The prognosis for cirrhotic patients who develop HCC continues to be poor, with a five year survival rate of 6% in the USA.1
The various forms of treatment available for these tumours are effective in improving survival only when the disease is diagnosed at an early stage (that is, when tumour diameter is less than 5 cm and liver function is still normal). For patients with larger tumours and decompensated cirrhosis (Child-Pugh class B or C), no treatment appears to be capable of prolonging survival.24
Ultrasound screening of patients with chronic hepatitis and cirrhosis has increased the frequency of preclinical diagnosis of HCC,25
and consequently curative therapy (that is, resection, liver transplantation, PEI, RFA, and TACE) is considered possible in a growing number of cases.
Tumour staging at the time of diagnosis is essential to identify these cases and decide which type of therapy is the most appropriate. The Okuda system is proving to be inadequate for today’s HCC cases, particularly those that are diagnosed early. Designed for use in a population with relatively advanced neoplastic disease, the Okuda system’s current shortcomings include a lack of distinction between uni- and multifocal tumours and its neglect of factors such as AFP levels, PVT, local-regional lymph node involvement and PS, whose prognostic significance has been unequivocally confirmed in both surgical and non-surgical series.26–30
In recent years, several alternative staging systems have been proposed8,11,31–33
but there is still a lack of consensus regarding their relative accuracies and applicability. Significant biological variability related to the various aetiological/pathogenetic aspects of these tumours and our incomplete understanding of their natural history are two of the factors complicating the staging process.34
The system proposed by the Cancer of the Liver Italian Program (CLIP) in 1998 was based on a retrospective study8
and was subsequently prospectively validated.35
The CLIP studies identified five independent prognostic variables: Child-Pugh class of cirrhosis, tumour size, number of lesions, presence/absence of PVT, and serum levels of AFP. On the whole, CLIP stages have proved to be more accurate than the Okuda classification scheme in the prediction of survival, particularly in early stage disease.8
The validity of this system has been confirmed in two large retrospective studies in Canada and Japan9,10
but in the largest series evaluated thus far (906 Patients in China), CLIP staging displayed very low correlation with survival.11
This discrepancy may be related to the fact that the majority of Chinese patients had HBV related liver disease whereas HCV was the most common risk factor in the Canadian and Japanese studies (as well as in those conducted in other Western countries).
The BCLC staging system was developed based on a retrospective analysis of various studies of HCC patients with early, intermediate, and advanced-terminal disease, which attempted to identify prognostically relevant variables for each group.12
For patients with early stage disease, survival was negatively correlated with portal hypertension and bilirubin levels >1.5 mg/dl; for intermediate stages, the significant variable was a large multinodular tumour; and for advanced disease, deterioration of PS and the presence of vascular infiltration. These variables were used to supplement those included in the Okuda staging system. To our knowledge, only two attempts have been made to compare the CLIP and BCLC systems. In the first study, both scores displayed prognostic values inferior to that of oestrogen receptor status36
; in the latter, BCLC proved to have a higher prognostic power than CLIP in 187 HCC patients undergoing surgical or non-surgical treatment.37
In our study, none of the patients had undergone surgical resection or liver transplantation, and all had received non-surgical forms of treatment. Furthermore, all of the tumours had been diagnosed before they had provoked symptoms as the vast majority of the patients had been subjected to periodic ultrasound screening for early detection of HCC. Mean duration of survival in the total population (25.7 months) was comparable (20 months) with that reported in a population similar to ours for the percentage of tumours diagnosed at the preclinical stages and for the number of patients with confirmed cirrhosis at the time of diagnosis.8
The high prevalence of cirrhosis in ours and the CLIP study populations8
is probably largely responsible for the lower survival rates with respect to those reported by Ueno et al
(mean 37.7 months) in a group that included a much higher percentage (19.2%) of patients with no evidence of cirrhosis at the time of HCC diagnosis.10
Multivariate analysis showed that independent predictors of survival were mostly related to the cancer itself (tumour diameter <3 cm, absence of PVT, and low serum AFP) while only a low bilirubin serum level was significantly related to survival among the parameters of liver function. CLIP and BCLC restaging of these patients was possible as information was available in all cases for all of the variables included in both systems, including PS. In fact, all of our patients had a PS of 0, reflecting the absence of symptoms at the time of diagnosis. Both the BCLC and CLIP systems proved to be superior to the Okuda system, distinguishing within each Okuda stage various subgroups that were distinct in terms of survival. On the whole, when the two new systems were compared, BCLC proved to be the more accurate predictor of survival, even if its discriminating power at three and five years did not differ significantly from that provided by the CLIP score.
Moreover, in our patients, BCLC staging offered two important advantages: better differentiation of early stage HCCs and inclusion in the score of PVT presence. In fact, stage A included four subgroups that were significantly different in terms of survival. The best prognosis was associated with stage A1 cases (mean survival 43.4 months) and this was probably due to the fact that none of the A1 patients had tumours >3 cm, portal hypertension, or elevated bilirubin levels—each of which is known to have a negative influence on survival in both surgical and non-surgical series.30,38,39
Interestingly, both tumour size and bilirubin level were independent predictors of survival, even in our series. In contrast, almost half (53/129) of the CLIP 0 patients had lesions >3 cm, and in 21 cases the tumours were >4 cm. Furthermore, findings indicative of portal hypertension (which is not considered in CLIP staging) were present in 163 (60.8%) patients. Consequently, CLIP stage 0 was associated with a mean survival of only 30.1 months. Other groups have reported considerably better survival values for patients of this type, ranging from 42.5 to 68.7 months.8,10
The difference is probably related to the inclusion in the latter two studies of a number of patients who underwent surgical resection.
The second advantage of BCLC staging is that it reflects the presence or absence of PVT. In our experience, survival in patients with PVT at the time of diagnosis is invariably limited, and this effect is independent of the presence of other prognostically negative factors. In patients with HCC, PVT is generally indicative of neoplastic invasion of the vascular compartment.40
In the present study, eight of the 11 patients with PVT died within eight months after diagnosis. The outcome of the other three cases is unknown as the patients were lost to follow up 3–4 months after diagnosis. BCLC staging classified all 11 of these patients as stage C (mean survival 7.4 months). In contrast, with the CLIP system, seven of the PVT patients were classified as stage 2 or 3, both of which were associated with considerably longer survival (17.7 and 16.8 months, respectively). The remaining four were classified as stage 4.
Several follow up studies have shown that even mild elevations in serum AFP levels predict a worse prognosis, regardless of whether the patient is treated with surgery or PEI.30,41
AFP levels are one of the variables considered in the CLIP system but are not included in the BCLC. In terms of prognostic accuracy, this difference does not appear to be important. In fact, the CLIP definition of an AFP elevation is >400 ng/ml. While this cut off is widely accepted as diagnostic for HCC, only 19/268 (7%) of our patients had levels this high at the time of diagnosis, and eight of these also had PVT, which automatically placed them in BCLC stage C.
In conclusion, in this series of patients with asymptomatic HCCs diagnosed at the early to intermediate phases and treated with non-surgical modalities, both the CLIP and BCLC systems provided more precise estimates of survival than the Okuda system. The BCLC system appeared to be more accurate than the CLIP score in identifying prognostically favourable cases (small tumours <3 cm in patients with well compensated liver function and no portal hypertension) as well as those in whom survival was likely to be limited (due to the presence of macroscopically evident vascular invasion).