumor progression and dropped out within 3 months (Table 4). It may be difficult to ascertain what the minimal observation period should be, serving fundamentally as a biological selection process until OLT.

The length of follow-up after OLT in this study is too short to accurately access the risk for HCC recurrence. However, it is encouraging to observe no HCC recurrence after a median follow-up of over a year after OLT, and a high proportion of transplanted patients (44%) with complete tumor necrosis in the liver explant. This response rate to loco-regional treatment intended for downstaging of advanced HCC is not too far below that in other studies in which loco-regional treatments were used as a bridge to OLT for patients meeting conventional criteria for OLT. In a prospective study by Mazzaferro et al.11 applying a single session of either percutaneous or laparoscopic RFA prior to OLT in 50 patients, the complete response rate was 55%, but rose to 63% for HCC within 3 cm. The radiologic complete response rate was 70%. As we continue to include more patients in this ongoing study, other parameters, including the changes in the alpha-fetoprotein level during treatment and tumor histologic characteristics, should be further evaluated as potential markers of response to downstaging treatments and as predictors of outcome after OLT.

A few patients in this study underwent hepatic resection as a bridge to OLT. A potential advantage of resection in this setting is the complete removal of the tumor with possibly a longer period of tumor control than other loco-regional therapies, such as RFA or TACE. Tumor histology available by way of resection also provides additional prognostic information. In 1 of our patients, the location of the tumor very close to the liver surface was another reason for choosing resection over RFA or TACE, because of the risk for tumor rupture. The number of patients undergoing resection in this study is too small to determine whether resection would yield better or worse outcome than other loco-regional treatments. Belghiti et al.31 reported that among patients with early-stage HCC meeting conventional criteria for OLT, secondary OLT that followed resection had similar survival when compared to primary OLT. In contrast, Adam et al.32 found that patients who had OLT after resection had a higher rate of recurrence and worse survival than patients who underwent primary OLT. While the uncertainties in the outcome following secondary OLT need to be further addressed in future studies, a competing-risk analysis28 is also needed to compare the intention-to-treat outcome of resection with other loco-regional therapies as bridging procedures prior to OLT.

The present study included 7 patients meeting the proposed UCSF criteria13 but exceeding T2 criteria who underwent OLT after tumor downstaging (Table 4). It may be argued that these patients are expected to do well after OLT even without downstaging,12, 13 thus representing a potential source of bias in this study. While some institutions have provided data independently supporting the prognostic power of the UCSF criteria,23, 25 others have shown less favorable outcome when the same criteria were retrospectively applied to their cohort.33 Prospective validation of the UCSF criteria based on clinical staging is still needed and is currently in progress.34 Under the current UNOS guidelines,3 tumor downstaging to meet T2 criteria remains the only means for patients with tumor stage beyond T2 but meeting UCSF criteria to be eligible for priority listing for cadaveric OLT.

Graziadel et al.9 reported the outcome of 15 patients with initial HCC stage exceeding T2 criteria who received a mean of 5.1 sessions (range = 2-12) of TACE before OLT. Three patients were removed from the waiting list due to tumor progression, and another patient died of liver failure without OLT. Among the 10 patients who underwent OLT, 3 developed recurrence of HCC. The 1- and 5-yr actuarial survival rates were 93 and 31%, respectively, by an intention-to-treat principle, and 82 and 41%, respectively, after OLT. Their study differed from ours in several key aspects. First, there were no defined upper limits in tumor size and number before downstaging. Compared to our study, a much higher proportion of their patients (60%) had T4a HCC (≥4 lesions of any size), including 4 patients with 4 lesions and 5 others with at least 5 lesions. Second, the criteria for successful downstaging were not clearly defined. It is unclear whether any of their patients achieved complete tumor necrosis or were downstaged to within T2 criteria prior to OLT. Consequently, the less favorable results reported in their study may be due to a lack of well-defined criteria for patient selection to undergo downstaging, as well as for treatment response prior to undergoing OLT.

In conclusion, our encouraging initial results support tumor downstaging as a potentially viable treatment option among carefully selected patients with HCC beyond conventional criteria for OLT. There is still a need for expanded studies with longer follow-up before one can draw firm conclusions regarding the feasibility and benefits of tumor downstaging prior to OLT. The 2 deaths in our series precipitated by hepatic decompensation and other complications shortly after downstaging treatments are important lesions learned and highlight the importance of counseling patients regarding the potential mortality and morbidity of downstaging treatments for OLT.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References