A novel and validated prognostic index in hepatocellular carcinoma: the Inflammation Based Index (IBI).

David J. Pinato^1,2, Justin Stebbing³, Mitsuru Ishizuka⁴, Shahid A. Khan⁵, Harpreet S. Wasan³, Bernard V. North⁶, Keiichi Kubota⁴, Rohini Sharma^1*

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumour and the third most lethal among all human neoplasms[1]. Approximately 70-90% of HCCs arise in the context of chronic liver disease[2]. Unlike other solid malignancies, the prognosis of HCC is not solely dependent on tumour burden but is also adversely influenced by impaired liver function secondary to the underlying pathogenic condition[3]. As a consequence, staging systems such as the Tumour Node Metastasis (TNM) that rely on purely pathological variables retain limited prognostic value in HCC[4, 5]. Several alternative systems have been proposed to predict patient prognosis including parameters such as functional liver reserve, performance status, circulating tumour markers and the extent of spread of the primary tumour[6]. At least 8 different models[5, 7-13] have been developed but there is a need to determine a reliable prognostic scoring system.

The most widely accepted staging system is the Barcelona Clinic Liver Cancer (BCLC) algorithm that not only considers prognostic stratification but also therapeutic allocation[14-16]. However, the superiority of BCLC to previously devised scores in terms of prognostic accuracy has been controversial[17]. Recent data suggests that, whilst the BCLC system has been shown to better categorize patients amenable to surgery[18], the prognosis of advanced HCC appears to be better predicted by the Cancer of the Liver Italian Program (CLIP), Chinese University Prognostic Index (CUPI) and the Groupe d’Etude et de Traitement du Carcinome Hépatocellulaire (GRETCH) systems[19]. The predictive accuracy of the CLIP score has been further validated in a comparative study considering the five most common clinical staging systems, including BCLC, Japanese Integrated Score (JIS), Tokyo and TNM score[20]. Many of these have not undergone independent validation in separate patient cohorts, and inconsistent results emerge from comparative studies making selection of an optimal prognostic model particularly difficult. Furthermore, many of these scores are cumbersome and rarely used outside of a clinical trials setting. There is a need therefore for a reliable prognostic score that can be utilized in routine clinical practice.

The pathogenesis of HCC is based on inflammation, with the chronically inflamed liver parenchyma representing a precancerous milieu in which 70-90% of the HCCs arise[2]. As the last and most redoubtable clinical consequence of cirrhosis, the onset of HCC is related to a myriad of pro-inflammatory stimuli, triggered by well recognized noxae such as infection by hepatotropic viruses, iron or copper accumulation or ethanol consumption[21]. Moreover, there is increasing evidence supporting the role of systemic inflammation as a predictor of outcome in several human cancers including HCC[22, 23]. This systemic inflammatory response is sustained by aberrant release of pro-inflammatory cytokines such as TNF-α, interleukins and inteferon-γ[24], as either a host response to the tumour or derived from the tumour itself[25]. Systemic inflammation has been proposed as a causative mechanism in the development of cancer cachexia and correlates negatively with prognosis in a number of cancer types[23]. Routinely, systemic inflammation can be evaluated by means of widely available markers such as C-reactive protein (CRP), albumin or other haematological parameters such as neutrophil-lymphocyte ratio (NLR) or platelet-lymphocyte ratio (PLR)[26]. A number of studies have shown that elevated levels of circulating CRP predict survival[27] and recurrence[28] after surgical resection in HCC whilst a NLR>5 is associated with poor clinical outcomes following resection and transplantation[29, 30].

The combination of serum CRP and albumin have previously been used to derive the modified Glasgow Prognostic Score (mGPS)[31] as a measure of systemic inflammation. The prognostic power of this system has been qualified in various solid tumours including lung[31-33], ovarian[34], gastro-oesophageal[35], colorectal[36] and renal cell cancer[37, 38]. Recently, the combination of hypoalbuminaemia and raised CRP has been shown to independently predict survival in a large case series of surgically treated HCC patients[39]. The aims of the current study were to validate the prognostic power of a prognostic score based on inflammation that we have defined as the Inflammation Based Index (IBI) together with other markers of systemic inflammation such as the NLR and PLR in HCC in large independent cohorts. We also wish to  compare their performance with established clinical prognostic models, including the CLIP and the BCLC scores, to ascertain whether systemic inflammation is an accurate marker of prognosis.      

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Several models to guide prognosis in HCC have been developed, each one including parameters reflective of both liver dysfunction and tumour stage. None of these previous prognostic indices is considered ideal and, despite the increasing number of comparative studies published, there is no consensus as to the optimal system that should be utilised[17]. Furthermore, many of these scores lack the simplicity for use outside of a clinical trial setting. As sustained inflammation acts as one of the principal factors thought to promote the development of neoplastic foci within the chronically injured liver parenchyma, we compared the utility of three, widely used inflammation based prognostic scores in determining overall survival in a heterogeneous group of patients with HCC[21]. To our knowledge the prognostic performance of these tests have never previously been studied in a comparative fashion, nor externally validated.

We have shown that the IBI is a novel and independent predictor of overall survival in both our primary set and in a large independent cohort of patients with HCC. Furthermore, we have shown that the combination of both the IBI and CLIP score improves the predictive power of the CLIP score alone. These results are provocative in suggesting that inflammation should be incorporated into an HCC prognostic score to improve its discriminative ability. The high death rates in our cohorts, a feature of HCC, lends itself to such validated prognostic indices.

Previous reports have shown that systemic inflammation as calculated by the GPS[39, 44] and the NLR are predictors of outcome in HCC[29, 30]; however these have only been investigated in patients with resectable disease. In our analysis NLR, PLR and IBI were associated with a number of clinico-pathologic characteristics of HCC, and with survival in univariate analyses. In particular an elevated NLR and IBI were associated with tumour stage, with patients with a higher score tending to have greater liver involvement and extrahepatic spread, suggesting the presence of a systemic inflammatory response is predictive of a more aggressive clinical phenotype. We subsequently compared the predictive ability of the IBI with the other prognostic scores by means of c index as reported in Table 5. The IBI is also superior to CRP and albumin alone, which do not appear to be independently associated with survival in our cohorts. Reduced serum albumin was included in the IBI as a reflection of subclinical inflammatory response and malnutrition, two overlapping conditions affecting the prognosis of cancer patients[45]. Hepatic albumin biosynthesis is down-regulated by pro-inflammatory stimuli as part of a negative acute phase reaction in patients with malignancy[46]. However, impaired synthetic function accompanying end stage liver disease probably needs to be considered as an additional determinant of reduced serum albumin that may have contributed to the results reported. Although previous reports show the independent prognostic value of hypoalbuminaemia in HCC[47, 48], our data are not consistent with this finding suggesting that the reduced survival observed in patients with an IBI of 2 was not solely a reflection of impaired liver function.

We also examined the predictive ability of the BCLC and CLIP score to assess survival. In the training cohort, which consisted predominantly of patients with intermediate to advanced stage disease, the CLIP score was an independent predictor of survival . BCLC is regarded as the most complete and widespread staging system, but with apparent limitations in the more advanced cases of HCC[19][49], whilst the commonly used CLIP score has been shown to retain prognostic ability in all disease stages[20].  This is not the first report suggesting that patient selection is crucial in determining the accuracy of the BCLC system in its predictive ability, validation of which has been carried out in patient populations with few advanced cases[50, 51]. Moreover, under the BCLC system, patients with portal vein thrombosis, nodal and extrahepatic invasion are incorporated into the single, broad category of advanced HCC (BCLC-C)[7]. However, there is a significant degree of variation in survival within this patient group which is not considered[19].  BCLC, however, remains the clinical standard by which treatment allocation is determined based on tumour stage, hepatic reserve and performance status.  Because of the small numbers of patients in this study and the retrospective design we were unable to investigate the relationship between IBI, the impact of the type of treatment received and overall survival, an important consideration which needs further investigation.

One of the main issues in the assessment of novel prognostic indices in HCC is the requirement for validation in independent patient cohorts. Significantly, we found that both the CLIP score and the IBI remained predictors of overall survival in an independent cohort of patients with a predominantly lower tumour burden, confirming the validity of these two scores across all disease stages, each with significantly different survival rates. Moreover, we confirmed that the predictive abilities of both the CLIP score and the IBI were conserved across both Caucasian and Asian populations in whom the distribution of risk factors are  different, with hepatitis B infection being endemic in Asia. The IBI is therefore a validated predictor of survival in two apparently heterogeneous patient populations with differences in their management[52]. 

Despite ranking as the most accurate prognostic score, the CLIP score is a seven grade cumulative system incorporating four different parameters, making this difficult to apply to routine clinical practice, whilst the IBI is derived from  two routinely available blood tests. Moreover, we validated the concept that the combination of the IBI with the CLIP score may increase the predictive ability of the latter, suggesting the additive value of systemic inflammation to an accurate prognostic assessment in HCC.

Recently, Proctor and colleagues investigated the prognostic significance of a number of inflammatory scores in 25,000 patients with various malignancies. They concluded the presence of systemic inflammation is an adverse prognostic marker independent of tumour type[38] and suggested that further development of prognostic scores based on inflammation should include CRP. A number of investigators have attempted to identify the individual cytokine(s) driving this systemic inflammatory response with little consensus in the literature, suggesting that this is likely to be mediated by a number of pro-inflammatory cytokines and growth factors released from the tumour itself or as a host reaction to the presence of malignancy[25]. Molecular profiling analysis confirmed a prognostic role for inflammation-related gene expression signatures in the specific context of HCC providing further insight into the impact of local inflammation on tumour progression[53]. More recent studies have confirmed that the presence of an intratumoural inflammatory infiltrate can exert detrimental effects on patient’s prognosis[54]. Taken together these results suggest that, given the underlying inflammatory nature in the pathogenesis of HCC combined with systemic inflammation, moderation of this inflammatory response may be as an important therapeutic target as the tumour itself.

A challenge for the future, and a limitation of the current study, is to develop and validate a consensus score combining the traditional variables assessed by the CLIP score with the previously unexplored markers of systemic inflammation that could represent a new and more accurate stratification parameter in HCC.  Furthermore, in the training set we identified prior therapy as an independent predictor of survival.  However, because of the small sample size it was not possible to conduct further subgroup analysis based on the type of therapy received.  This is an important  question as currently BCLC remains the gold standard by which treatment is allocated.  This requires further exploration in a future, prospectively designed study.

Another consideration when interpreting the data presented is the differences between the two cohorts: the relative under-representation of early stage HCC in the training set (15%) as opposed to the validation set (56%).  This difference in stage may have contributed to the underperformance of the BCLC score compared to the CLIP and the IBI which is consistent with previous studies[19]. To this respect, the uneven proportion of patients receiving best supportive care across the groups (32% versus 3%) should also to be acknowledged as a potential confounder.

Despite these limitations, IBI remained a statistically independent predictor of survival in patients with differing stage and underlying aetiologies. The impact of unbalanced staging in the ranking of the tested prognostic models should be taken into consideration and further tested in patient cohorts with uniform stage grouping. As BCLC is endorsed by the European Association for the Study of the Liver (EASL) and remains the most followed treatment allocation system, adequately powered studies should be performed in order to clarify whether the IBI can be used to sub-classify patient survival across early, intermediate as well as advanced stage disease in both treated and untreated patients.  We have not shown an association between the IBI and treatment allocation which requires further investigation as part of large, prospectively designed study.

In conclusion, despite the acknowledged limitations, these data suggest that the IBI offers additional prognostic information in the clinical management of HCC in early as well as in the more advanced stages of the disease. In addition we confirmed that the IBI qualifies as an independent, inexpensive and universally available method to predict prognosis in advanced HCC patients, and, when combined with the CLIP score, may represent a unique, more accurate prognostic score. Future, prospectively designed studies should investigate and compare IBI with BCLC not only in terms of prognosis but also in optimizing treatment allocation.