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Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome
226
Journal ofHepatology, 1993; 18:226-234 © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0168-8278/93/$06.00
HEPAT 01395
Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome J.R. M c P e a k e a, J.G. O ' G r a d y " , S. Z a m a n a, B. P o r t m a n n a, D . G . D . Wight b, K.C. Tan", R.Y. Calne b and R o g e r Williams a "The Institute ~['Lfl'er Studies, King's College Hospital, London and bAddenbrooke's ltospital, Cambridge, United Kingdom (Received 13 July 1992)
Liver transplantation for primary hepatocellular carcinoma (HCC) has in general been complicated by high recurrence rates. In the present study results from experience of 87 patients were analyzed [56 cirrhotic, 31 non-cirrhotic, 6 with the fibrolamellar (FL) variant] in relation to curative potential. Sixty-two survived > 9 0 days and form the study cohort. Fifty-six had non-fibrolamellar HCC and, of these, 39 had discrete lesions, measuring 0.8-21 cm (median 5.0 cm) including 4 in whom the diagnosis was made after examination of the explanted liver; 23 had multifocal lesions (>2 tumor masses). There was no tumor recurrence in the group of 14 cases with single dominant lesions measuring < 4 cm, whereas in the 15 cases with lesions of 4-8 cm the recurrence rate was 40%, and 78% in those > 8 cm and the multifocal lesions (n=27, P=0.0001). Five-year actuarial survival figures were 57.1%, 44.4% and 11.1% (P<0.003) respectively. The mean survival times in patients who died of recurrence were: 4-8 cm, 3.3 years (range 10 months to 6.3 years): > 8 cm or multifocal, 13 months (3-25 months). Reduction of serum ~-fetoprotein (AFP) to normal levels does not exclude a later recurrence (7 of 17 cases) and this was documented after maintenance of normal AFP levels for up to 29 months. Five of the 6 fibrolamellar tumors were multifocal and recurred leading to death in 4 after prolonged periods of palliation (mean survival 4.4 years, range 1.8-7.9 years); the one solitary lesion measuring 9 cm did not recur, death being due to a lymphoma after 4.2 years. Key words: Cancer: Surgery; Orthotopic: Fibrolamellar
In the early history of clinical liver transplantation, although there were good immediate postoperative survival figures for patients with hepatocellular carcinoma (HCC) (1) this early enthusiasm was not sustained since tumor recurrence rates ranging from 50% to 80% were reported (2-5) with longer-term survival figures falling well below elective cases without malignant disease (6). Indeed, with greater competition for donor organs, some centers recommend that patients with HCC should not be treated by transplantation (2,7,8), while others recommend that this treatment should only be carried out in patients with extensive tumors involving both lobes and who were unsuitable for more limited resection procedures (17). These changes in policy were advocated despite the considerable number of patients with HCC worldwide who had been cured by liver transplantation (5).
In a number of more recent studies the rate of tumor recurrence is influenced by tumor size, the number of tumors, histological type and differentiation, and the presence of gross vascular or lymph node involvement (2,5,6,9,10). Since results for small single HCC lesions have been encouraging we re-examined our experience of transplantation for HCC in an attempt to determine the curative potential in this condition and to define the preoperative criteria for selection of appropriate cases.
Patients and Methods Liver transplantation for HCC was performed in 87 patients in the Cambridge/King's College Hospital joint series between May 1968 and December 1986 and subse-
Correspondence to: Dr. Roger Williams, The Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 8RX, U.K.
LIVER TRANSPLANTATION FOR HCC
quently in the separate programmes to December 1990. Twenty-five patients died within 90 days of surgery. The causes of death in these patients were primary or secondary hemorrhage (7), bacterial sepsis (9), graft infarction (7), graft failure due to recurrent hepatitis B (1), and cardiac tamponade (1). Only 1 patient, a 52-year-old male with cirrhosis who survived for 66 days, had evidence of tumor deposits at autopsy, which had not directly contributed to death. Sixty-four transplants were performed in the remaining 62 patients. This includes 37 patients reported in an earlier analysis (5). The minimum follow-up period was 12 months or until death. T u m o r size and number of deposits were determined by histological examination of the explanted liver. Six patients (1 male, 5 female, age 13-33, mean 23 years) had a fibrolamellar (FL) variant of HCC without cirrhosis. One case in the earlier report with an FL lesion was reclassified as a cholangiocarcinoma on the basis of further histological examination, and is not included here. The remaining 56 patients had nonfibrolamellar HCC (37 male, 19 female, age 16-65, mean 47 years). HCC developed in a cirrhotic liver in 40 patients, while [6 were non-cirrhotic. In 4 patients the diagnosis of HCC was not established until the explanted liver was examined after transplantation. The etiologies of the cirrhotic patients were as follows: cryptogenic/nonA, non-B hepatitis in 18 (of the 18 patients with cryptogenic hepatitis, 2 were known to have positive anti-HCV antibody tests; stored serum was available for 5 of the remaining 16, and on testing, 4 of these gave positive results); hepatitis B in 11; alcohol in 5; primary biliary cirrhosis in 2; secondary biliary cirrhosis in 2; autoimmune chronic active hepatitis in 1; and ~l-antitrypsin deficiency in I. Statistical methods used were Kaplan-Meier cumulative survival curves, the chi-square test, and the MannWhitney U-test.
Results There were 1 or 2 discrete lesions measuring 0.8 to 21 cm in diameter (median 4.8 cm) with or without small satellite lesions in 38 of the 56 patients with nonfibrolamellar HCC. This includes 4 tumors found incidentally in the explanted livers. These ranged from 0.8 to 3 cm in diameter. T u m o r size tended to be smaller in patients with cirrhosis (mean diameter 4.3 cm, range 0.8-15 cm) than in the non-cirrhotic ~roup (mean diameter 14 cm, range 8-21 cm, P<0.05). The other 18 lesions were classified as multifocal HCC with 3 or more tumor masses often of similar size at different sites within the
227 liver. This pattern was observed in I I (27%) of the 40 tumors in the cirrhotic group and 7 (44%) of the 16 patients without cirrhosis (P =0.0007). Of the 9 discrete lesions arising in non-cirrhotic livers, 3 were found to be irresectable at laparotomy, and the remaining 6 were centrally located. Seventeen (30%) of the 56 patients are alive, and 14 (25%) are tumor-free after a mean follow-up period of 3.5 years (range 1.6-16.0 years). Of these 14, there are 4 at 1-2 years post-transplant, 6 at 2 3 years, 3 at 3-5 years, and one who has survived for 16 years. The 3 patients alive with recurrence are at 2.2, 4.1 and 5.2 years after transplantation. Thirty-nine patients have died. The causes of death are tumor recurrence 22, graft reinfection with hepatitis B9 (1 patient also had recurrence), bacterial sepsis 4 (including another with recurrent tumor), tuberculosis 1, endocarditis 1, chronic graft rejection 1, and respiratory failure 1. Two patients required a second transplant. The first was a 56-year-old male who had a discrete 4-cm tumor and who died from surgical complications within days of a second transplant for chronic rejection at 5 months. The other patient was a 58-year-old female with an incidentally discovered lesion measuring 0.8 cm who required a second transplant after 6 months for recurrent hepatitis C. This patient survived for another 7 months before dying of liver failure due to further recurrence of hepatitis C infection. Tumor recurrence was found in 27 (48%) of the 56 patients in this group. Overall survival in the 24 who died as a result of tumor recurrence was 83.3% at 6 months, 50% at 1 year and 25% at 2 years (Fig. 1). Initial tumor size in patients with recurrence ranged from 4 to 21 cm (mean 10.7 cm); 14 were multifocal, compared to 0.8-14cm (mean 3.7 cm) in the group with no tumor recurrence (Fig. 2). The diagnosis of recurrence was based on elevated serum AFP levels, or radiological evidence of tumor deposits, or both. There was histological confirmation whenever possible. Evidence of tumor recurrence was found within 6 months of transplantation in 11 patients, between 6 and 12 months in 9, and in the second year in 3. The remaining 4 patients survived 2.7-5.2 years before recurrence. The documented sites of tumor recurrence were liver (55%), lung (46%), adrenal bed (23%), abdominal cavity (18%), bone (23%), skin 14% [-including 1 deposit (4.5%) at the site of the preoperative biopsy], and brain (14%). Three patients had localized deposits which were surgically removed: 2 from the adrenal bed, and 1 from the transplanted liver. Only 4 of the 18 patients with multifocal tumors had no evidence of recurrence. One of these survived 5.2
228
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80'
°m
40
I 20
I 0 0.0
I
I
i
I
I
|
|
1.0
2.0
3.0
4.0
5.0
6.0
Years after transplantation Fig. I. Overall survival after tumor recurrence in 24 patients.
20
15 Tumour size (cm)
10
4.0
m
--
I II Recurrence
No r e c u r r e n c e
Fig. 2. Tumor size versus recurrence (discrete lesions).
years before dying of biliary sepsis, the other 3 survived for only short periods. One died at 9 months of chronic rejection, another had a second transplant after 6 months for chronic rejection, but died soon afterwards from sepsis, and the remaining patient lived for 4 months, and died of sepsis. The 14 patients who are currently alive and free of tumor had discrete lesions measuring !.5-7 cm (mean 3.7 cm). On the basis of clinical outcome, the patients were further considered as 3 groups (Table 1): Group A consisted of 14 patients with discrete tumors
TABLE 1 Patient characteristics and outcome Group
Cirrhosis
Recurrence Alive
n (%)
n (%)
A ( n = 14) B(n=15) C(n=27)
14(100) 14(93) 12(44)
0(0) 6(40) 21 (78)
8(57) 7(47) 2(7)
14(100) 13(87) 12 (44)
Total
40(71)
27(48)
17(30)
39 (70)
(P = O.O001 ) (P = O.O001 )
n
(%)
Cyclosporin Follow-up n (%) ),ears Median (range) 1.9(0.6-4.1) 2.1 (0.4-16) 0.9 (0.3-5.2)
LIVER TRANSPLANTATION FOR HCC < 4 cm in diameter without tumor recurrence. Followup periods ranged from 7 months to 4.1 years (mean 23 months) with 2 patients between 6 months and 1 year, 6 between 1 and 2 years, 4 between 2 and 3 years, and 2 followed up for more than 3 years. All patients in this group had pre-existing cirrhosis. Six have died, 4 due to reinfection with hepatitis B and 2 due to bacterial sepsis. Of the 4 patients in this group whose tumors were not found until the explanted liver was examined histologically ('incidental HCC'), 2 are alive and tumor-free at 1.7 and 2.8 years. The other 2 died at 1 and 1.1 years respectively of recurrent HBV-related diseases with no evidence of tumor recurrence. Group B contained 15 patients, 14 (93%) with cirrhosis and discrete tumor masses measuring 4-8 cm. Tumors recurred in 6 patients (40%): 5 of these had lesions measuring 4-6 cm, while the sixth measured 8 cm. Of the 6, recurrence was diagnosed in 2 between 6 and 12 months, in 3 between 1 and 3 years, and in 1 at 4.9 years (mean time to diagnosis of recurrence, 16 months). Tumor recurrence has led to the death of 5 at a mean of 3.3 years (range 10 months to 6.3 years). The 1 surviving patient with recurrence originally had a 6-cm lesion. He remained asymptomatic for 4.9 years, and is currently receiving chemotherapy for tumor deposits in his graft at 5.2 years. The other 3 deaths in this group were from recurrent hepatitis B. Group C included 9 patients with discrete lesions measuring > 8 c m and 18 patients with multifocal tumors. Cirrhosis was present in 12 (44%) of the patients in this group. Tumors recurred in 21 (78%), causing death in 19 at a mean of 13 months (range 3-25 months, compared with group B, P=n.s.). Of the 21, 13 were diagnosed with recurrent tumors within 6 months, 4 between 6 and 12 months, 3 in the second post-transplant year, and 1 at 2.8 years (mean time before diagnosis, 8 months). The 2 patients still alive are 2.2 and 4.1 years post-transplantation and, like all survivors in the other two groups, had pre-existing cirrhosis prior to transplantation. The remaining 6 patients died (due to sepsis 3, endocarditis 1, respiratory failure 1, and chronic rejection 1) at a mean of 16 months (range 3 months to 5.2 years). The actuarial survival curves for the 3 groups incorporating all causes of death after 3 months differed significantly (P<0.003), with 1-year survival rates of 85.7%, 66.7% and 44.4% respectively for groups A, B, and C. At 3 years the corresponding figures were 57.1%, 66.7% and 11.1%, while at 5 years the only change was a fall for group B to 44.4% (Fig. 3). Comparison of tumor characteristics and recurrence in the pre- and post-cyclosporine eras showed that of 17
229 patients who received a transplant in the precyclosporine era, 11 had had multifocal lesions, and the other 6 had discrete lesions measuring 6-21 cm (mean 13 cm). Only 1 of these 6 is still alive, a male with a 6-cm lesion, who remains tumor-free at 16 years. Eight of the 11 multifocal lesions recurred, as did the remaining 5 discrete lesions. Of the 39 patients who received transplants under cyclosporine immunosuppression, only 7 were multifocal (P=0.0001), and the 32 with discrete tumors had much smaller lesions overall, measuring 0.8-15cm (mean 5.2, P<0.05). Two of the 7 patients with multifocal lesions are still alive, but with recurrence. Fourteen of the remaining 32 are alive, and 13 of these are free of recurrence after 1.6-4.8 (mean 2.6) years of follow-up.
Reduction in ~-fetoprotein levels Serum ~-fetoprotein (AFP) levels were raised prior to transplantation in 22 of the 34 patients measured, and values ranged from 27 to 960 000 ng/ml. Twenty of these patients had serial estimations (Fig. 4), 12 of which were included in a previous report (11). The AFP fell to normal (< 25 ng/ml) within 12 months of transplantation in 17 of the 20 cases, but in 7 of these tumor recurrence was demonstrated in association with a rise in AFP levels. One patient, a male aged 53 with cirrhosis secondary to hepatitis B with a pre-transplant AFP level of 2640 ng/ml from a discrete 6-cm tumor, developed recurrent deposits in the graft in the fifth year without a rise in AFP levels. Of the I 1 with normal preoperative AFP values, none has had increases of AFP values despite tumor recurrence in 4. In 3 patients, the AFP level remained elevated after transplantation, and recurrence of the tumor was observed within a year. Three other cases had raised AFP levels in serum after having normal values for periods of 10-29 months (Fig. 5). One was a female with primary biliary cirrhosis and a 5.5cm discrete tumor, the other two were males with alcoholic and cryptogenic cirrhosis, both with multifocal lesions. The pre-transplant AFP levels in these patients were 3680, 5000 and 218 ng/ml. AFP concentrations fell to normal values 2 months after transplantation in 2 patients, and 4 months after transplantation in the third. In each case, the rise in AFP levels has been accompanied by evidence of tumor recurrence. The AFP doubling times after recurrence was established were 8, 2 and 4 months, respectively. The first of these patients (a, Fig. 5) has died of tumor recurrence, at 4.4 years. Another (b, Fig. 5) is receiving treatment with mitozantrone chemotherapy, and showed an initial, short-lived, serological response with AFP levels returning to normal. Levels rose above the normal range after only 5 months of
230
J.R. McPEAKE et al.
|.0
"
p=0.0006 (Mantel-Cox) p=0.0029 (Breslow)
0.8
Group A: <4 cm
L1
"i 0.6 0.4
Group B: 4-8 cm
D.,
0.2
0.0
!
0
I
Group C: >Scm/multifocal
5 Time
,
,
10
15
(years after transplantation)
Fig. 3. Actuarial survival by group incorporating all causes of death after 3 months, r---recurrence r'=recm-renceoccurred at a later date
ICO0(~O •
r
1OO13OO r r
1OO13O r
.
10(30
r
r
Serum AFP (ng/ml)
100
I U p p e r limit of n o r m a l
.
r
-1
I
I
I
I
5
11 Months
17
23
r'
Fig. 4. Serial serum AFP levels in 20 patients before and up to 2 years after liver transplantation.
treatment, and he has now undergone a segmental resection. The third (c, Fig. 5) is also being treated with chemotherapy and is alive at 2.2 years.
Use of chemotherapy Twenty-one patients received chemotherapy with various agents, chiefly adriamycin and mitozantrone, but there was no uniform protocol. Fourteen patients were given preoperative or immediately postoperative adjuvant chemotherapy, 2 using an intra-arterial combination of adriamycin and lipiodol, as described in an earlier
paper (12). Eight of the 14 later suffered recurrence, and 4 had further chemotherapy. Five of the 8 tumors which recurred were multifocal, and the other 3 were discrete lesions measuring 4.5, 12 and 14 cm. For the 8, the mean time for diagnosis of recurrence after transplantation was 6 months, and mean survival time 18 months, including 1 patient who is still alive. The remaining 6 of the 14 who did not display recurrence had smaller discrete tumors measuring 2-7.6 cm (median 3.4 cm). The remaining 7 patients did not receive perioperative adjuvant chemotherapy, and were treated only after
231
LIVER T R A N S P L A N T A T I O N F O R H C C
5
•
Patient a
4
--
Patient b
;~
Patient c
3
Chemotherapy
log 10 A F P
2 Upper limit of normal
0
10
20 Time
30 after
transplant
40
50
60
(months)
Fig. 5. Serological recurrence in 3 patients.
tumor recurrence had been diagnosed. Recurrence occurred in all 7 at a mean time of 23 months posttransplantation, and the mean survival time was 3.2 years, including 2 patients who are currently alive. In all, 11 patients had chemotherapy following the diagnosis of recurrence. Mean survival from this time was 14 months (range 2-38, including 3 patients who are still alive) compared with 8 months in the 16 patients who were not given chemotherapy.
Follow-upoffibrolamellar hepatocellularcarcinoma At the time of the earlier report, of the 6 patients with fibrolamellar hepatocellular carcinoma, 3 were alive and free of tumor recurrence at 3 months, 1.8 and 4.5 years. All 3 have since died, 2 of recurrent tumor and 1 from a lymphoma at 4.2 years, giving an overall recurrence rate for F L - H C C of'83.3%. One of the patients with tumor recurrence died at 2.2 years, but the second remained asymptomatic for 6 years before succumbing 7.9 years after transplantation. This patient was our longest survivor in this category, and was the only one of the group with an hepatic artery embolization using gelfoam pretransplant. Thus, the overall 1-, 3- and 5-year survival rates were 100%, 50%, and 33%. This compares favorably with overall survival rates of 50%, 6.3% and 6.3% for the same periods in our 16 patients with non-fibrolamellar HCC in non-cirrhotic livers (Fig. 6).
Discussion Recurrence of HCC after liver transplantation is thought to be due to clinically and radiologically un-
detectable extrahepatic micrometastases, or to malignant cells which escape from the liver during surgical manipulation. De novo development of another HCC within the graft has only been described in I patient after transplantation for cirrhosis due to chronic active hepatitis B (13). The problem of recurrent tumors may be further exacerbated by immunosuppression after transplantation which, it has been suggested on the basis of changes in doubling time, may accelerate tumor growth, although the evidence is far from certain (14). The data presented here show that postoperative tumor recurrence rates correlate with tumor size and with the number of lesions present preoperatively as determined by examination of the explanted liver. The most encouraging results were obtained in patients with discrete tumors measuring less than 4 c m (group A). These patients have all remained tumor-free with I- and 5-year actuarial survivals of 85.7% and 57.1%. The question of optimal management for patients suitable for either transplantation or resection, on the basis of tumor size and location of the tumor, is difficult, since there is a well-recognized risk of recurrent disease in the remaining liver after tumor resection (15). Belghiti and colleagues demonstrated intrahepatic recurrence rates of 81% and 100% at 3 and 5 years in 47 patients after resection, with a corresponding overall survival of 35% and 17% (16). This recurrent disease presumably originates from pre-existing dysplastic foci in the remaining cirrhotic liver. Because of this substantial risk, we recommend liver transplantation in all these patients.
232
J.R. M c P E A K E et al.
1.0
Lt
0.8
=
0.6
Fibrolamellar HCC (n=6)
~.~
=" =
0.4
I 0.2
J t
p:0.0041 ( M a n t e l - C o x ) p=0.0058 (Breslow)
Non-fibrolamellar HCC (n=16)
0.0
I
|
1
2
!
!
!
I
3 4 5 Years after transplantation
i
I
6
7
Fig. 6. Overall survival in non-cirrhotic patients.
The majority (60~) of patients with discrete lesions measuring 4-8 cm (group B) also did not suffer recurrance of tumor and had relatively favorable 1- and 5-year actuarial survivals of 66.7~ and 44.4%. Moreover, those who suffered recurrence were diagnosed on average 16 months after transplantation and overall survival was more than 3 years. It is reasonable to advocate that these patients should continue to receive transplants, in the expectation of a cure for many, and good long-term palliation in the remainder. In contrast, of the patients in group C with tumors larger than 8 cm or multifocal lesions, 78¢;~ suffered recurrent disease diagnosed an average of 8 months after transplantation and thereafter exhibited disappointingly shorter survival times, averaging 13 months. In consequence, the actuarial survival figures in this group at I and 3 years were significantly lower at 44.4c~ and l l.l%. With donor organs in short supply, and waiting lists for transplantation increasing (in the USA now nearing 2000), it is reasonable to give these patients a low priority for transplantation. The recurrence rates in groups B and C illustrate the importance of earlier diagnosis of HCC by ultrasound screening of cirrhotic patients to prolong survival after transplantation. Recurrence of tumors in association with a rise in serum AFP levels has now been observed in our series even after maintenance of normal AFP levels for a period of 29 months. There was also a patient with high preoperative AFP levels who remained seronegative despite recurrent tumor deposits in the graft after 5 years. One of our patients suffered skin implantation metastases at the site of a preoperative biopsy. Preopera-
tive liver biopsy therefore carries a small risk of HCC recurrence. Our group of patients with FL lesions enjoyed lengthy survival despite large tumors at presentation (one 9 cm, 5 multifocal) and recurrence in 5 of the 6 grafts. The FL variant of HCC appears to be slower to develop and less aggressive than the non-FL type, and for this reason, transplantation is still justified even if the tumor is extensive at presentation. This group of patients with the FL variant of HCC has been shown to have a significantly better prognosis than that with the nonfibrolamellar type of similar dimensions and number and our experience supports these findings (2,5,9,19). Characteristics of the subgroup of patients who survive longer than others have recently been identified. Iwatsuki and colleagues reported 12 of 13 patients with incidental HCC who remained tumor-free during a median followup period of 16 months (2). The same group of investigators obtained better results in patients with small single tumors less than 5 cm in diameter. Recurrence was only seen in 2 out of 28 of these patients, in contrast to 21 of 34 patients with larger lesions, and corresponding disease-free percentages at 5 years of 71.4 and 29.1 (2,9,10). Lymph node status has also been shown to be important: 13 node-negative patients had a median survival of 13 months, compared with only 8 months median survival in those with lymph node involvement in the Birmingham series, and a 2-year actuarial survival of 64.1% in 13 patients without nodal tumor in contrast to no survivors after 15 months in tumor-positive lymphadenopathy patients in the Hanover experience (7,18). Pre-existing cirrhosis was identified as a risk factor
LIVER TRANSPLANTATION FOR HCC for poor survival in data reviewed from 7 E u r o p e a n ccnters up to September 1987, with a m e d i a n survival of 0 m o n t h s in cirrhotic patients versus 13 m o n t h s in non-cirrhotic patients in the B i r m i n g h a m series (6,18). However, all of o u r 17 survivors came from the cirrhotic group of patients, a n d 15 of these have remained t u m o r free after a m e a n follow-up period of 42 months. We suggest that the higher recurrence rate and shorter survival in the n o n - c i r r h o t i c patients is due to the significantly larger size a n d n u m b e r of t u m o r s in these patients at the time of surgery. Patients u n d e r medical supervision with k n o w n cirrhosis are screened for the development of H C C by serum A F P estimations and radiological m e t h o d s a n d are hence more likely to be diagnosed earlier for H C C when still a s y m p t o m a t i c with small lesions, while patients w i t h o u t cirrhosis usually come to medical a t t e n t i o n when s y m p t o m s occur and the t u m o r is more extensive. A d j u v a n t preoperative or postoperative c h e m o t h e r a p y
233 tion as observed in the 1 1 treated patients with survival times of 14 m o n t h s c o m p a r e d to the 8 m o n t h s in those not receiving chemotherapy. The use of lipiodol with c h e m o t h e r a p e u t i c agents or radio-isotopes may be beneficial while the patient is waiting for a suitable organ. To evaluate t u m o r size a n d n u m b e r , and to search for extrahepatic disease, all candidates for orthotopic liver t r a n s p l a n t a t i o n with H C C now undergo preoperative radiological studies which include a b d o m i n a l ultrasonography, computerized t o m o g r a p h y (CT) of thorax and a b d o m e n , hepatic a n g i o g r a p h y a n d radioisotope bone scanning. These techniques have limitations: C T has been shown to have a detection rate of 87% in H C C lesions over 2 cm, of 25'7~ in those less than 1.5 cm, and both C T and s o n o g r a p h y frequently fail to show the size and n u m b e r of lesions, especially with u n d e r l y i n g cirrhosis (20-22). New radiological methods such as magnetic resonance imaging, radiolabelled a n t i b o d y techniques, and arterial e n h a n c e d C T may prove more sensitive in detecting small t u m o r deposits (23-25).
or both did not prevent or reduce t u m o r recurrence in our patients with larger tumors. T i m i n g of recurrence was not delayed in these patients either (mean 6 m o n t h s ,
Acknowledgement
compared with m e a n s of 8 a n d 16 m o n t h s respectively for groups B a n d C). C h e m o t h e r a p y after recurrence may result in t e m p o r a r y remission a n d prolonged pallia-
References [ Bismuth H, Castaing D, Ericzon BG, et al. Hepatic transplantation in Europe. First Report of the European Liver Transplant Registry. Lancet 1987; ii: 674-6. 2 Iwatsuki S, Shaw BW, Starzl TE. Role of liver transplantation in cancer therapy. Ann Surg 1985; 202: 401-7. 3 lwatsuki S, Starzl TE, Todo S. et al. Experience in 1000 liver transplants under cyclosporine/steroid therapy: survival report. Transplant Proc 1988:20 (Suppl 1~:498-504. 4 Calne RY, Williams R., Rolles K. Liver transplantation in the adult. World J Surg 1986: 10: 422-31. 5 O'Grady JG, Poison RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg 1988; 207: 373-9. ~, Pichlmayr R. Is there a place for liver grafting for malignancy? Transplant Proc 1988; 20: 487-92. Ringe B, Wittekind C, Bechstein WO, Bunzendahl H, Pichlmayr R. The role of liver transplantation in hepatobiliary malignancy. A retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Ann Surg 1989; 209: 88-98. National Institutes of Health Consensus Development Conference on Liver Transplantation, June 20-23, 1983. Hepatology 1983: [Suppl.): 107S-110S. t~ Yokoyama I, Todo S, lwatsuki S, Starzl TE. Liver transplantation in the treatment of primary liver cancer. Hepatogastroenterology 1990; 37: 188-93. II~ Yokoyama I, Sheahan DG, Carr B, et al. Clinicopathologic factors affecting patient survival and tumor recurrence after orthotopic liver transplantation for hepatocellular carcinoma. Transplant Proc 1991; 23: 2194-6.
We should like to acknowledge the c o - o p e r a t i o n of Mrs. K. Hayllar in analysis of the statistics.
11 O'Grady JG. Johnson PJ, Zaman S, Calne RY. Williams R. Decreased rate of growth of hepatocellular carcinoma recurrence after liver transplantation in patients maintained on cyclosporine immunosuppression. Transplant Proc 1988:20 [Suppl 3): 394-6. 12 Johnson PJ, Kalayci C. Dobbs N. et al. Pharmacokinetics and toxicity of intraarterial adriamycin for hepatocellular carcinoma: effect of coadministration of lipiodol. J Hepatol 1991: 13: 120-7. 13 Luketic VA. Shiffman ML, McCall JB, Posner MP, Mills AS. Carithers RJ. Primary hepatocellular carcinoma after orthotopic liver transplantation for chronic hepatitis B infection. Ann Intern Med 1991: 114: 212-3. 14 Yokoyama I, Carr B, Saitsu H, lwatsuki S, Starzl TE. AcceLerated growth rates of recurrent hepatocel[ular carcinoma after liver transplantation. Cancer 1991: 68:2095 100. 15 Belli L, Romani F, Be[li LS, et al. Reappraisal of surgical treatment of small hepatocellular carcinomas in cirrhosis: clinicopathological study of resection or transplantation. Dig Dis Sci 1989:34: 1571-5. 16 BelghitiJ. Panis Y, Farges O, Benhamou JP, Fekete F. Intrahepatic recurrence after resection of hepatocellular carcinoma complicating cirrhosis. Ann Surg 1991: 214: 114-7. 17 Kirby RM, Clements D, Jurewicz WA. et al. Large hepatocellular cancers: hepatic resection or liver transplantation'? [LetterJ. Br Med J Clin Res 1985: 291: 1122. 18 lsmail T, Angrisani L, Gunson BK, et al. Primary hepatic malignancy: the role of liver transplantation. Br J Surg 1990: 77: 983-7. 19 Starz[ TE, lwatsuki S, Shaw BJ, Nalesnik MA, Farhi DC, Van TD. Treatment of fibrolamellar hepatoma with partial or total hepatectomy and transplantation of the liver. Surg Gynecol Obstet 1986: 162: 145-8. 20 Tsunetomi S, Ohlo M, Lino Y. et al. Diagnosis of small hepatocellular carcinoma by computed tomography: correlation of CT findings and histopathology. J Gastroenterol Hepatol 1989:4: 395-404.
234 21 Mittal R, Kowal C, Starzl T, et al. Accuracy of computerized tomography in determining hepatic tumor size in patients receiving liver transplantation or resection. J Clin Oncol 1984: 2: 637-42. 22 Miller W J, Federle MP, Campbell WL. Diagnosis and staging of hepatocellular carcinoma: comparison of CT and sonography in 36 liver transplantation patients. Am J Roentgenol 1991: 157: 303-6. 23 Hirai K, Aoki Y, Majima Y, et al. Magnetic resonance imaging of
J.R. McPEAKE et al. small hepatocellular carcinoma. Am J Gastroenterol 1991; 86: 205-9. 24 Goldenberg DM. Imaging and therapy of gastrointestinal cancers with radiolabeled antibodies. Am J Gastroenterol 1991: 86: 1392-403. 25 Goulet RJ, Seekri I, lnman M, Kopecky KK, Madura JA, Grosfeld JL. The diagnosis and definition of hepatic malignancies by use of arterial enhanced computerized tomographic scanning. Surgery 1990: 108: 694-700.
Journal ofHepatology, 1993; 18:226-234 © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved. 0168-8278/93/$06.00
HEPAT 01395
Liver transplantation for primary hepatocellular carcinoma: tumor size and number determine outcome J.R. M c P e a k e a, J.G. O ' G r a d y " , S. Z a m a n a, B. P o r t m a n n a, D . G . D . Wight b, K.C. Tan", R.Y. Calne b and R o g e r Williams a "The Institute ~['Lfl'er Studies, King's College Hospital, London and bAddenbrooke's ltospital, Cambridge, United Kingdom (Received 13 July 1992)
Liver transplantation for primary hepatocellular carcinoma (HCC) has in general been complicated by high recurrence rates. In the present study results from experience of 87 patients were analyzed [56 cirrhotic, 31 non-cirrhotic, 6 with the fibrolamellar (FL) variant] in relation to curative potential. Sixty-two survived > 9 0 days and form the study cohort. Fifty-six had non-fibrolamellar HCC and, of these, 39 had discrete lesions, measuring 0.8-21 cm (median 5.0 cm) including 4 in whom the diagnosis was made after examination of the explanted liver; 23 had multifocal lesions (>2 tumor masses). There was no tumor recurrence in the group of 14 cases with single dominant lesions measuring < 4 cm, whereas in the 15 cases with lesions of 4-8 cm the recurrence rate was 40%, and 78% in those > 8 cm and the multifocal lesions (n=27, P=0.0001). Five-year actuarial survival figures were 57.1%, 44.4% and 11.1% (P<0.003) respectively. The mean survival times in patients who died of recurrence were: 4-8 cm, 3.3 years (range 10 months to 6.3 years): > 8 cm or multifocal, 13 months (3-25 months). Reduction of serum ~-fetoprotein (AFP) to normal levels does not exclude a later recurrence (7 of 17 cases) and this was documented after maintenance of normal AFP levels for up to 29 months. Five of the 6 fibrolamellar tumors were multifocal and recurred leading to death in 4 after prolonged periods of palliation (mean survival 4.4 years, range 1.8-7.9 years); the one solitary lesion measuring 9 cm did not recur, death being due to a lymphoma after 4.2 years. Key words: Cancer: Surgery; Orthotopic: Fibrolamellar
In the early history of clinical liver transplantation, although there were good immediate postoperative survival figures for patients with hepatocellular carcinoma (HCC) (1) this early enthusiasm was not sustained since tumor recurrence rates ranging from 50% to 80% were reported (2-5) with longer-term survival figures falling well below elective cases without malignant disease (6). Indeed, with greater competition for donor organs, some centers recommend that patients with HCC should not be treated by transplantation (2,7,8), while others recommend that this treatment should only be carried out in patients with extensive tumors involving both lobes and who were unsuitable for more limited resection procedures (17). These changes in policy were advocated despite the considerable number of patients with HCC worldwide who had been cured by liver transplantation (5).
In a number of more recent studies the rate of tumor recurrence is influenced by tumor size, the number of tumors, histological type and differentiation, and the presence of gross vascular or lymph node involvement (2,5,6,9,10). Since results for small single HCC lesions have been encouraging we re-examined our experience of transplantation for HCC in an attempt to determine the curative potential in this condition and to define the preoperative criteria for selection of appropriate cases.
Patients and Methods Liver transplantation for HCC was performed in 87 patients in the Cambridge/King's College Hospital joint series between May 1968 and December 1986 and subse-
Correspondence to: Dr. Roger Williams, The Institute of Liver Studies, King's College Hospital, Denmark Hill, London, SE5 8RX, U.K.
LIVER TRANSPLANTATION FOR HCC
quently in the separate programmes to December 1990. Twenty-five patients died within 90 days of surgery. The causes of death in these patients were primary or secondary hemorrhage (7), bacterial sepsis (9), graft infarction (7), graft failure due to recurrent hepatitis B (1), and cardiac tamponade (1). Only 1 patient, a 52-year-old male with cirrhosis who survived for 66 days, had evidence of tumor deposits at autopsy, which had not directly contributed to death. Sixty-four transplants were performed in the remaining 62 patients. This includes 37 patients reported in an earlier analysis (5). The minimum follow-up period was 12 months or until death. T u m o r size and number of deposits were determined by histological examination of the explanted liver. Six patients (1 male, 5 female, age 13-33, mean 23 years) had a fibrolamellar (FL) variant of HCC without cirrhosis. One case in the earlier report with an FL lesion was reclassified as a cholangiocarcinoma on the basis of further histological examination, and is not included here. The remaining 56 patients had nonfibrolamellar HCC (37 male, 19 female, age 16-65, mean 47 years). HCC developed in a cirrhotic liver in 40 patients, while [6 were non-cirrhotic. In 4 patients the diagnosis of HCC was not established until the explanted liver was examined after transplantation. The etiologies of the cirrhotic patients were as follows: cryptogenic/nonA, non-B hepatitis in 18 (of the 18 patients with cryptogenic hepatitis, 2 were known to have positive anti-HCV antibody tests; stored serum was available for 5 of the remaining 16, and on testing, 4 of these gave positive results); hepatitis B in 11; alcohol in 5; primary biliary cirrhosis in 2; secondary biliary cirrhosis in 2; autoimmune chronic active hepatitis in 1; and ~l-antitrypsin deficiency in I. Statistical methods used were Kaplan-Meier cumulative survival curves, the chi-square test, and the MannWhitney U-test.
Results There were 1 or 2 discrete lesions measuring 0.8 to 21 cm in diameter (median 4.8 cm) with or without small satellite lesions in 38 of the 56 patients with nonfibrolamellar HCC. This includes 4 tumors found incidentally in the explanted livers. These ranged from 0.8 to 3 cm in diameter. T u m o r size tended to be smaller in patients with cirrhosis (mean diameter 4.3 cm, range 0.8-15 cm) than in the non-cirrhotic ~roup (mean diameter 14 cm, range 8-21 cm, P<0.05). The other 18 lesions were classified as multifocal HCC with 3 or more tumor masses often of similar size at different sites within the
227 liver. This pattern was observed in I I (27%) of the 40 tumors in the cirrhotic group and 7 (44%) of the 16 patients without cirrhosis (P =0.0007). Of the 9 discrete lesions arising in non-cirrhotic livers, 3 were found to be irresectable at laparotomy, and the remaining 6 were centrally located. Seventeen (30%) of the 56 patients are alive, and 14 (25%) are tumor-free after a mean follow-up period of 3.5 years (range 1.6-16.0 years). Of these 14, there are 4 at 1-2 years post-transplant, 6 at 2 3 years, 3 at 3-5 years, and one who has survived for 16 years. The 3 patients alive with recurrence are at 2.2, 4.1 and 5.2 years after transplantation. Thirty-nine patients have died. The causes of death are tumor recurrence 22, graft reinfection with hepatitis B9 (1 patient also had recurrence), bacterial sepsis 4 (including another with recurrent tumor), tuberculosis 1, endocarditis 1, chronic graft rejection 1, and respiratory failure 1. Two patients required a second transplant. The first was a 56-year-old male who had a discrete 4-cm tumor and who died from surgical complications within days of a second transplant for chronic rejection at 5 months. The other patient was a 58-year-old female with an incidentally discovered lesion measuring 0.8 cm who required a second transplant after 6 months for recurrent hepatitis C. This patient survived for another 7 months before dying of liver failure due to further recurrence of hepatitis C infection. Tumor recurrence was found in 27 (48%) of the 56 patients in this group. Overall survival in the 24 who died as a result of tumor recurrence was 83.3% at 6 months, 50% at 1 year and 25% at 2 years (Fig. 1). Initial tumor size in patients with recurrence ranged from 4 to 21 cm (mean 10.7 cm); 14 were multifocal, compared to 0.8-14cm (mean 3.7 cm) in the group with no tumor recurrence (Fig. 2). The diagnosis of recurrence was based on elevated serum AFP levels, or radiological evidence of tumor deposits, or both. There was histological confirmation whenever possible. Evidence of tumor recurrence was found within 6 months of transplantation in 11 patients, between 6 and 12 months in 9, and in the second year in 3. The remaining 4 patients survived 2.7-5.2 years before recurrence. The documented sites of tumor recurrence were liver (55%), lung (46%), adrenal bed (23%), abdominal cavity (18%), bone (23%), skin 14% [-including 1 deposit (4.5%) at the site of the preoperative biopsy], and brain (14%). Three patients had localized deposits which were surgically removed: 2 from the adrenal bed, and 1 from the transplanted liver. Only 4 of the 18 patients with multifocal tumors had no evidence of recurrence. One of these survived 5.2
228
J.R. McPEAKE et al.
80'
°m
40
I 20
I 0 0.0
I
I
i
I
I
|
|
1.0
2.0
3.0
4.0
5.0
6.0
Years after transplantation Fig. I. Overall survival after tumor recurrence in 24 patients.
20
15 Tumour size (cm)
10
4.0
m
--
I II Recurrence
No r e c u r r e n c e
Fig. 2. Tumor size versus recurrence (discrete lesions).
years before dying of biliary sepsis, the other 3 survived for only short periods. One died at 9 months of chronic rejection, another had a second transplant after 6 months for chronic rejection, but died soon afterwards from sepsis, and the remaining patient lived for 4 months, and died of sepsis. The 14 patients who are currently alive and free of tumor had discrete lesions measuring !.5-7 cm (mean 3.7 cm). On the basis of clinical outcome, the patients were further considered as 3 groups (Table 1): Group A consisted of 14 patients with discrete tumors
TABLE 1 Patient characteristics and outcome Group
Cirrhosis
Recurrence Alive
n (%)
n (%)
A ( n = 14) B(n=15) C(n=27)
14(100) 14(93) 12(44)
0(0) 6(40) 21 (78)
8(57) 7(47) 2(7)
14(100) 13(87) 12 (44)
Total
40(71)
27(48)
17(30)
39 (70)
(P = O.O001 ) (P = O.O001 )
n
(%)
Cyclosporin Follow-up n (%) ),ears Median (range) 1.9(0.6-4.1) 2.1 (0.4-16) 0.9 (0.3-5.2)
LIVER TRANSPLANTATION FOR HCC < 4 cm in diameter without tumor recurrence. Followup periods ranged from 7 months to 4.1 years (mean 23 months) with 2 patients between 6 months and 1 year, 6 between 1 and 2 years, 4 between 2 and 3 years, and 2 followed up for more than 3 years. All patients in this group had pre-existing cirrhosis. Six have died, 4 due to reinfection with hepatitis B and 2 due to bacterial sepsis. Of the 4 patients in this group whose tumors were not found until the explanted liver was examined histologically ('incidental HCC'), 2 are alive and tumor-free at 1.7 and 2.8 years. The other 2 died at 1 and 1.1 years respectively of recurrent HBV-related diseases with no evidence of tumor recurrence. Group B contained 15 patients, 14 (93%) with cirrhosis and discrete tumor masses measuring 4-8 cm. Tumors recurred in 6 patients (40%): 5 of these had lesions measuring 4-6 cm, while the sixth measured 8 cm. Of the 6, recurrence was diagnosed in 2 between 6 and 12 months, in 3 between 1 and 3 years, and in 1 at 4.9 years (mean time to diagnosis of recurrence, 16 months). Tumor recurrence has led to the death of 5 at a mean of 3.3 years (range 10 months to 6.3 years). The 1 surviving patient with recurrence originally had a 6-cm lesion. He remained asymptomatic for 4.9 years, and is currently receiving chemotherapy for tumor deposits in his graft at 5.2 years. The other 3 deaths in this group were from recurrent hepatitis B. Group C included 9 patients with discrete lesions measuring > 8 c m and 18 patients with multifocal tumors. Cirrhosis was present in 12 (44%) of the patients in this group. Tumors recurred in 21 (78%), causing death in 19 at a mean of 13 months (range 3-25 months, compared with group B, P=n.s.). Of the 21, 13 were diagnosed with recurrent tumors within 6 months, 4 between 6 and 12 months, 3 in the second post-transplant year, and 1 at 2.8 years (mean time before diagnosis, 8 months). The 2 patients still alive are 2.2 and 4.1 years post-transplantation and, like all survivors in the other two groups, had pre-existing cirrhosis prior to transplantation. The remaining 6 patients died (due to sepsis 3, endocarditis 1, respiratory failure 1, and chronic rejection 1) at a mean of 16 months (range 3 months to 5.2 years). The actuarial survival curves for the 3 groups incorporating all causes of death after 3 months differed significantly (P<0.003), with 1-year survival rates of 85.7%, 66.7% and 44.4% respectively for groups A, B, and C. At 3 years the corresponding figures were 57.1%, 66.7% and 11.1%, while at 5 years the only change was a fall for group B to 44.4% (Fig. 3). Comparison of tumor characteristics and recurrence in the pre- and post-cyclosporine eras showed that of 17
229 patients who received a transplant in the precyclosporine era, 11 had had multifocal lesions, and the other 6 had discrete lesions measuring 6-21 cm (mean 13 cm). Only 1 of these 6 is still alive, a male with a 6-cm lesion, who remains tumor-free at 16 years. Eight of the 11 multifocal lesions recurred, as did the remaining 5 discrete lesions. Of the 39 patients who received transplants under cyclosporine immunosuppression, only 7 were multifocal (P=0.0001), and the 32 with discrete tumors had much smaller lesions overall, measuring 0.8-15cm (mean 5.2, P<0.05). Two of the 7 patients with multifocal lesions are still alive, but with recurrence. Fourteen of the remaining 32 are alive, and 13 of these are free of recurrence after 1.6-4.8 (mean 2.6) years of follow-up.
Reduction in ~-fetoprotein levels Serum ~-fetoprotein (AFP) levels were raised prior to transplantation in 22 of the 34 patients measured, and values ranged from 27 to 960 000 ng/ml. Twenty of these patients had serial estimations (Fig. 4), 12 of which were included in a previous report (11). The AFP fell to normal (< 25 ng/ml) within 12 months of transplantation in 17 of the 20 cases, but in 7 of these tumor recurrence was demonstrated in association with a rise in AFP levels. One patient, a male aged 53 with cirrhosis secondary to hepatitis B with a pre-transplant AFP level of 2640 ng/ml from a discrete 6-cm tumor, developed recurrent deposits in the graft in the fifth year without a rise in AFP levels. Of the I 1 with normal preoperative AFP values, none has had increases of AFP values despite tumor recurrence in 4. In 3 patients, the AFP level remained elevated after transplantation, and recurrence of the tumor was observed within a year. Three other cases had raised AFP levels in serum after having normal values for periods of 10-29 months (Fig. 5). One was a female with primary biliary cirrhosis and a 5.5cm discrete tumor, the other two were males with alcoholic and cryptogenic cirrhosis, both with multifocal lesions. The pre-transplant AFP levels in these patients were 3680, 5000 and 218 ng/ml. AFP concentrations fell to normal values 2 months after transplantation in 2 patients, and 4 months after transplantation in the third. In each case, the rise in AFP levels has been accompanied by evidence of tumor recurrence. The AFP doubling times after recurrence was established were 8, 2 and 4 months, respectively. The first of these patients (a, Fig. 5) has died of tumor recurrence, at 4.4 years. Another (b, Fig. 5) is receiving treatment with mitozantrone chemotherapy, and showed an initial, short-lived, serological response with AFP levels returning to normal. Levels rose above the normal range after only 5 months of
230
J.R. McPEAKE et al.
|.0
"
p=0.0006 (Mantel-Cox) p=0.0029 (Breslow)
0.8
Group A: <4 cm
L1
"i 0.6 0.4
Group B: 4-8 cm
D.,
0.2
0.0
!
0
I
Group C: >Scm/multifocal
5 Time
,
,
10
15
(years after transplantation)
Fig. 3. Actuarial survival by group incorporating all causes of death after 3 months, r---recurrence r'=recm-renceoccurred at a later date
ICO0(~O •
r
1OO13OO r r
1OO13O r
.
10(30
r
r
Serum AFP (ng/ml)
100
I U p p e r limit of n o r m a l
.
r
-1
I
I
I
I
5
11 Months
17
23
r'
Fig. 4. Serial serum AFP levels in 20 patients before and up to 2 years after liver transplantation.
treatment, and he has now undergone a segmental resection. The third (c, Fig. 5) is also being treated with chemotherapy and is alive at 2.2 years.
Use of chemotherapy Twenty-one patients received chemotherapy with various agents, chiefly adriamycin and mitozantrone, but there was no uniform protocol. Fourteen patients were given preoperative or immediately postoperative adjuvant chemotherapy, 2 using an intra-arterial combination of adriamycin and lipiodol, as described in an earlier
paper (12). Eight of the 14 later suffered recurrence, and 4 had further chemotherapy. Five of the 8 tumors which recurred were multifocal, and the other 3 were discrete lesions measuring 4.5, 12 and 14 cm. For the 8, the mean time for diagnosis of recurrence after transplantation was 6 months, and mean survival time 18 months, including 1 patient who is still alive. The remaining 6 of the 14 who did not display recurrence had smaller discrete tumors measuring 2-7.6 cm (median 3.4 cm). The remaining 7 patients did not receive perioperative adjuvant chemotherapy, and were treated only after
231
LIVER T R A N S P L A N T A T I O N F O R H C C
5
•
Patient a
4
--
Patient b
;~
Patient c
3
Chemotherapy
log 10 A F P
2 Upper limit of normal
0
10
20 Time
30 after
transplant
40
50
60
(months)
Fig. 5. Serological recurrence in 3 patients.
tumor recurrence had been diagnosed. Recurrence occurred in all 7 at a mean time of 23 months posttransplantation, and the mean survival time was 3.2 years, including 2 patients who are currently alive. In all, 11 patients had chemotherapy following the diagnosis of recurrence. Mean survival from this time was 14 months (range 2-38, including 3 patients who are still alive) compared with 8 months in the 16 patients who were not given chemotherapy.
Follow-upoffibrolamellar hepatocellularcarcinoma At the time of the earlier report, of the 6 patients with fibrolamellar hepatocellular carcinoma, 3 were alive and free of tumor recurrence at 3 months, 1.8 and 4.5 years. All 3 have since died, 2 of recurrent tumor and 1 from a lymphoma at 4.2 years, giving an overall recurrence rate for F L - H C C of'83.3%. One of the patients with tumor recurrence died at 2.2 years, but the second remained asymptomatic for 6 years before succumbing 7.9 years after transplantation. This patient was our longest survivor in this category, and was the only one of the group with an hepatic artery embolization using gelfoam pretransplant. Thus, the overall 1-, 3- and 5-year survival rates were 100%, 50%, and 33%. This compares favorably with overall survival rates of 50%, 6.3% and 6.3% for the same periods in our 16 patients with non-fibrolamellar HCC in non-cirrhotic livers (Fig. 6).
Discussion Recurrence of HCC after liver transplantation is thought to be due to clinically and radiologically un-
detectable extrahepatic micrometastases, or to malignant cells which escape from the liver during surgical manipulation. De novo development of another HCC within the graft has only been described in I patient after transplantation for cirrhosis due to chronic active hepatitis B (13). The problem of recurrent tumors may be further exacerbated by immunosuppression after transplantation which, it has been suggested on the basis of changes in doubling time, may accelerate tumor growth, although the evidence is far from certain (14). The data presented here show that postoperative tumor recurrence rates correlate with tumor size and with the number of lesions present preoperatively as determined by examination of the explanted liver. The most encouraging results were obtained in patients with discrete tumors measuring less than 4 c m (group A). These patients have all remained tumor-free with I- and 5-year actuarial survivals of 85.7% and 57.1%. The question of optimal management for patients suitable for either transplantation or resection, on the basis of tumor size and location of the tumor, is difficult, since there is a well-recognized risk of recurrent disease in the remaining liver after tumor resection (15). Belghiti and colleagues demonstrated intrahepatic recurrence rates of 81% and 100% at 3 and 5 years in 47 patients after resection, with a corresponding overall survival of 35% and 17% (16). This recurrent disease presumably originates from pre-existing dysplastic foci in the remaining cirrhotic liver. Because of this substantial risk, we recommend liver transplantation in all these patients.
232
J.R. M c P E A K E et al.
1.0
Lt
0.8
=
0.6
Fibrolamellar HCC (n=6)
~.~
=" =
0.4
I 0.2
J t
p:0.0041 ( M a n t e l - C o x ) p=0.0058 (Breslow)
Non-fibrolamellar HCC (n=16)
0.0
I
|
1
2
!
!
!
I
3 4 5 Years after transplantation
i
I
6
7
Fig. 6. Overall survival in non-cirrhotic patients.
The majority (60~) of patients with discrete lesions measuring 4-8 cm (group B) also did not suffer recurrance of tumor and had relatively favorable 1- and 5-year actuarial survivals of 66.7~ and 44.4%. Moreover, those who suffered recurrence were diagnosed on average 16 months after transplantation and overall survival was more than 3 years. It is reasonable to advocate that these patients should continue to receive transplants, in the expectation of a cure for many, and good long-term palliation in the remainder. In contrast, of the patients in group C with tumors larger than 8 cm or multifocal lesions, 78¢;~ suffered recurrent disease diagnosed an average of 8 months after transplantation and thereafter exhibited disappointingly shorter survival times, averaging 13 months. In consequence, the actuarial survival figures in this group at I and 3 years were significantly lower at 44.4c~ and l l.l%. With donor organs in short supply, and waiting lists for transplantation increasing (in the USA now nearing 2000), it is reasonable to give these patients a low priority for transplantation. The recurrence rates in groups B and C illustrate the importance of earlier diagnosis of HCC by ultrasound screening of cirrhotic patients to prolong survival after transplantation. Recurrence of tumors in association with a rise in serum AFP levels has now been observed in our series even after maintenance of normal AFP levels for a period of 29 months. There was also a patient with high preoperative AFP levels who remained seronegative despite recurrent tumor deposits in the graft after 5 years. One of our patients suffered skin implantation metastases at the site of a preoperative biopsy. Preopera-
tive liver biopsy therefore carries a small risk of HCC recurrence. Our group of patients with FL lesions enjoyed lengthy survival despite large tumors at presentation (one 9 cm, 5 multifocal) and recurrence in 5 of the 6 grafts. The FL variant of HCC appears to be slower to develop and less aggressive than the non-FL type, and for this reason, transplantation is still justified even if the tumor is extensive at presentation. This group of patients with the FL variant of HCC has been shown to have a significantly better prognosis than that with the nonfibrolamellar type of similar dimensions and number and our experience supports these findings (2,5,9,19). Characteristics of the subgroup of patients who survive longer than others have recently been identified. Iwatsuki and colleagues reported 12 of 13 patients with incidental HCC who remained tumor-free during a median followup period of 16 months (2). The same group of investigators obtained better results in patients with small single tumors less than 5 cm in diameter. Recurrence was only seen in 2 out of 28 of these patients, in contrast to 21 of 34 patients with larger lesions, and corresponding disease-free percentages at 5 years of 71.4 and 29.1 (2,9,10). Lymph node status has also been shown to be important: 13 node-negative patients had a median survival of 13 months, compared with only 8 months median survival in those with lymph node involvement in the Birmingham series, and a 2-year actuarial survival of 64.1% in 13 patients without nodal tumor in contrast to no survivors after 15 months in tumor-positive lymphadenopathy patients in the Hanover experience (7,18). Pre-existing cirrhosis was identified as a risk factor
LIVER TRANSPLANTATION FOR HCC for poor survival in data reviewed from 7 E u r o p e a n ccnters up to September 1987, with a m e d i a n survival of 0 m o n t h s in cirrhotic patients versus 13 m o n t h s in non-cirrhotic patients in the B i r m i n g h a m series (6,18). However, all of o u r 17 survivors came from the cirrhotic group of patients, a n d 15 of these have remained t u m o r free after a m e a n follow-up period of 42 months. We suggest that the higher recurrence rate and shorter survival in the n o n - c i r r h o t i c patients is due to the significantly larger size a n d n u m b e r of t u m o r s in these patients at the time of surgery. Patients u n d e r medical supervision with k n o w n cirrhosis are screened for the development of H C C by serum A F P estimations and radiological m e t h o d s a n d are hence more likely to be diagnosed earlier for H C C when still a s y m p t o m a t i c with small lesions, while patients w i t h o u t cirrhosis usually come to medical a t t e n t i o n when s y m p t o m s occur and the t u m o r is more extensive. A d j u v a n t preoperative or postoperative c h e m o t h e r a p y
233 tion as observed in the 1 1 treated patients with survival times of 14 m o n t h s c o m p a r e d to the 8 m o n t h s in those not receiving chemotherapy. The use of lipiodol with c h e m o t h e r a p e u t i c agents or radio-isotopes may be beneficial while the patient is waiting for a suitable organ. To evaluate t u m o r size a n d n u m b e r , and to search for extrahepatic disease, all candidates for orthotopic liver t r a n s p l a n t a t i o n with H C C now undergo preoperative radiological studies which include a b d o m i n a l ultrasonography, computerized t o m o g r a p h y (CT) of thorax and a b d o m e n , hepatic a n g i o g r a p h y a n d radioisotope bone scanning. These techniques have limitations: C T has been shown to have a detection rate of 87% in H C C lesions over 2 cm, of 25'7~ in those less than 1.5 cm, and both C T and s o n o g r a p h y frequently fail to show the size and n u m b e r of lesions, especially with u n d e r l y i n g cirrhosis (20-22). New radiological methods such as magnetic resonance imaging, radiolabelled a n t i b o d y techniques, and arterial e n h a n c e d C T may prove more sensitive in detecting small t u m o r deposits (23-25).
or both did not prevent or reduce t u m o r recurrence in our patients with larger tumors. T i m i n g of recurrence was not delayed in these patients either (mean 6 m o n t h s ,
Acknowledgement
compared with m e a n s of 8 a n d 16 m o n t h s respectively for groups B a n d C). C h e m o t h e r a p y after recurrence may result in t e m p o r a r y remission a n d prolonged pallia-
References [ Bismuth H, Castaing D, Ericzon BG, et al. Hepatic transplantation in Europe. First Report of the European Liver Transplant Registry. Lancet 1987; ii: 674-6. 2 Iwatsuki S, Shaw BW, Starzl TE. Role of liver transplantation in cancer therapy. Ann Surg 1985; 202: 401-7. 3 lwatsuki S, Starzl TE, Todo S. et al. Experience in 1000 liver transplants under cyclosporine/steroid therapy: survival report. Transplant Proc 1988:20 (Suppl 1~:498-504. 4 Calne RY, Williams R., Rolles K. Liver transplantation in the adult. World J Surg 1986: 10: 422-31. 5 O'Grady JG, Poison RJ, Rolles K, Calne RY, Williams R. Liver transplantation for malignant disease. Results in 93 consecutive patients. Ann Surg 1988; 207: 373-9. ~, Pichlmayr R. Is there a place for liver grafting for malignancy? Transplant Proc 1988; 20: 487-92. Ringe B, Wittekind C, Bechstein WO, Bunzendahl H, Pichlmayr R. The role of liver transplantation in hepatobiliary malignancy. A retrospective analysis of 95 patients with particular regard to tumor stage and recurrence. Ann Surg 1989; 209: 88-98. National Institutes of Health Consensus Development Conference on Liver Transplantation, June 20-23, 1983. Hepatology 1983: [Suppl.): 107S-110S. t~ Yokoyama I, Todo S, lwatsuki S, Starzl TE. Liver transplantation in the treatment of primary liver cancer. Hepatogastroenterology 1990; 37: 188-93. II~ Yokoyama I, Sheahan DG, Carr B, et al. Clinicopathologic factors affecting patient survival and tumor recurrence after orthotopic liver transplantation for hepatocellular carcinoma. Transplant Proc 1991; 23: 2194-6.
We should like to acknowledge the c o - o p e r a t i o n of Mrs. K. Hayllar in analysis of the statistics.
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