Ann Surg Oncol (2011) 18:1964–1971 DOI 10.1245/s10434-011-1551-4
ORIGINAL ARTICLE – HEPATOBILIARY TUMORS
Prognosis of Hepatocellular Carcinoma in Relation to Treatment Across BCLC Stages Delia D’Avola, MD1,2, Mercedes In˜arrairaegui, MD, PhD1,2, Fernando Pardo, MD3, Fernando Rotellar, MD, PhD3, Pablo Marti, MD3, Jose´ I. Bilbao, MD, PhD4, Antonio Martinez-Cuesta, MD4, Alberto Benito, MD, PhD4, Felix Alegre, MD1, Erica Mauleo´n, MD1, Jose´ I. Herrero, MD, PhD1,2, Jorge Quiroga, MD, PhD1,2, Jesus Prieto, MD, PhD1,2, and Bruno Sangro, MD, PhD1,2 ´ rea Liver Unit, Clinica Universitaria de Navarra, Pamplona, Spain; 2Centro de Investigacio´n Biome´dica en Red en el A 3 tema´tica de Enfermedades Hepa´ticas y Digestivas (CIBERehd), Pamplona, Spain; Department of Hepatobiliary Surgery, Clinica Universitaria de Navarra, Pamplona, Spain; 4Department of Radiology, Clinica Universitaria de Navarra, Pamplona, Spain 1
ABSTRACT Background. The Barcelona Clinic Liver Cancer (BCLC) staging system recommends first-line therapy for each tumor stage. We evaluated the effect of compliance with BCLC treatment allocation on the prognosis of patients with hepatocellular carcinoma (HCC). Methods. We retrospectively analyzed 359 consecutive, newly diagnosed HCC patients treated in our Liver Unit during a 14-year period. For each stage, survival was compared according to whether treatment matched the BCLC recommendation. We also compared the survival of patients in the same BCLC stage who received different treatments, and patients in different BCLC stages receiving the same treatment. Results. BCLC-A patients treated with radical therapies (66%) survived longer (117 vs. 20 months; p \ 0.001) than patients (33%) who received locoregional or systemic therapies. Survival of BCLC-B patients treated with locoregional treatments (57%) was shorter (24 vs. 71 months; p \ 0.001) than that of patients receiving radical therapies (32%). BCLC-C patients treated with systemic therapy or supportive care survived shorter (6 vs. 11 months; p = 0.003) than those receiving locoregional therapies (39%). Survival of BCLC-D patients receiving systemic therapies or supportive care was significantly lower than that of patients treated by liver transplantation (5 vs. 137 months; p \ 0.001). Ó Society of Surgical Oncology 2011 First Received: 18 May 2010; Published Online: 26 January 2011 B. Sangro, MD, PhD e-mail:
[email protected]
Conclusions. In addition to BCLC stage, actual treatment determines survival in patients with HCC. The Barcelona Clinic Liver Cancer (BCLC) classification is the staging system for hepatocellular carcinoma (HCC) most widely used in western countries. It incorporates variables related to tumor burden, liver functional reserve, and general performance status.1 Unlike other staging systems, BCLC not only identifies subgroups of HCC patients with different prognosis but also offers treatment guidance. However, there are additional factors that modulate therapeutic decisions in daily clinical practice. Some factors are related to specific patient and tumor characteristics, such as presence of comorbidities or anatomical location of tumors, and others depend on the availability of therapeutic procedures and the expertise of the involved teams. Since the original publication, two changes have been introduced into the BCLC classification. Single tumors[5 cm are now classified as stage A, and stage C patients are allocated to sorafenib therapy.2,3 The BCLC classification currently recommends radical therapies (liver transplantation, surgical resection, or percutaneous ablation) for early stage, locoregional therapies (transarterial chemoembolization or TACE) for intermediate stage, sorafenib for advanced stage, and supportive care for endstage HCC. However, there is no absolute agreement with this treatment allocation, especially for the management of early or intermediate tumors. The surgical approach to HCC is a matter of debate, and during the past years, many centers have published their experience with surgical management of intermediate and
HCC Survival by BCLC and Treatment
advanced HCC, showing that in selected patients a radical approach can be offered with encouraging survival and morbidity.4–7 Similarly, several studies have shown that liver transplantation can be performed in selected patients with intermediate stage disease, with survival rates not inferior to those obtained with early tumors.8,9 TACE or bland embolization (TAE) have been classically indicated for patients with intermediate tumors who have a preserved liver function and are free from portal vein thrombosis because of the low potential risk of inducing liver failure. However, several studies have shown that superselective TACE or TAE and Y90 radioembolization (Y90-RE) can be safely performed in selected patients with advanced HCC, including those with portal vein thrombosis and preserved liver function with promising survival rates.10–13 This study was designed to evaluate the effect of treatment choice on prognosis in patients with HCC across the different BCLC stages.
1965
actual therapy matched the first-line recommended by the BCLC system (matched treatment) to that of patients in whom actual therapy corresponded to first-line for a different stage (undertreatment or overtreatment). We also compared the survival of patients in different BCLC stages who received the same treatment. Subgroups of patients treated by different procedures within each BCLC stage were analyzed for differences in demographic, clinical, analytical, and radiological data collected from clinical records relative to the characteristics of the patients, their liver disease, and tumors at the time of diagnosis. Mortality and the following parameters related to morbidity were recorded: days of hospital staying, readmission for any cause within 30 days after initial treatment (except a second session of radioembolization when this procedure was performed in two sessions, one for each lobe), and the occurrence of ascites, jaundice, encephalopathy, and upper gastrointestinal bleeding within 90 days after treatment.
PATIENTS AND METHODS Treatment Allocation Study Design Patients admitted to our institution between September 1994 and October 2008 for newly diagnosed, previously untreated HCC were retrospectively analyzed. The diagnosis of liver cancer was made by histological or cytological confirmation, or by noninvasive imaging methods following the European Association for the Study of the Liver (EASL) criteria.14 For patients diagnosed by imaging methods, the presence of tumor washout on dynamic CT or MRI was retrospectively confirmed. Patients were staged according to the 2009 version of the BCLC classification,3 and survival was calculated from the date of diagnosis to the date of death. Patients lost to follow-up were censored at the time of their last visit. Patients may have received a treatment different from that proposed by the BCLC staging system for several reasons. Our criteria for liver transplantation and liver resection have always been broader than those recommended by the BCLC system.8 Y90-RE is not included in the BCLC staging system as a first-line locoregional therapy. Percutaneous ablation may not be feasible in some patients due to the location of tumors near biliary or vascular structures or the lack of percutaneous accessibility. In addition, each procedure has specific contraindications based on comorbidities or patients may simply have strong preference for or against a particular procedure. To evaluate the impact of treatment on prognosis in patients with HCC across different BCLC stages, we compared survival of patients in each BCLC stage, and within each BCLC stage, the survival of patients in whom
Treatment decisions for HCC patients were made by a multidisciplinary team involving surgeons, interventional radiologists, medical and radiation oncologists, and hepatologists. The workup for HCC is based on what we have called the sieve system, in which the different treatments are considered in a stepwise manner as summarized in Fig. 1. Patients received treatments different from the BCLC recommendations for different reasons. Our criteria for liver resection and transplantation are broader than those recommended by the BCLC system. Since 2002, we have consistently performed bland embolization with calibrated particles instead of TACE. In 2003, we incorporated Y90-RE as a second form of transarterial therapy. Sorafenib was incorporated as the only agent for the systemic treatment of HCC only in 2008. Each procedure also has specific contraindications due to comorbidities or patients may have specific preferences for a particular modality. It should be stressed that the main factor considered for resectability is the quality and quantity of the remnant liver tissue. For noncirrhotic livers, the volume of remnant liver tissue has to be at least 20–30% of the total hepatic volume, and for cirrhotic livers, a major hepatectomy is contraindicated in the presence of significant portal hypertension (esophageal or gastric varices or a hepatic venous pressure gradient of more than 12 mmHg) or a Child-Pugh score higher than 7. Minor resections are considered for patients with compensated cirrhosis in a Child B stage in a highly restricted, individual basis. Portal vein embolization has been used in cirrhotic and noncirrhotic patients as a means to increase remnant liver volume and the safety of resection.
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D. D’Avola et al.
Extrahepatic spread
Surgical Therapies
Resection
Sufficient remnant liver tissue (quantity and quality)
Liver Transplantation
Cirrhosis Age < 70 and lack of comorbidity 1 nod < 6 cm or 3 < 5 for cm PVI absent 1–4 nod < 3 for PEI < 5 for RFA Compensated cirrhosis PVI absent
Percutaneous Ablation
TACE/TAE Transarterial Therapies
Non-bulky disease Segmental occlusion possible Compensated cirrhosis or NCL PVI absent
Child A cirrhosis or NCL Y90 Radioembolization Massive lung shunting absent Sorafenib
Compensated cirrhosis or NCL No other contraindications to SOR
FIG. 1 Summary of treatment protocol for HCC patients followed in our institution. TACE transarterial chemoembolization, TAE transarterial embolization, Y90 90Yttrium-radioembolization, PVI portal vein invasion, NCL noncirrhotic liver, SOR sorafenib
Statistical Analysis Differences in continuous variables between groups were compared using Student’s t test or Mann-Whitney U test depending on whether variables had a normal distribution or not. Differences in noncontinuous variables were compared using the chi-square test. Survival was plotted using the Kaplan-Meier method and compared using log-rank test or Tarone Ware test. Survival was calculated from the date of diagnosis to the date of death. Patients who were alive at the time of the analysis were censored at the last follow-up. Survival analysis included peri-procedural mortality. A p value\0.05 was considered statistically significant. SPSS 15.0.1 (SPSS Inc., Chicago, IL) software was used to perform statistical analyses. RESULTS Characteristics of the 359 newly diagnosed, previously untreated patients with HCC who were retrospectively studied are shown in Table 1. Most patients (72%) were in BCLC stages A and B because our Liver Unit is a tertiary care center where patients are referred for radical therapies. However, only 42% of patients actually received radical therapy (liver transplantation, surgical resection, or percutaneous ablation), and 36% received transarterial locoregional treatment (TACE, TAE, or Y90-RE; Table 2). Median survival for the whole series was 27 (95% confidence interval (CI), 20.7–33.3) months. Survival significantly and progressively worsened among patients with higher BCLC stage from A to D, when BCLC-D patients who underwent liver transplantation were excluded from analysis (Fig. 2). When transplanted BCLC-D patients were included, they showed better survival than BCLC-C patients did.
Analysis by BCLC Stage BCLC-A Fifty-two BCLC-A patients (34%) did not receive radical therapy and the reasons for this discrepancy are summarized in Table 3. In 42 patients, all three alternatives (liver transplantation, resection, and PA) were contraindicated due to several reasons that are summarized in Table 3. The remaining ten patients were listed for liver transplantation and were later withdrawn or died without having had any treatment while in the waiting list. Locoregional therapy was then indicated to most of these patients. Main contraindications were age for liver transplantation, portal hypertension for resection, and tumor size for percutaneous ablation. The distribution of radical therapies among the remaining 104 (66%) of patients was as follows: 34% liver transplantation, 17% surgical resection, and 15% percutaneous ablation (Table 2). Patients who received radical therapies survived significantly longer than those treated with locoregional therapy (117 months, 95% CI not reached vs. 23 months, 95% CI 19.3–26.7; p \ 0.001; Fig. 3). Compared with patients who were treated with radical therapies, those treated by palliative therapies showed a higher main lesion median diameter (44 mm, interquartile range (IQR) 30–84 vs. 28 mm, IQR 19–40; p \ 0.001) and were more likely to have bilobar involvement (11 vs. 4%; p = 0.086) and higher levels of alpha-fetoprotein (AFP [ 400 IU/ml 15 vs. 5%; p = 0.096). BCLC-B Among the 101 patients in BCLC-B stage, 55 (55%) were treated with transarterial locoregional therapy (TACE/TAE 38% and Y90-RE 17%) in accordance with the BCLC recommendation, whereas 35 (35%) received radical therapy (percutaneous ablation 4%, resection 9%, and liver transplantation 22%). Ten patients (10%) received systemic chemotherapy or supportive care due to poor liver function (Child-Pugh scores 8 or 9) or because locoregional therapies were contraindicated for technical reasons (contrast allergy, large arteriovenous shunts, hypovascular tumors, etc.; Table 2). Survival of patients treated with radical therapies was significantly longer than that of patients who received transarterial locoregional therapies (59 months, 95% CI 14.8–103.1 vs. 22 months, 95% CI 14.4–29.5; p \ 0.001; Fig. 3). The main differences between patients who received radical therapies and those who received transarterial therapies were smaller tumor size (size of main lesion[5 cm 29 vs. 58%; p = 0.009) and fewer nodules (C 5 nodules 17 vs. 42%; p = 0.02). There was no significant difference in liver function (Child-Pugh score A 76 vs. 83%; p = 0.58). The 11 patients treated with systemic therapies (54%) or just supportive care (45%) had a worse liver function compared with patients treated with locoregional therapies
HCC Survival by BCLC and Treatment TABLE 1 Characteristics of the study population
Results are expressed as % (n) unless otherwise specified AFP alpha-fetoprotein a
Mean (standard deviation)
b
Median (interquartile range)
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BCLC stage (n)
A (156)
B (101)
C (69)
D (33)
Age (year)a
66 (58–70)
64 (56–71)
62 (54–71)
54 (46–62)
Male gender
79% (123)
82% (83)
83% (57)
94% (31)
Cirrhosis
83% (130)
89% (89)
79% (54)
93% (31)
Platelet count (/pL)b
106 (73–157)
106 (79–191)
136 (88–199)
115 (68–179)
Bilirubin (mg/dl)b
1.4 (0.9–2.2)
1.2 (0.8–1.9)
1.4 (0.9–1.9)
4.7 (2.9–7.7)
Child-Pugh A class
66% (102)
76% (75)
68% (47)
3% (1)
Main lesion [5 cm
24% (37)
49% (48)
84% (57)
29% (9)
Multinodular disease
15% (23)
100% (101)
66% (45)
56% (18)
[3 nodules
0
50% (50)
44% (29)
28% (9)
[5 nodules
0
36% (36)
35% (23)
19% (6)
Bilobar extension
6% (10)
65% (65)
56% (38)
48% (15)
Portal Invasion
0
0
85% (59)
36% (12)
AFP [ 400 UI/mL
9% (11)
22% (20)
52% (28)
5% (1)
(Child Pugh A 36 vs. 83%; p = 0.003). Survival among this group of patients was lower than that of patients treated with locoregional therapies (14 months, 95% CI 1.8–6.1 vs. 22 months, 95% CI 14.4–29.5; p = 0.001; Fig. 3). BCLC-C Among patients in BCLC-C stage, 23 (34%) received systemic therapies, 27 (39%) received locoregional treatment (Y90-RE 27% and superselective TAE 12%), and 19 (27%) did not receive any antineoplastic therapy (Table 2). Patients treated with locoregional therapies had a better hepatic function compared with patients who were treated with systemic therapy or who received supportive care (Child-Pugh A 85 vs. 57%; p = 0.018). Survival of patients who were treated with locoregional therapies was longer compared with patients who were treated with systemic therapies (11 months, 95% CI 9.2–12.5 vs. 6 months, 95% CI 4.8–7.1; p = 0.033; Fig. 3). BCLC-D Among the 33 patients in BCLC-D stage, 13 (40%) underwent liver transplantation, and the remaining 20 (60%) were treated with systemic chemotherapy or received only supportive care (Table 2). Compared with patients who were treated with liver transplantation, those who were treated by systemic therapy or supportive care had larger tumors and a higher frequency of vascular invasion (main lesion[5 cm 45 vs. 0%, p = 0.003, and vascular invasion 60 vs. 0%, p = 0). No difference in survival was observed between patients who were treated with systemic therapy and patients who received supportive care (5 months, 95% CI 1.3–8.6 vs. 5 months, 95% CI 3.6–6.3; p = 0.281). Analysis by Treatment Considering all patients treated with radical therapies (liver transplantation, resection and percutaneous ablation), survival was significantly longer in BCLC-A than in
BCLC-B stage (117 months, 95% CI not reached vs. 59 months, 95% CI 15–103 months; p = 0.019). Interestingly, when analyzed by type of treatment, patients who underwent liver transplantation showed similar survival independent of their BCLC stage (A, B, or D). On the other hand, patients in BCLC stages A and B who underwent locoregional treatments (TACE/TAE and Y90-Radioembolization) had similar survival (BCLC-A: 23 months, 95% CI 19–26 vs. B: 22 months, 95% CI 14–29; p = not significant). However, BCLC-C patients who received locoregional treatments had a lower survival (11 months, 95% CI 9–12) than BCLC-A and B patients (p = 0.003 and p = 0.011, respectively). As shown in Table 2, no significant differences were observed in mortality or morbidity between patients who were treated according to BCLC indication and those who received a treatment indicated for a higher BCLC stage. In our series, three patients died within 30 days after initial therapy. One patient in BCLC B stage died because for tumoral and microparticle pulmonary embolism after transarterial embolization. Two patients in stage BCLC-A died: one because of liver failure after an extended right hepatectomy, and the other due to a vascular complication after liver transplantation. DISCUSSION The BCLC staging system has been validated as a prognostic tool able to differentiate five subgroups of patients with HCC that have significantly different probability of survival.15–17 The authors also proposed its use as a method for treatment allocation, and this role has been endorsed by renowned scientific societies.14–18 However, the selection of individual therapy in clinical practice is determined by several factors. Specific contraindications or technical limitations can influence treatment decision for
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D. D’Avola et al.
TABLE 2 Distribution of treatments and complications of radical and locoregional therapies across different BCLC stages BCLC-A
BCLC-B
BCLC-C
BCLC-D
No. of patients (n) LT
54 (34%)
22 (22%)
0
13 (39%)
Surgery
27 (17%)
9 (9%)
0
0
RFA/PEI
23 (15%)
4 (4%
0
0
TACE/TAE
42 (27%)
38 (38%)
8 (12%)
2 (6%)
Y90 RE
5 (4%)
17 (17%)
19 (27%)
0
Systemic or BSC Total
5 (3%) 156
10 (10%) 101
38 (61%) 69
18 (55%) 33
Days of hospital stay (median, IQR) LT
10 (8.5)
9 (4)
–
9 (11.5)
Surgery
10 (7)
7 (6.5)
–
–
RFA/PEI
3 (2)
3.5 (2)
–
–
TACE/TAE
3 (1.5)
3 (1.7)
2.5 (1.7)
3.5 (1)
Y90 RE
2 (0)
2 (0)
2 (0)
–
Patients readmitted within 30 daysa LT
10 (19%)
4 (18%)
–
2 (15%)
Surgery
3 (11%)
3 (33%)
–
–
RFA/PEI
2 (9%)
0
–
–
TACE/TAE
0
1 (3%)
1 (12%)
0
Y90 RE
0
0
2 (10%)
–
LT Surgery
1 1
0 0
– –
0 –
RFA/PEI
0
0
–
–
TACE/TAE
0
1
0
0
Y90 RE
0
0
0
–
30-day mortality (n)
30-day jaundice (n) Surgery
4 (15%)
0
–
–
RFA/PEI
1 (4%)
0
–
–
TACE/TAE
6 (14%)
2 (5%)
1 (12%)
0
Y90 RE
1 (20%)
2 (12%)
5 (26%)
–
Surgery
2 (7%)
3 (33%)
–
–
RFA/PEI
4 (17%)
1 (25%)
–
–
TACE/TAE
6 (14%)
1 (3%)
0
1 (50%)
Y90 RE
1 (20%)
0
1 (5%)
–
0 0
– –
– –
30-day ascites (n)
30-day encephalopathy (n) Surgery RFA/PEI
0 0
TACE/TAE
1 (2%)
1 (3%)
0
0
Y90 RE
0
0
3 (16%)
–
–
–
30-day gastrointestinal bleeding (n) Surgery
0
0
RFA/PEI
1 (4%)
0
–
–
TACE/TAE
0
0
1 (12%)
0
TABLE 2 continued
Y90 RE
BCLC-A
BCLC-B
BCLC-C
BCLC-D
1 (20%)
0
1 (6%)
–
RFA radiofrequency ablation, PEI percutaneous ethanol injection, TACE transarterial chemoembolization, TAE transarterial embolization, LT liver transplantation, Y90 RE radioembolization with Y90 microspheres, BSC best supportive care Systemic therapies include chemotherapy, hormonal therapy, sorafenib, and gene therapy a
Readmissions for sequential treatments among patients treated by Y90-RE and TACE or TAE were not considered. Jaundice was considered to be present when reported in the medical records or when a relevant increase in serum bilirubin was observed
individual patients. On the other hand, the scientific basis for treatment allocation at the extremes of each BCLC stage is far from being robust. Expanded criteria for liver transplantation are followed in an increasing number of centers with encouraging results.8,19,20 Surgical resection may result in prolonged survival for patients with large or multinodular tumors, as well as in patients with mild portal hypertension, and locoregional therapies, including TACE and Y90-RE, may yield good results among patients with tumors producing segmental or branch portal vein invasion.11,12,21–24 Accordingly, treatments of liver cancer do not exactly match the BCLC paradigm in many tertiary centers caring for HCC patients. For the past 15 years, we have followed a treatment protocol for HCC in which treatments with progressively poorer outcomes (from liver transplantation to best supportive care) or better evidence of efficacy (resection vs. percutaneous ablation, or TACE vs. Y90-RE) are considered in a stepwise manner. This resulted in treatment allocation that differs slightly from that proposed by the BCLC staging system. In this study, we retrospectively evaluated the effect of treatment allocation on the survival of HCC patients within each BCLC stage. Our results indicate that prognosis of HCC is not only determined by tumor stage but is greatly influenced by treatment choice, at least for specific treatment groups. Thus, the limits of BCLC stages should not be considered rigid barriers to treatment allocation. In fact, prognosis in BCLC-A patients treated by locoregional therapies was not significantly different from the prognosis of BCLC-B patients treated with the same modality. In addition, BCLC-B patients undergoing radical therapies survived significantly longer than those treated by locoregional therapies. The indication of radical therapies for BCLC stages other than A and locoregional therapies for BCLC stages other than B did not pose an increased risk of morbidity or mortality. This is
HCC Survival by BCLC and Treatment FIG. 2 Survival according to BCLC stage. Kaplan-Meier plots of survival for each BCLC stage, including (a) or excluding (b) those patients in D stage who were treated by liver transplantation. Median survival (95% CI) for each group is provided
1969
(a)
(b) Cumulative survival
Cumulative survival 1.00
BCLC A 59 months (40.5–77.4) BCLC B 24 months (17.3–30.6) BCLC C 9 months (7.1–10.8) BCLC D 11 months (5.3–16.6)
1.00
0.75
0.75
0.50
0.50
0.25
0.25
0
24
48
72
96
120
144
BCLC A 59 months (40.5–77.4) BCLC B 24 months (17.3–30.6) BCLC C 9 months (7.1–10.8) BCLC D 5 months (3.6–6.3)
0
168
24
48
BCLC A BCLC B BCLC C BCLC D
155 101 69 33
91 40 6 11
38 8 0 5
58 15 1 8
22 5 0 4
TABLE 3 Contraindications to specific radical therapies among 52 patients in BCLC stage A who did not receive a radical therapy Transplantation
Resection
RFA
Any
42 (81%)
50 (96%)
47 (90%)
Size of main tumor
21 (40%)
–
25 (48%)
Age (year)
27 (52%)
–
–
Comorbidity Insufficient remnant
4 (8%) –
8 (15%) 11 (21%)
– –
Portal hypertension
–
34 (65%)
–
Accessibility
–
–
8 (15%)
Location
–
–
3 (6%)
Ascites
–
–
7 (13%)
Other
3 (6%)a
2 (4%)b
3 (6%)c
Technical reasons include mainly lack of accessibility due to the location of the tumors in the liver surface or the liver dome, or inability to detect them by US imaging. Location means proximity to large vessels or bile ducts, or the gallbladder. More than one contraindication for each treatment could be present in a same patient a
Includes one patient with an ill-defined 3-cm poorly differentiated HCC and two patients with uncertain staging for which the decision to perform a radical therapy was deferred to discard early progression after TACE
b
Includes one patient who refused surgery and one patient with uncertain staging c Includes one patient with uncertain staging, one patient with tumor progression while on the waiting list, and one patient with extracapsular tumor spill-over
likely to be due to the fact that resection and locoregional therapies were only indicated in the presence of a preserved liver functional reserve. Regarding liver transplantation, the similar survival observed in BCLC stages A and D can be explained by the use of the same criteria regarding tumor size and number; the only difference is more advanced liver disease that is cured by liver transplantation in BCLC-D patients.
8 3 0 2
2 1 0 1
72
96
120
144
168
Months of survival
Months of survival 0 0 0 0
BCLC A BCLC B BCLC C BCLC D
155 101 69 20
91 40 6 0
58 15 1 0
38 8 0 0
22 5 0 0
8 3 0 0
2 1 0 0
0 0 0 0
These observations emphasize the fact that patients with early tumors achieve prolonged survival only if they are effectively treated with radical therapies and underscore the inability of BCLC to define completely the indication for surgery. Conversely, BCLC-C patients receiving systemic ineffective therapies or best supportive care (most probably those with a shorter life expectancy) had similar survival as BCLC-D patients treated in the same way. A potential explanation for our findings is that BCLC stages are heterogeneous and include subgroups of patients with different prognosis—because of the natural history of the disease or because of access to specific effective therapies. As an example, two asymptomatic patients with good liver function may be at BCLC-A stage even if one has two 3-cm tumors and the other has a single 15-cm lesion. Because the BCLC system includes variables related to the tumor and liver function, when the tumor effect is modified by treatment, the role of chronic liver disease may become more important in affecting prognosis. Thus, optimization of prognosis of HCC patients relies on the availability of all therapeutic options and a sound selection of patients for each therapeutic modality. In conclusion, these results suggest that in addition to the BCLC stage, other variables must be considered when making therapeutic decisions for patients with HCC. The retrospective design of this study does not allow assessment of the superiority of a different treatment algorithm; however, our results suggest that at least a subgroup of BCLC-B patients is likely to benefit from radical therapies, including surgical resection and liver transplantation. The BCLC staging system provides a good framework, but the decision-making process for HCC treatment should be handled by comprehensive multidisciplinary teams, which can consider the potential of each therapy in any individual patient irrespective of stage.
1970 FIG. 3 Survival across different BCLC stages according to treatment. Sys systemic therapy, BSC best supportive care
D. D’Avola et al. Cumulative survival
Cumulative survival
BCLC-A
1.00
Radical therapy Locoregional therapy
0.75
BCLC-B
1.00
Radical therapy Locoregional therapy Systemic therapy/ Best supportive care
0.75
0.50
0.50 p < 0.001
p < 0.001
0.25
0.25 p = 0.001
0
24
48
72
96
120
144
168
0
24
Months of survival Radical 104 Locoregional 52
75 15
Cumulative survival
51 7
37 1
21 1
8 0
2 0
0 0
Radical 35 Locoregional 55 Sys/BSC 11
23 17 0
Cumulative survival
BCLC-C
1.00
48
72
96
120
144
168
1 0 0
0 0 0
Months of survival
Locoregional therapy Systemic therapy/ Best supportive care
7 1 0
13 2 0
5 0 0
BCLC-D
1.00
0.75
0.75
0.50
0.50
3 0 0
Liver transplantation Systemic therapy/ Best supportive care
p 0.003
p < 0.001
0.25
0.25
0
24
48
72
96
120
144
168
0
Months of survival 42 Sys/BSC Locoregional 27
3 3
1 0
0 0
ACKNOWLEDGMENT CIBEREHD is funded by Insituto de Salud Carlos III. This work also was funded in part by Accio´n Transversal contra el Ca´ncer.
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0 0
0 0
24
48
72
96
120
144
168
0 1
0 0
Months of survival 0 0
0 0
Sys/BSC 18 Transplantation 13
0 9
0 8
0 7
0 4
0 3
7. Torzilli G, Donadon M, Marconi M, Palmisano A, Del Fabbro D, Spinelli A, et al. Hepatectomy for stage B and stage C hepatocellular carcinoma in the Barcelona Clinic Liver Cancer classification: results of a prospective analysis. Arch Surg. 2008;143: 1082–90. 8. Herrero JI, Sangro B, Pardo F, Quiroga J, Inarrairaegui M, Rotellar F, et al. Liver transplantation in patients with hepatocellular carcinoma across Milan criteria. Liver Transpl. 2008;14:272–8. 9. Vauthey JN, Ribero D, Abdalla EK, Jonas S, Bharat A, Schumacher G, et al. Outcomes of liver transplantation in 490 patients with hepatocellular carcinoma: validation of a uniform staging after surgical treatment. J Am Coll Surg. 2007;204:1016–27; discussion 1027–8. 10. D’Avola D, In˜arrairaegui M, Bilbao JI, Martinez-Cuesta A, Alegre F, Herrero JI, et al. A retrospective comparative analysis of the effect of Y90-radioembolization on the survival of patients with unresectable hepatocellular carcinoma. Hepatogastroenterology. 2009;56:1683–8. 11. Kim KM, Kim JH, Park IS, Ko GY, Yoon HK, Sung KB, et al. Reappraisal of repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma with portal vein invasion. J Gastroenterol Hepatol. 2009;24:806–14. 12. Kulik LM, Carr BI, Mulcahy MF, Lewandowski RJ, Atassi B, Ryu RK, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology. 2008;47:71–81.
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