Long-Term Results With Multimodal Adjuvant Therapy and Liver Transplantation for the Treatment of Hepatocellular Carcinomas Larger Than 5 Centimeters

Abstract

Objective

To determine the long-term results of liver transplantation for hepatocellular carcinoma (HCC) measuring 5 cm or larger treated in a multimodality adjuvant protocol.

Summary Background Data

Transplant has been established as a viable treatment of HCC measuring less than 5 cm, but the results for larger tumors have been disappointing. Several studies have shown promising preliminary results when combining transplant with preoperative transarterial chemoembolization and/or perioperative systemic chemotherapy in the treatment of advanced HCC that is not amenable to resection. However, follow-up in the studies has been limited and the number of patients has been small.

Methods

Beginning in October 1991, all patients with unresectable HCC measuring 5 cm or larger, as measured by computed tomography, were considered for enrollment in the authors’ multimodality protocol. Entry criteria required that all patients be free of extrahepatic disease based on computed tomography scans of the chest and abdomen and bone scan and have a patent main portal vein and major hepatic veins on duplex ultrasonography. Patients received subselective arterial chemoembolization with mitomycin C, doxorubicin, and cisplatin at the time of diagnosis, repeated as necessary based on tumor response. Patients received a single systemic intraoperative dose of doxorubicin (10 mg/m²) before revascularization of the new liver and systemic doxorubicin (50 mg/m²) every 3 weeks as tolerated, for a total of six cycles, beginning on the sixth postoperative week.

Results

Eighty patients were enrolled; 37 were eventually excluded, due mainly to disease progression while on the waiting list, and 43 underwent liver transplant. Mean pathologic tumor diameter was 5.8 ± 2.7 cm. Median follow-up of surviving transplanted patients was 55.1 ± 24.9 months. There were two (4.7%) perioperative deaths. Median overall survival was significantly longer in transplanted patients (49.9 ± 10.42 months) than in those who were excluded (6.83 ± 1.34 months). Overall and recurrence-free survival rates in transplanted patients at 5 years were 44% and 48%, respectively. A tumor size larger than 7 cm and the presence of vascular invasion correlated significantly with recurrence. Recurrence-free survival at 5 years was significantly higher for the 32 patients with tumors measuring 5 to 7 cm (55%) than the 12 patients with tumors larger than 7 cm (34%).

Conclusions

A significant proportion of patients with HCC measuring 5 cm or larger can achieve long-term survival after liver transplantation in the context of multimodal adjuvant therapy. Patients with tumors measuring 5 to 7 cm have significantly longer recurrence-free survival compared with those with larger tumors.

Hepatocellular carcinoma (HCC) is the most common solid organ tumor worldwide and is believed to be responsible for more than 1 million deaths annually. ¹ Its incidence in the United States has nearly doubled during the past two decades to 2.4 per 100,000 population, with a disproportionate increase among the younger population. ² Because of the scarcity of screening programs, tumors are generally bigger at presentation in Western countries, making treatment significantly more difficult. ³

Liver transplant has proven to be an effective treatment for both incidentally discovered and known small, unresectable HCCs in patients with cirrhosis. ^4,5 However, results of transplantation alone for advanced HCC have been traditionally disappointing, with 5-year survival rates ranging from 18% to 25%. ^6,7 A more recent review of the International Registry of Hepatic Tumors in Liver Transplantation revealed only a modest improvement of the 5-year survival rate to 32% for tumors larger than 5 cm. ⁸ As a result, most centers do not offer liver transplant to patients with large unresectable HCCs, leaving them only the option of palliative chemotherapy.

Several studies, including one from our institution, have shown promising preliminary results when combining transplant with preoperative transarterial chemoembolization (TACE) and/or perioperative systemic chemotherapy in the treatment of advanced HCC that is not amenable to resection. ^9–14 However, follow-up has been limited and the number of patients has been small. Because of the lack of long-term results, treatment of large or advanced HCC with liver transplant and adjuvant therapy remains controversial. In this study, we report on a prospective trial of preoperative TACE followed by transplantation and systemic chemotherapy in the treatment of large (≥5 cm) HCC.

METHODS

All patients with cirrhosis referred to Mount Sinai Medical Center for evaluation for hepatic transplantation are screened for HCC by computed tomography (CT) and measurement of α-fetoprotein (AFP) levels. Beginning in October 1991, all patients with unresectable HCCs measuring 5 cm or larger, as measured by CT scan, were considered for enrollment in a multimodality protocol that included preoperative TACE, liver transplant, and intra- and postoperative doxorubicin. Informed consent was obtained from all patients and all procedures performed were in accord with the ethical standards of our institutional review board.

Entry criteria required that the patient be free of extrahepatic disease based on CT scans of the chest and abdomen and bone scan and have a patent main portal vein and major hepatic veins on duplex ultrasonography. Patients with regional lymph node involvement discovered by CT scan or at the time of surgery were excluded. Tumor involvement of intrahepatic portal branches and multicentricity in one lobe were not considered contraindications to entry into the protocol. However, in patients with bilateral disease, the largest tumor in the less-involved lobe could not exceed 5 cm. Patients with tumor replacing more than 75% of the total hepatic volume on CT scan, as well as those with diffusely infiltrating HCC, were excluded.

Patients needed to be free of significant ascites and hepatic encephalopathy. They were also required to have a prothrombin time less than 1.5 times control, a creatinine level less than 2 mg/dL, and a total bilirubin value less than 2 mg/dL, unless they had concomitant cholestatic liver disease. Patients with abnormal multiple gated arteriography (MUGA) scans and those with a history of prior radiation or chemotherapy were excluded. Patients with end-stage liver disease from hepatitis B were also excluded until January 1994, after which such patients received hepatitis B immune globulin prophylaxis.

Patients received subselective arterial chemoembolization with mitomycin C, doxorubicin, and cisplatin at the time of diagnosis. TACE was repeated as required by tumor size and progression based on CT scans and AFP levels, which were obtained every 3 months while on the waiting list. Patients with tumors that progressed despite TACE such that they no longer met the above criteria were excluded from the protocol.

When a donor organ became available, the patient was taken to the operating room with a “backup” recipient in the hospital. A complete exploratory laparotomy was performed to evaluate portal and hepatic vein involvement and extrahepatic disease. The hepatectomy was performed in the standard fashion. Patients received a single systemic dose of doxorubicin (10 mg/m²) before revascularization of the new liver.

Beginning on the sixth postoperative week, patients received systemic doxorubicin (50 mg/m²), followed by granulocyt colony stimulating factor G-CSF (5 μg/kg) subcutaneously for 14 days or until 3 days past the granulocyte nadir and a total neutrophil count of more than 10,000/μL. This regimen was repeated, as tolerated, every 3 weeks for a total of six cycles. Postoperative immunosuppression was with corticosteroids and cyclosporine or tacrolimus; patients in the protocol did not receive azathioprine while receiving doxorubicin. Rejection episodes were treated with pulse steroids, and OKT3 was used for steroid-resistant rejection episodes.

All patients were followed after surgery at Mount Sinai Hospital with CT scans of the chest and abdomen performed every 3 months for the first year and every 6 months thereafter. In addition, AFP was measured every 6 weeks for the first year and every 3 months thereafter. Actuarial survival was calculated using the Kaplan-Meier method. Differences in survival were examined using the log-rank test. Cox proportional hazards regression analysis was used for multivariate analysis of variables found to be significant with univariate analysis. Student t test, Mann-Whitney test, Fisher exact test, and chi-square were also used to compare groups. P < .05 was considered significant.

RESULTS

Between October 1991 and January 1999, 80 patients were enrolled into the protocol. Of these, 43 underwent liver transplant. The reasons for the eventual exclusion of the remaining 37 patients included progression of the primary tumor (n = 2), portal vein occlusion by tumor (n = 9), liver failure (n = 5), positive lymph nodes (n = 6), distant metastatic disease (n = 6), gastrointestinal bleeding (n = 4), cancers other than HCC (n = 2), and patient preference (n = 3). Patients whose underlying liver disease was hepatitis B were significantly less likely to be excluded from the protocol than patients with other underlying diseases (Table 1). Patients who were excluded had a significantly larger mean tumor size compared with those who were able to undergo transplant, although there was significant overlap between the two groups. Transplanted patients underwent an average of 1.53 ± 0.92 rounds of TACE and spent an average of 142 ± 168 (range 9–696) days on the waiting list before transplant. The mean number of TACE treatments in those eventually removed from the protocol was 2.1 ± 1.4, and these patients spent an average of 207.3 ± 306.3 (range 8–1,491) days on the waiting list. Two of the 80 (2.5%) patients undergoing TACE died of treatment-related hepatic failure. A decrease in AFP by 50% or more after embolization was noted in 14 of 43 (32.5%) of the transplanted patients.

Table 1. PATIENT AND TUMOR CHARACTERISTICS

AFP, α-fetoprotein.

* Mean ± standard deviation.

† Median ± standard deviation.

Four patients received no postoperative chemotherapy, two as a result of early postoperative deaths, one due to poor cardiac function, and one due to patient’s refusal. Transplanted patients received an average of 4.83 ± 1.79 cycles of chemotherapy after surgery. Postoperative chemotherapy was discontinued prematurely secondary to thrombocytopenia in three (7%) patients, hepatotoxicity in two (5%) patients, progressive recurrent disease in four (9%) patients, and refusal to continue with further therapy by two (5%) patients.

At the time of this study, 19 of 43 (44%) of the transplanted patients were alive (17/43 [40%] both alive and disease-free) with a median follow-up of 55.1 ± 24.9 months in surviving patients. None of the transplanted patients have required retransplant. Median actuarial survival was significantly longer in patients who eventually underwent transplant (49.9 ± 15.84 months, 95% confidence interval [CI] 18.85–80.95 months) compared with those removed from the protocol (6.83 ± 1.34 months,95% CI 4.21–9.46 months) (P < .0001) (Fig. 1). Median recurrence-free survival was 45.5 months for those undergoing liver transplant (Fig. 2). Tumor size larger than 7 cm (P = .024, odds ratio = 5.098) and the presence of vascular invasion, micro- or macroscopic (P = .036, odds ratio = 4.418), correlated significantly with recurrence (Table 2). However, only tumor size larger than 7 cm affected actuarial freedom from recurrence in a significant manner (Fig. 3). The number of lesions, grade of tumor, etiology of underlying liver disease, presence of bilateral disease, and AFP response to TACE all had no correlation with tumor recurrence after transplant by univariate analysis. There was no difference in tumor recurrence or overall survival among patients who spent less than the median number of days on the waiting list compared with those who waited longer than the median.

Figure 1. Overall survival of patients entered into the protocol based on eventual transplant or removal from protocol (P < .0001).

Figure 2. Recurrence-free survival of patients entered into protocol and transplanted.

Table 2. TUMOR CHARACTERISTICS AND RECURRENCE

* Recurrence-free survival did not fall below 50%.

Figure 3. (A) Recurrence-free survival based on tumor size (P = .0237). (B) Recurrence-free survival based on presence of vascular invasion (P = .101).

Seventeen (40%) patients were diagnosed with recurrent HCC after transplant, with a median time to recurrence of 12.5 ± 12.6 months. Recurrences occurred in the liver (n = 5), lung (n = 9), bone (n = 5), celiac nodes (n = 2), and adrenal (n = 1). Patterns of recurrence included two patients with intrahepatic disease only, nine with extrahepatic only, five with both intra- and extrahepatic, and one patient diagnosed only by an increase in postoperative AFP.

DISCUSSION

Liver transplantation is a logical treatment for HCC in the absence of extrahepatic spread because it addresses both the tumor and the underlying liver disease. The role of transplantation for the treatment of small, asymptomatic tumors in patients with cirrhosis has been well established. ⁵ Despite isolated cases of prolonged survival, published results of liver transplant for advanced HCC have been uniformly disappointing because of high rates of tumor recurrence. ^4,15–19 The extent to which recurrence results from the presence of preexisting micrometastases as opposed to intraoperative dissemination of tumor resulting from surgical manipulation, and whether tumor growth is accelerated by immunosuppression, remain controversial. ^20–23

Several studies have reported improved posttransplant survival in HCC patients with the use of preoperative TACE ^13,24 or with systemic chemotherapy. ^10,12 Others have used both modalities. ^9,11 It is meaningless to compare the results of these reports with our patients because the majority of the subjects in these studies did not have tumors larger than 5 cm. In addition, the number of patients and the length of follow-up in these studies have been limited. The current study represents the largest reported series of patients with HCC measuring 5 cm or larger treated with TACE, perioperative chemotherapy, and transplant. The size of this series, in combination with the long follow-up (median 55 months), makes the results presented herein far more significant than any previously reported in similar patients.

TACE has been widely used as a palliative treatment for patients with inoperable disease, with mixed results. ^25–27 Some centers have reported its use as a preoperative adjunct to liver transplantation in patients with HCC. ^13,24 The rationale for its use as a neoadjuvant therapy has been its potential to control tumor growth during the waiting period and to cause tumor necrosis, which may reduce tumor dissemination during surgery. In patients undergoing transplant, Majno et al ¹³ found no benefit from preoperative TACE. They did find that patients with tumors larger than 3 cm in whom downstaging occurred had an improved 5-year recurrence-free survival rate compared with those who were not downstaged or did not receive TACE. Our study found no difference in recurrence-free survival between those who did or did not respond to TACE. The discrepancies between our findings and those of Majno et al can be attributed to different definitions of response to TACE as well as different tumor characteristics. Whereas Majno et al defined response to TACE as tumor necrosis on pathologic examination or a decrease in tumor size by 50% on CT scan, we looked for a decrease in AFP levels to half of preembolization levels. In addition, only 15% of the transplanted patients in the Majno study had tumors larger than 5 cm, whereas our patients by definition all had tumors measuring 5 cm or larger.

Postoperative chemotherapy has been used in attempts to eliminate micrometastases that might be present at the time of transplant or malignant cells that are shed during surgical manipulation of the tumor. Doxorubicin, the single most effective agent against HCC, produces only modest objective response rates, ranging from 15% to 20% in most studies. ^28–30 Olthoff et al ¹² reported an improvement in the 3-year survival rate from 5.8% to 46% with the use of intravenous fluorouracil, doxorubicin, and cisplatin in 25 patients after transplant. Stone et al ¹⁰ also found significant improvement from historical controls in 20 patients receiving pre- and postoperative doxorubicin in combination with liver transplant, with 3-year overall and recurrence-free survival rates of 59% and 54%, respectively. In studies similar to our own, Cherqui et al ¹¹ and Carr et al ⁹ reported promising preliminary results with the use of preoperative TACE and postoperative intravenous chemotherapy in conjunction with liver transplant. Results for these studies have shown significant improvements in survival, but the size of the studies and their follow-up have been limited.

It is difficult to reach any definitive conclusions regarding the role of preoperative chemoembolization or postoperative chemotherapy based on this study because it was not randomized and nearly all of the patients received neoadjuvant and adjuvant therapies. At the time that this protocol was developed, extremely poor results were being reported for liver transplant in the treatment of large HCCs, and it was widely believed that transplanting such patients was not justified. The protocol attempted to address the issues of tumor progression while waiting and micrometastasis that are the basis for failure. Currently, we still favor chemoembolization and other methods of controlling tumor growth while the patients are on the waiting list. However, we are more skeptical about the role of postoperative systemic therapy. Improved case selection based on advances in imaging of liver tumors surely underlies some of the difference between these and previously reported results.

The effect of the time spent on the waiting list is also difficult to qualify or quantify. The average time spent waiting for a cadaveric liver allograft for patients in our study was 142 days for those who were transplanted and 207 days for those who were eventually excluded. Nearly one third of our patients were removed from the protocol for disease progression during this waiting period. The mean waiting time for patients with known HCC who underwent cadaveric transplant between August 1998 and October 2000 at our institution has increased to 414 days. The most recent figures available from the United Network of Organ Sharing (UNOS) report a median waiting time of 331 days for status 3 patients awaiting a cadaveric liver allograft. ³¹ Undoubtedly, more time spent on the waiting list translates into greater risk that the tumor will grow and metastasize. One can argue, however, that the time spent waiting will select out the more aggressive tumors that would be more likely to recur after transplant. We found no difference in terms of overall survival or freedom from recurrence when we compared transplanted patients who spent more than the median number of days on the waiting list with those who waited less than the median.

It is clear from reviewing the demographic data that patients who were eventually removed from the protocol had, on average, significantly larger tumors than those who eventually went on to transplant. There was a large overlap in the size of tumors between the two groups, however, making it difficult to predict progression of disease while on the waiting list based on tumor size alone. Patients with HCC in the setting of hepatitis B versus other underlying diseases were much less likely to experience tumor progression on the waiting list, with a significantly higher proportion able to undergo transplant. This finding is consistent with previous reports from our institution that have shown that HCCs in patients with hepatitis B behave less aggressively and can reach a large size with less propensity to metastasize. ³²

The correlation of recurrence after transplant with tumor size larger than 7 cm and with vascular invasion is not surprising. Iwatsuki et al ³³ reported similar findings in their review of 344 liver transplants in the presence of HCC. Before surgery, vascular invasion can be diagnosed definitively only if it has progressed to macroscopic involvement of the portal or hepatic vein tributaries, leaving tumor size as the most useful preoperative discriminator. Nevertheless, one third of patients with tumors larger than 7 cm achieve long-term survival, making it difficult to categorically deny these patients treatment.

In conclusion, our experience shows a median survival of 49.9 months and freedom from recurrence in 48% of patients with HCC measuring 5 cm or larger who underwent liver transplantation within a multimodality protocol. Although these results represent success from an oncologic point of view, they fall short of the 83% recurrence-free survival rate at 4 years reported by Mazzaferro et al ⁵ for transplant in patients with smaller tumors. This decreased survival is the basis for the policy decision in the United States by UNOS not to grant patients with HCC measuring 5 cm or larger waiting list priority, thereby effectively denying them the possibility of cadaveric transplantation. The response at our institution has been to consider patients with unresectable HCC not meeting UNOS prioritization criteria for adult living-donor liver transplantation. We believe that the significant chance for long-term survival, especially in patients with tumors measuring 5 to 7 cm, justifies this approach. Further, the ability to proceed expeditiously to transplant eliminates the need for potentially harmful treatments to contain the tumor during the waiting period, and may well lead to improved results.