- Email: [email protected]
An inflammation-based prognostic index predicts survival advantage after transarterial chemoembolization in hepatocellular carcinoma
An inflammation-based prognostic index predicts survival advantage after transarterial chemoembolization in hepatocellular carcinoma DAVID J. PINATO, and ROHINI SHARMA LONDON, UK; AND NOVARA, ITALY
Transarterial chemoembolization (TACE) is the preferred treatment for unresectable, intermediate-stage hepatocellular carcinoma (HCC). However, survival after TACE can be highly variable, suggesting the need for more accurate patient selection to improve therapeutic outcome. We have explored the prognostic ability of the blood neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, as a predictor of survival after TACE. Fifty-four patients with a diagnosis of HCC eligible for TACE were selected. Clinicopathologic variables were collected, including demographics, tumor staging, liver functional reserve, and laboratory variables. Dynamic changes in the NLR before and after TACE were studied as predictors of survival using both a univariate and multivariate Cox regression model. Patients in whom the NLR remained stable or normalized after TACE showed a significant improvement in overall survival of 26 months compared with patients showing a persistently abnormal index (P 5 0.006). Other predictors of survival on univariate analysis were Cancer of the Liver Italian Program score (P 5 0.05), intrahepatic spread (P 5 0.01), tumor diameter . 5 cm (P 5 0.02), . 1 TACE (P 5 0.01), alpha-fetoprotein $ 400 (P 5 0.002), and radiologic response to TACE (P , 0.001). Improved NLR after TACE (P 5 0.03) and radiologic response after TACE (P 5 0.003) remained independent predictors of survival on multivariate analysis. Changes in alpha-fetoprotein after treatment did not predict survival. Patients with a persistently increased NLR have a worse outcome after TACE. NLR is a simple and universally available stratifying biomarker that can help identify patients with a significant survival advantage after TACE. (Translational Research 2012;160:146–152) Abbreviations: AFP ¼ alpha-fetoprotein; BCLC ¼ Barcelona Clinic Liver Cancer; CI ¼ confidence interval; HCC ¼ hepatocellular carcinoma; IL ¼ interleukin; NLR ¼ neutrophilto-lymphocyte ratio; TACE ¼ transarterial chemoembolization
t has been estimated that up to 60% to 70% of patients with hepatocellular carcinoma (HCC) present with intermediate- to advanced-stage disease at diagnosis.1 For these patients, overall survival can vary between 6 and 20 months.1,2 Provision of treatment to this composite patient group is essentially palliative,
I
aimed at prolonging survival while maintaining quality of life. Among patients who are not amenable to curative treatments, a well-defined subgroup identified within the Barcelona Clinic Liver Cancer (BCLC) B stage, characterized by large or multinodular, asymptomatic tumors without extrahepatic spread, can be
From the Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London, UK; Division of Internal Medicine, Universita degli Studi del Piemonte Orientale, Department of Clinical and Experimental Medicine, Novara, Italy.
Reprint requests: Rohini Sharma, FRACP, PhD, Senior Lecturer in Oncology and Clinical Pharmacology, Imperial College London, Hammersmith Campus, Du Cane Road, W12 0HS, London, UK; e-mail: [email protected].
Conflict of Interest: none
1931-5244/$ - see front matter
Funding: This work was supported in part by the Fondazione DeAgostini Research Grant for PhD studies to DJP.
Ó 2012 Mosby, Inc. All rights reserved.
Submitted for publication December 1, 2011; accepted for publication January 10, 2012.
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AT A GLANCE COMMENTARY Pinato and Sharma Background
The pathogenesis of HCC is based on inflammation, with 80% of the tumors arising in a context of chronic liver disease. Several prognostic scores have been devised, but there is no consensus as to the optimal staging system. Translational Significance
We showed that the normalization of a prognostic score based on inflammation, the NLR, predicts survival advantage after TACE. This suggests that the NLR can improve the prognostication of HCC and contribute to the assessment of response to TACE, allowing for a better selection of patients in the routine clinical setting and in clinical research. safely and effectively treated by locoregional treatments such as transarterial chemoembolization (TACE).3 TACE is the preferred first-line treatment for intermediate-stage HCC, and evidence obtained from randomized controlled trials has confirmed its beneficial effect in improving median survival.2 The positioning of TACE in the treatment algorithm of HCC has been supported by consensus statements and international guidelines.4-6 However, there is variation across the guidelines as to the selection criteria for TACE, and there is no consensus as to the optimal number of TACE administrations.7 Because of the palliative intent of TACE, a careful risk–benefit assessment is essential before treatment is administered. The ability to accurately select patients who may benefit from TACE is a desirable and potentially achievable aim in the clinical setting. A number of clinicopathologic features have been proven to predict outcome after TACE. Total bilirubin, as a reflection of liver functional reserve, has been used to select patients for TACE in randomized controlled trials.2,8 Other factors, such as a performance status $ 1, the presence of tumor multifocality, and failure to achieve a complete response after the first session of TACE, have been identified as poor prognostic determinants.9 Given the role played by chronic inflammation in the pathogenesis of HCC,10 there is increasing interest in the role of systemic inflammation as a predictor of outcome in HCC. The presence of a systemic inflammatory reaction, as a cancer-related phenomenon or as part of the host’s innate immune response toward the tumor, has been repeatedly shown to represent a stage-independent prognostic factor across a wide range of solid tumors,
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including HCC.11 It is also recognized that a key component driving the malignant progression of cancer is the aberrant activation of signaling pathways that are physiologically involved in inflammation, such as nuclear factor kappa-B and signal transducer and activator of transcription 3.12 A sustained proinflammatory status is closely linked to several adverse prognostic features in malignancy, such as malnutrition,13 weight loss,14 and increasing risk of toxicity to systemic treatment.15 Recent evidence has shown that systemic inflammation can be reverted by treatment and that normalization of inflammatory indices shortly after the commencement of chemotherapy is an early predictor of a significant improvement in survival in a number of tumor types.16-18 Clinically, there is no consensus as to the most accurate method of quantifying systemic inflammation.19 Although pyrexia . 38 C, . 10% weight loss, night sweats, and anorexia are the most representative symptoms suggesting the presence of an inflammatory response,20 this condition can often remain subclinical and evidence itself with the presence of deranged routine blood test results, such as hypoalbuminemia, lymphopenia, and elevation of C-reactive protein.21,22 Among the biomarkers of inflammation, the neutrophil-to-lymphocyte ratio (NLR) reflects derangements in the full blood count induced by the systemic release of proinflammatory mediators. A number of published reports have shown that patients with an NLR $ 5 at diagnosis have a poor clinical outcome after resection and transplantation of HCC23,24 and that changes of the NLR after TACE have recently been confirmed to predict survival benefit from treatment in patients with unresectable HCC.25 The aim of this study was to assess whether changes in the NLR after the administration of TACE can predict a significant survival advantage in patients with unresectable HCC. METHODS
Fifty-four patients eligible for TACE were identified and included in the study. All patients satisfied the diagnostic criteria for HCC based on radiologic or histologic grounds according to the American Association for the Study of the Liver guidelines.6 Clinical variables were collected, including demographic data, complete blood count, albumin, C-reactive protein, alpha-fetoprotein (AFP), aspartate and alanine aminotransferases, alkaline phosphatase, staging of the tumor (including the number of focal hepatic lesions and maximum diameter detected during contrast-enhancement phase), ChildTurcotte-Pugh class, and BCLC and Carcinoma of the Liver Italian Program scores. Treatment sessions were
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planned according to an ‘‘ a la demande’’ scheme using doxorubicin emulsified in lipiodol and gelatin sponge particles as embolizing agent. Radiologic response to TACE was assessed 6 weeks after the procedure using multiphase contrast-enhanced computed tomography. Treatment outcomes were subdivided into complete or partial response and stable or progressive disease according to the European Association for the Study of the Liver criteria.26 The NLR was calculated by dividing the absolute neutrophil to the absolute lymphocyte count, with 5 being the cutoff value to define high-risk ($5) versus lowrisk (,5) individuals as previously described.23 All the laboratory parameters were collected at baseline, defined as the time of referral to our Unit, and after 6 weeks from the first TACE session. In patients with AFPsecreting tumors (ie, with AFP values . 35 ng/mL), response to TACE was further assessed on the basis of post-treatment changes in AFP compared with baseline, qualifying a 20% decrease as a cutoff value according to the previously published literature.27,28 The study was approved by the local research ethics committee. Statistical analysis. Pearson chi-square test and analysis of variance were used to assess for any associations between variables. Univariate analysis of the different clinical factors associated with survival was carried out using Kaplan–Meier statistics and log– rank test. The independent prognostic value of each factor was explored with multivariate analysis according to the Cox proportional hazard model using SPSS version 11.5 (SPSS Inc, Chicago, Ill). A stepwise backward procedure was used, and variables with P . .10 were removed from the model. Statistical analysis was performed using SPSS version 11.5. RESULTS Demographics. Fifty-four patients with HCC were recruited; their clinicopathologic features are reported in Table I. All clinical variables were obtained at baseline, defined as the time of referral to our Unit. The majority of patients were classified with intermediate HCC according to the BCLC staging algorithm (68%), with compensated liver function (Child-Turcotte-Pugh Class A, 80%). The median age of the patients at study baseline was 63 years (range 33–82 years). The minimum follow-up was 3 months or until the date of death. At the time of analysis, 46% patients had died and overall median survival was 11.7 months. The majority of patients received more than 1 session of TACE (54%). Radiologic response to was evaluated in 87% of the patients (Table II). Radiologic response was reported in 32 patients (68%), whereas 15 patients had progressive
Table I. Demographic and clinical characteristics of patients with hepatocellular carcinoma treated with TACE Characteristic
Age (y), median (range) Gender, M/F Cause of liver disease, viral/nonviral/ unknown Cirrhosis present/absent/unknown Child-Turcotte Pugh Class, A/B No. of tumors 1/2/3/$4 Maximum diameter of largest lesion cm (range) Extrahepatic spread N/Y CLIP score 0–1/$2 BCLC score A/B/C Total bilirubin (mmol/L) Albumin (mg/dL) INR AST (IU/L) ALT (IU/L) ALP (IU/L) Platelet count (3109/L) AFP (ng/mL), Median (range) Median overall survival (mo, range) No. of TACE procedures 1 2 $3 Prior treatment First-line TACE Resection Transplantation Radiofrequency ablation
N 5 54
63 (33–82) 40/14 22/26/6 41/11/2 43/11 23/12/7/12 5.6 (1.6–18) 52/2 25/29 9/37/8 14 (4–124) 33 (14–43) 1.1 (1.0–1.4) 71 (22–365) 63 (10–348) 122 (53–563) 145 (40–446) 39 (2–130.000) 11.7 (1–82) 25 (47) 17 (31) 12 (22) 47 (66) 6 (11) 1 (2) 11 (21)
Abbreviations: CLIP, carcinoma of the Liver Italian Program; INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.
disease (32%). Twenty-four patients (44%) had AFPsecreting tumors. Within this patient subgroup, no response in serum AFP was observed in 14 subjects (58%), whereas 10 patients (42%) had a significant reduction in AFP. Inflammatory scores and clinical outcomes. NLR was available in 42 patients at baseline and in 38 patients after TACE. At baseline, 9 patients (18%) had a deranged NLR. The NLR normalized in 29 patients (76%) after TACE, whereas NLR increased in 9 patients (24%). Univariate analysis showed that patients with a persistently normal or improved NLR had significantly improved overall survival than patients with worsening or persistent elevation of the NLR after TACE, with a hazard ratio of 4.2 (95% confidence interval [CI], 1.5–11.7, P 5 0.006) (Fig 1). NLR responders had a median overall survival of 36.7 months (95% CI, 7.9–65.4) compared with 10.6 months for NLR nonresponders (95% CI, 8.7–12.6). Post-
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Table II. Univariate and multivariate analyses of prognostic factors of overall survival Univariate analysis Variable
Intrahepatic spread Uninodular , 50% Multinodular , 50% Massive $ 50% Maximum tumor diameter ,5 $5 AFP, ng/mL ,400 $400 CLIP score* 0 1 2 3 4–5 No. of TACE sessions 1 .1 Radiologic response CR PR SD PD NLR outcome Normalized Elevated
N 5 54 (%)
Multivariate analysis
Hazard ratio (95% CI)
P value
14 (26) 29 (54) 11 (20)
2.0 (1.1–4.2)
25 (46) 29 (54)
2.8 (1.1–6.8)
0.02*
43 (80) 11 (20)
4.3 (1.7–10.8)
0.002*
13 (24) 12 (23) 20 (37) 6 (11) 3 (5)
1.4 (1.1–1.9)
0.05*
25 (46) 29 (54)
0.3 (0.1–0.8)
0.01*
7 (15) 9 (20) 16 (34) 15 (32)
0.2 (0.1–0.5)
,0.001*
29 (76) 9 (24)
4.2 (1.5–11.7)
Hazard ratio (95% CI)
P value
0.01*
0.006*
0.3 (0.1–0.6)
0.003*
3.8 (1.1–13.1)
0.03*
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CLIP, Carcinoma of the Liver Italian Program. *For survival analysis, patients with CLIP score of 4 (n 5 2) and 5 (n 5 1) were considered together. Associations reaching statistical significance (P , 0.05) are marked with an asterisk (*). The cutoff values for AFP and intrahepatic spread follow the CLIP prognostic scores. Categorization of AST, ALT, and ALP was carried out using clinically used cutoff values.
treatment improvement in the NLR status was associated with a less-advanced intrahepatic spread (P 5 0.02). Other univariate predictors of survival included the extent of intrahepatic spread (P 5 0.01), number of neoplastic nodules (0.04), Carcinoma of the Liver Italian Program score (P 5 0.05), radiologic response (P , 0.001), and . 1 session of TACE (P 5 0.01). A baseline value of AFP $ 400 was predictive of worse survival (P 5 0.01), whereas changes in AFP after treatment did not affect survival (P 5 0.79) (Table II). On multivariate analysis, the achievement of complete radiologic response (P 5 0.003) and improvement in the NLR (P 5 0.03) remained as independent predictors of overall survival. DISCUSSION
TACE is the preferred palliative treatment for unresectable, liver-confined tumors in patients with compensated liver function.29 TACE has been shown to delay tumor progression and vascular invasion, resulting in improved
patient survival.30 Despite the acceptable safety profile, TACE can cause significant post-embolization syndrome in more than 50% of the patients.6 Given the noncurative intent of TACE and the potentially associated adverse effects, patient selection is imperative to stratify treatment options and avoid unnecessary morbidities. Therefore, the ability to accurately predict the course of the disease after TACE would exert a direct benefit in the management of patients with unresectable HCC. We have shown that the changes in a simple inflammatory biomarker (NLR) assessed before and 6 weeks after the first administration of TACE independently correlates with improved overall survival. In our study, the NLR performed better changes in AFP, which is often used to guide treatment decisions in HCC.31 We demonstrated a survival advantage of 26 months in NLR responders compared with patients displaying a persistent derangement or worsening of the NLR. Moreover, NLR response was associated with the extent of intrahepatic spread of HCC, suggesting that a persistently deranged NLR could be a feature of a more aggressive tumor phenotype. When
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Fig 1. Kaplan–Meier survival curves for patients stratified by the changes in the NLR status after TACE. NLR, neutrophil-to-lymphocyte ratio. (Color version of figure is available online.)
tested on multivariate analyses, NLR response remained an independent predictor of overall survival. These results are consistent with previously published literature showing that the presence of a sustained inflammatory reaction is an independent prognostic factor in HCC.23-25 In the study by Chen et al, an elevated NLR after radiofrequency ablation exerts detrimental effects on recurrence-free and overall survival times in patients with unresectable HCC. However, because the impact of the NLR has been explored as a continuous explanatory variable, the lack of a clear cutoff value reduces its clinical applicability.32 Likewise, in the recent article by Huang and colleagues,25 the authors explored the dynamic changes of the NLR immediately after TACE using the pretreatment mean NLR value of 3.3 as a cutoff, instead of the more commonly used and cross-validated value of 5.33 Moreover, the observed association between an increased NLR and better survival outcomes is inconsistent with the previously published literature23,24 suggesting that the repeat measurement of the NLR taken 3 days post-embolization is likely to reflect a factitious increase in the inflammatory markers secondary to TACE, therefore biasing the study. Systemic inflammation is a feature of advanced cancer and is a stage-independent prognostic factor underlying some of the clinical manifestations of malignancy, such as cachexia, nutritional decline, and impaired performance status.34 The advantage of inflammation-based prognostic indices is that of providing simple, inexpen-
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sive, and universally available biomarkers whose accuracy has been repeatedly tested in large cohorts of patients diagnosed with a variety of tumor types.11,15,35,36 In addition to holding prognostic value, some of the inflammatory scores may predict toxicity15 and efficacy of systemic anticancer treatments.17 The clinical onset of HCC is related to chronic inflammation, with 70% to 80% of the cases arising in the setting of end-stage liver disease.37 The dissection of the molecular pathways sustaining the neoplastic potential of HCC has revealed a connection between several proinflammatory mediators, such as interleukin (IL)-1, IL-6, and IL-8, and the clinical progression of HCC.38 Moreover, there is a recognized role in tumor promotion and sustained angiogenesis in HCC played by the peritumoral stroma through the activation of innate immunity.39 An increased NLR reflects a condition of combined neutrophilia and relative lymphopenia, both sustained by tumor-secreted cytokines or as part of the host’s immune response against neoplastic cells. Lymphocyte depletion is not only an adverse prognostic trait21 but also the likely reflection of an impaired T-lymphocyte– mediated antitumor response40 and a dysfunctional cytotoxic CD81 lymphocyte subpopulation.41 On the other hand, neutrophilia is functionally related to the systemic release of chemokines and ILs, which in addition to holding proinflammatory activity can also influence disease progression by increasing tumor proliferation and angiogenesis.39,42 We have provided evidence that systemic inflammation is a dynamic and potentially reversible process affecting the prognosis of unresectable HCC and that a simple, universally available and inexpensive biomarker such as the NLR can stratify patients into different clinical and biological categories, with diverse survival outcomes. In the specific setting of TACE, the translational relevance of our results seems multifaceted. To date there is no consensus as to the optimal treatment schedule, with some centers performing sequential sessions of TACE at fixed intervals, whereas others choose ‘‘a la demande’’ protocols.43 In addition, it is the opinion of some investigators that patients who do not achieve an adequate response after 2 sessions of TACE should be switched to systemic treatment with sorafenib.44 However, this opinion is not shared by others who have shown that a selected subset of patients may benefit from sequential retreatment.9 Our results are provocative in suggesting that the presence of a persistently elevated NLR after treatment may support the clinicians in formulating better tailored treatment decisions after the first session of TACE. Because poor NLR response is associated with worse outcome, clinicians may omit retreatment TACE and consider systemic therapy, a concept that needs to be evaluated in any
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future studies. A number of limitations applying to our study need to be considered, including the retrospective and single-institution nature of our study and the small sample size tested. Therefore, we believe that crossvalidation in independent and that larger patient cohorts, possibly in a prospective setting, should be mandatory before the NLR can be confidently incorporated as a validated biomarker to guide treatment decisions. CONCLUSIONS
The results of the present study suggest that the presence of a systemic inflammatory response, as indicated by NLR, is a useful tool in the assessment of survival benefit in patients undergoing TACE. As described, the NLR may reflect the complex interplay between inflammatory mediators and angiogenic factors that are known to influence patients’ survival. Unlike other more complex molecular markers, the NLR is easy to compute and universally available because it is derived from laboratory measures that are routinely assessed in patients before treatment. The NLR therefore should be further evaluated not only as a prognostic marker in patients with HCC at diagnosis but also as a surrogate marker of outcome after locoregional treatments of HCC. We would like to acknowledge Ms. Lynn Maslen for her critical revision of this manuscript and Dr Harpreet Wasan for the kind support he offered to this study.
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10. Alison MR, Nicholson LJ, Lin WR. Chronic inflammation and hepatocellular carcinoma. Recent Results Cancer Res 2011;185: 135–48. 11. Proctor MJ, Morrison DS, Talwar D, et al. An inflammation-based prognostic score (mGPS) predicts cancer survival independent of tumour site: a Glasgow Inflammation Outcome Study. Br J Cancer 2011;104:726–34. 12. Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 2009;15:425–30. 13. Van Cutsem E, Arends J. The causes and consequences of cancerassociated malnutrition. Eur J Oncol Nurs 2005;9(Suppl 2):S51–63. 14. Vlachostergios PJ, Gioulbasanis I, Kamposioras K, et al. Baseline insulin-like growth factor-I plasma levels, systemic inflammation, weight loss and clinical outcome in metastatic non-small cell lung cancer patients. Oncology 2011;81:113–8. 15. Sharma R, Zucknick M, London R, et al. Systemic inflammatory response predicts prognosis in patients with advanced-stage colorectal cancer. Clin Colorectal Cancer 2008;7:331–7. 16. Chua W, Charles KA, Baracos VE, et al. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer 2011;104:1288–95. 17. Kao SC, Pavlakis N, Harvie R, et al. High blood neutrophil-tolymphocyte ratio is an indicator of poor prognosis in malignant mesothelioma patients undergoing systemic therapy. Clin Cancer Res 2010;16:5805–13. 18. Chua W, Clarke SJ, Charles KA. Systemic inflammation and prediction of chemotherapy outcomes in patients receiving docetaxel for advanced cancer. Support Care Cancer 2011 Oct 11 [Epub ahead of print]. 19. Clarke SJ, Chua W, Moore M, et al. Use of inflammatory markers to guide cancer treatment. Clin Pharmacol Ther 2011;90:475–8. 20. Seymour JF, Talpaz M, Cabanillas F, et al. Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. J Clin Oncol 1995;13:575–82. 21. Ray-Coquard I, Cropet C, Van Glabbeke M, et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res 2009;69:5383–91. 22. Roxburgh CS, Salmond JM, Horgan PG, et al. The relationship between the local and systemic inflammatory responses and survival in patients undergoing curative surgery for colon and rectal cancers. J Gastrointest Surg 2009;13:2011–9. 23. Halazun KJ, Hardy MA, Rana AA, et al. Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma. Ann Surg 2009;250:141–51. 24. Gomez D, Farid S, Malik HZ, et al. Preoperative neutrophil-tolymphocyte ratio as a prognostic predictor after curative resection for hepatocellular carcinoma. World J Surg 2008;32:1757–62. 25. Huang ZL, Luo J, Chen MS, et al. Blood neutrophil-tolymphocyte ratio predicts survival in patients with unresectable hepatocellular carcinoma undergoing transarterial chemoembolization. J Vasc Interv Radiol 2011;22:702–9. 26. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001;35:421–30. 27. Lee MH, Kim SU, Kim DY, et al. Early on-treatment predictions of clinical outcomes using AFP and DCP responses in patients with advanced hepatocellular carcinoma. J Gastroenterol Hepatol 2011 Jul 28 [Epub ahead of print]. 28. Yau T, Yao TJ, Chan P, et al. The significance of early alphafetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. Oncologist 2011;16:1270–9.
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29. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet 2002;359:1734–9. 30. Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004;127(5 Suppl. 1):S179–88. 31. Miraglia R, Pietrosi G, Maruzzelli L, et al. Predictive factors of tumor response to trans-catheter treatment in cirrhotic patients with hepatocellular carcinoma: a multivariate analysis of pretreatment findings. World J Gastroenterol 2007;13:6022–6. 32. Chen TM, Lin CC, Huang PT, et al. Neutrophil-to-lymphocyte ratio associated with mortality in early hepatocellular carcinoma patients after radiofrequency ablation. J Gastroenterol Hepatol 2011 Sep 13 [Epub ahead of print]. 33. Proctor MJ, Morrison DS, Talwar D, et al. A comparison of inflammation-based prognostic scores in patients with cancer. A Glasgow Inflammation Outcome Study. Eur J Cancer 2011;47: 2633–41. 34. Roxburgh CS, McMillan DC. Role of systemic inflammatory response in predicting survival in patients with primary operable cancer. Future Oncol 2010;6:149–63. 35. Sharma R, Hook J, Kumar M, et al. Evaluation of an inflammation-based prognostic score in patients with advanced ovarian cancer. Eur J Cancer 2008;44:251–6. 36. Forrest LM, McMillan DC, McArdle CS, et al. Comparison of an inflammation-based prognostic score (GPS) with performance status (ECOG) in patients receiving platinum-based chemotherapy
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Transarterial chemoembolization (TACE) is the preferred treatment for unresectable, intermediate-stage hepatocellular carcinoma (HCC). However, survival after TACE can be highly variable, suggesting the need for more accurate patient selection to improve therapeutic outcome. We have explored the prognostic ability of the blood neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation, as a predictor of survival after TACE. Fifty-four patients with a diagnosis of HCC eligible for TACE were selected. Clinicopathologic variables were collected, including demographics, tumor staging, liver functional reserve, and laboratory variables. Dynamic changes in the NLR before and after TACE were studied as predictors of survival using both a univariate and multivariate Cox regression model. Patients in whom the NLR remained stable or normalized after TACE showed a significant improvement in overall survival of 26 months compared with patients showing a persistently abnormal index (P 5 0.006). Other predictors of survival on univariate analysis were Cancer of the Liver Italian Program score (P 5 0.05), intrahepatic spread (P 5 0.01), tumor diameter . 5 cm (P 5 0.02), . 1 TACE (P 5 0.01), alpha-fetoprotein $ 400 (P 5 0.002), and radiologic response to TACE (P , 0.001). Improved NLR after TACE (P 5 0.03) and radiologic response after TACE (P 5 0.003) remained independent predictors of survival on multivariate analysis. Changes in alpha-fetoprotein after treatment did not predict survival. Patients with a persistently increased NLR have a worse outcome after TACE. NLR is a simple and universally available stratifying biomarker that can help identify patients with a significant survival advantage after TACE. (Translational Research 2012;160:146–152) Abbreviations: AFP ¼ alpha-fetoprotein; BCLC ¼ Barcelona Clinic Liver Cancer; CI ¼ confidence interval; HCC ¼ hepatocellular carcinoma; IL ¼ interleukin; NLR ¼ neutrophilto-lymphocyte ratio; TACE ¼ transarterial chemoembolization
t has been estimated that up to 60% to 70% of patients with hepatocellular carcinoma (HCC) present with intermediate- to advanced-stage disease at diagnosis.1 For these patients, overall survival can vary between 6 and 20 months.1,2 Provision of treatment to this composite patient group is essentially palliative,
I
aimed at prolonging survival while maintaining quality of life. Among patients who are not amenable to curative treatments, a well-defined subgroup identified within the Barcelona Clinic Liver Cancer (BCLC) B stage, characterized by large or multinodular, asymptomatic tumors without extrahepatic spread, can be
From the Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, London, UK; Division of Internal Medicine, Universita degli Studi del Piemonte Orientale, Department of Clinical and Experimental Medicine, Novara, Italy.
Reprint requests: Rohini Sharma, FRACP, PhD, Senior Lecturer in Oncology and Clinical Pharmacology, Imperial College London, Hammersmith Campus, Du Cane Road, W12 0HS, London, UK; e-mail: [email protected].
Conflict of Interest: none
1931-5244/$ - see front matter
Funding: This work was supported in part by the Fondazione DeAgostini Research Grant for PhD studies to DJP.
Ó 2012 Mosby, Inc. All rights reserved.
Submitted for publication December 1, 2011; accepted for publication January 10, 2012.
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AT A GLANCE COMMENTARY Pinato and Sharma Background
The pathogenesis of HCC is based on inflammation, with 80% of the tumors arising in a context of chronic liver disease. Several prognostic scores have been devised, but there is no consensus as to the optimal staging system. Translational Significance
We showed that the normalization of a prognostic score based on inflammation, the NLR, predicts survival advantage after TACE. This suggests that the NLR can improve the prognostication of HCC and contribute to the assessment of response to TACE, allowing for a better selection of patients in the routine clinical setting and in clinical research. safely and effectively treated by locoregional treatments such as transarterial chemoembolization (TACE).3 TACE is the preferred first-line treatment for intermediate-stage HCC, and evidence obtained from randomized controlled trials has confirmed its beneficial effect in improving median survival.2 The positioning of TACE in the treatment algorithm of HCC has been supported by consensus statements and international guidelines.4-6 However, there is variation across the guidelines as to the selection criteria for TACE, and there is no consensus as to the optimal number of TACE administrations.7 Because of the palliative intent of TACE, a careful risk–benefit assessment is essential before treatment is administered. The ability to accurately select patients who may benefit from TACE is a desirable and potentially achievable aim in the clinical setting. A number of clinicopathologic features have been proven to predict outcome after TACE. Total bilirubin, as a reflection of liver functional reserve, has been used to select patients for TACE in randomized controlled trials.2,8 Other factors, such as a performance status $ 1, the presence of tumor multifocality, and failure to achieve a complete response after the first session of TACE, have been identified as poor prognostic determinants.9 Given the role played by chronic inflammation in the pathogenesis of HCC,10 there is increasing interest in the role of systemic inflammation as a predictor of outcome in HCC. The presence of a systemic inflammatory reaction, as a cancer-related phenomenon or as part of the host’s innate immune response toward the tumor, has been repeatedly shown to represent a stage-independent prognostic factor across a wide range of solid tumors,
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including HCC.11 It is also recognized that a key component driving the malignant progression of cancer is the aberrant activation of signaling pathways that are physiologically involved in inflammation, such as nuclear factor kappa-B and signal transducer and activator of transcription 3.12 A sustained proinflammatory status is closely linked to several adverse prognostic features in malignancy, such as malnutrition,13 weight loss,14 and increasing risk of toxicity to systemic treatment.15 Recent evidence has shown that systemic inflammation can be reverted by treatment and that normalization of inflammatory indices shortly after the commencement of chemotherapy is an early predictor of a significant improvement in survival in a number of tumor types.16-18 Clinically, there is no consensus as to the most accurate method of quantifying systemic inflammation.19 Although pyrexia . 38 C, . 10% weight loss, night sweats, and anorexia are the most representative symptoms suggesting the presence of an inflammatory response,20 this condition can often remain subclinical and evidence itself with the presence of deranged routine blood test results, such as hypoalbuminemia, lymphopenia, and elevation of C-reactive protein.21,22 Among the biomarkers of inflammation, the neutrophil-to-lymphocyte ratio (NLR) reflects derangements in the full blood count induced by the systemic release of proinflammatory mediators. A number of published reports have shown that patients with an NLR $ 5 at diagnosis have a poor clinical outcome after resection and transplantation of HCC23,24 and that changes of the NLR after TACE have recently been confirmed to predict survival benefit from treatment in patients with unresectable HCC.25 The aim of this study was to assess whether changes in the NLR after the administration of TACE can predict a significant survival advantage in patients with unresectable HCC. METHODS
Fifty-four patients eligible for TACE were identified and included in the study. All patients satisfied the diagnostic criteria for HCC based on radiologic or histologic grounds according to the American Association for the Study of the Liver guidelines.6 Clinical variables were collected, including demographic data, complete blood count, albumin, C-reactive protein, alpha-fetoprotein (AFP), aspartate and alanine aminotransferases, alkaline phosphatase, staging of the tumor (including the number of focal hepatic lesions and maximum diameter detected during contrast-enhancement phase), ChildTurcotte-Pugh class, and BCLC and Carcinoma of the Liver Italian Program scores. Treatment sessions were
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planned according to an ‘‘ a la demande’’ scheme using doxorubicin emulsified in lipiodol and gelatin sponge particles as embolizing agent. Radiologic response to TACE was assessed 6 weeks after the procedure using multiphase contrast-enhanced computed tomography. Treatment outcomes were subdivided into complete or partial response and stable or progressive disease according to the European Association for the Study of the Liver criteria.26 The NLR was calculated by dividing the absolute neutrophil to the absolute lymphocyte count, with 5 being the cutoff value to define high-risk ($5) versus lowrisk (,5) individuals as previously described.23 All the laboratory parameters were collected at baseline, defined as the time of referral to our Unit, and after 6 weeks from the first TACE session. In patients with AFPsecreting tumors (ie, with AFP values . 35 ng/mL), response to TACE was further assessed on the basis of post-treatment changes in AFP compared with baseline, qualifying a 20% decrease as a cutoff value according to the previously published literature.27,28 The study was approved by the local research ethics committee. Statistical analysis. Pearson chi-square test and analysis of variance were used to assess for any associations between variables. Univariate analysis of the different clinical factors associated with survival was carried out using Kaplan–Meier statistics and log– rank test. The independent prognostic value of each factor was explored with multivariate analysis according to the Cox proportional hazard model using SPSS version 11.5 (SPSS Inc, Chicago, Ill). A stepwise backward procedure was used, and variables with P . .10 were removed from the model. Statistical analysis was performed using SPSS version 11.5. RESULTS Demographics. Fifty-four patients with HCC were recruited; their clinicopathologic features are reported in Table I. All clinical variables were obtained at baseline, defined as the time of referral to our Unit. The majority of patients were classified with intermediate HCC according to the BCLC staging algorithm (68%), with compensated liver function (Child-Turcotte-Pugh Class A, 80%). The median age of the patients at study baseline was 63 years (range 33–82 years). The minimum follow-up was 3 months or until the date of death. At the time of analysis, 46% patients had died and overall median survival was 11.7 months. The majority of patients received more than 1 session of TACE (54%). Radiologic response to was evaluated in 87% of the patients (Table II). Radiologic response was reported in 32 patients (68%), whereas 15 patients had progressive
Table I. Demographic and clinical characteristics of patients with hepatocellular carcinoma treated with TACE Characteristic
Age (y), median (range) Gender, M/F Cause of liver disease, viral/nonviral/ unknown Cirrhosis present/absent/unknown Child-Turcotte Pugh Class, A/B No. of tumors 1/2/3/$4 Maximum diameter of largest lesion cm (range) Extrahepatic spread N/Y CLIP score 0–1/$2 BCLC score A/B/C Total bilirubin (mmol/L) Albumin (mg/dL) INR AST (IU/L) ALT (IU/L) ALP (IU/L) Platelet count (3109/L) AFP (ng/mL), Median (range) Median overall survival (mo, range) No. of TACE procedures 1 2 $3 Prior treatment First-line TACE Resection Transplantation Radiofrequency ablation
N 5 54
63 (33–82) 40/14 22/26/6 41/11/2 43/11 23/12/7/12 5.6 (1.6–18) 52/2 25/29 9/37/8 14 (4–124) 33 (14–43) 1.1 (1.0–1.4) 71 (22–365) 63 (10–348) 122 (53–563) 145 (40–446) 39 (2–130.000) 11.7 (1–82) 25 (47) 17 (31) 12 (22) 47 (66) 6 (11) 1 (2) 11 (21)
Abbreviations: CLIP, carcinoma of the Liver Italian Program; INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase.
disease (32%). Twenty-four patients (44%) had AFPsecreting tumors. Within this patient subgroup, no response in serum AFP was observed in 14 subjects (58%), whereas 10 patients (42%) had a significant reduction in AFP. Inflammatory scores and clinical outcomes. NLR was available in 42 patients at baseline and in 38 patients after TACE. At baseline, 9 patients (18%) had a deranged NLR. The NLR normalized in 29 patients (76%) after TACE, whereas NLR increased in 9 patients (24%). Univariate analysis showed that patients with a persistently normal or improved NLR had significantly improved overall survival than patients with worsening or persistent elevation of the NLR after TACE, with a hazard ratio of 4.2 (95% confidence interval [CI], 1.5–11.7, P 5 0.006) (Fig 1). NLR responders had a median overall survival of 36.7 months (95% CI, 7.9–65.4) compared with 10.6 months for NLR nonresponders (95% CI, 8.7–12.6). Post-
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Table II. Univariate and multivariate analyses of prognostic factors of overall survival Univariate analysis Variable
Intrahepatic spread Uninodular , 50% Multinodular , 50% Massive $ 50% Maximum tumor diameter ,5 $5 AFP, ng/mL ,400 $400 CLIP score* 0 1 2 3 4–5 No. of TACE sessions 1 .1 Radiologic response CR PR SD PD NLR outcome Normalized Elevated
N 5 54 (%)
Multivariate analysis
Hazard ratio (95% CI)
P value
14 (26) 29 (54) 11 (20)
2.0 (1.1–4.2)
25 (46) 29 (54)
2.8 (1.1–6.8)
0.02*
43 (80) 11 (20)
4.3 (1.7–10.8)
0.002*
13 (24) 12 (23) 20 (37) 6 (11) 3 (5)
1.4 (1.1–1.9)
0.05*
25 (46) 29 (54)
0.3 (0.1–0.8)
0.01*
7 (15) 9 (20) 16 (34) 15 (32)
0.2 (0.1–0.5)
,0.001*
29 (76) 9 (24)
4.2 (1.5–11.7)
Hazard ratio (95% CI)
P value
0.01*
0.006*
0.3 (0.1–0.6)
0.003*
3.8 (1.1–13.1)
0.03*
Abbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; CLIP, Carcinoma of the Liver Italian Program. *For survival analysis, patients with CLIP score of 4 (n 5 2) and 5 (n 5 1) were considered together. Associations reaching statistical significance (P , 0.05) are marked with an asterisk (*). The cutoff values for AFP and intrahepatic spread follow the CLIP prognostic scores. Categorization of AST, ALT, and ALP was carried out using clinically used cutoff values.
treatment improvement in the NLR status was associated with a less-advanced intrahepatic spread (P 5 0.02). Other univariate predictors of survival included the extent of intrahepatic spread (P 5 0.01), number of neoplastic nodules (0.04), Carcinoma of the Liver Italian Program score (P 5 0.05), radiologic response (P , 0.001), and . 1 session of TACE (P 5 0.01). A baseline value of AFP $ 400 was predictive of worse survival (P 5 0.01), whereas changes in AFP after treatment did not affect survival (P 5 0.79) (Table II). On multivariate analysis, the achievement of complete radiologic response (P 5 0.003) and improvement in the NLR (P 5 0.03) remained as independent predictors of overall survival. DISCUSSION
TACE is the preferred palliative treatment for unresectable, liver-confined tumors in patients with compensated liver function.29 TACE has been shown to delay tumor progression and vascular invasion, resulting in improved
patient survival.30 Despite the acceptable safety profile, TACE can cause significant post-embolization syndrome in more than 50% of the patients.6 Given the noncurative intent of TACE and the potentially associated adverse effects, patient selection is imperative to stratify treatment options and avoid unnecessary morbidities. Therefore, the ability to accurately predict the course of the disease after TACE would exert a direct benefit in the management of patients with unresectable HCC. We have shown that the changes in a simple inflammatory biomarker (NLR) assessed before and 6 weeks after the first administration of TACE independently correlates with improved overall survival. In our study, the NLR performed better changes in AFP, which is often used to guide treatment decisions in HCC.31 We demonstrated a survival advantage of 26 months in NLR responders compared with patients displaying a persistent derangement or worsening of the NLR. Moreover, NLR response was associated with the extent of intrahepatic spread of HCC, suggesting that a persistently deranged NLR could be a feature of a more aggressive tumor phenotype. When
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Fig 1. Kaplan–Meier survival curves for patients stratified by the changes in the NLR status after TACE. NLR, neutrophil-to-lymphocyte ratio. (Color version of figure is available online.)
tested on multivariate analyses, NLR response remained an independent predictor of overall survival. These results are consistent with previously published literature showing that the presence of a sustained inflammatory reaction is an independent prognostic factor in HCC.23-25 In the study by Chen et al, an elevated NLR after radiofrequency ablation exerts detrimental effects on recurrence-free and overall survival times in patients with unresectable HCC. However, because the impact of the NLR has been explored as a continuous explanatory variable, the lack of a clear cutoff value reduces its clinical applicability.32 Likewise, in the recent article by Huang and colleagues,25 the authors explored the dynamic changes of the NLR immediately after TACE using the pretreatment mean NLR value of 3.3 as a cutoff, instead of the more commonly used and cross-validated value of 5.33 Moreover, the observed association between an increased NLR and better survival outcomes is inconsistent with the previously published literature23,24 suggesting that the repeat measurement of the NLR taken 3 days post-embolization is likely to reflect a factitious increase in the inflammatory markers secondary to TACE, therefore biasing the study. Systemic inflammation is a feature of advanced cancer and is a stage-independent prognostic factor underlying some of the clinical manifestations of malignancy, such as cachexia, nutritional decline, and impaired performance status.34 The advantage of inflammation-based prognostic indices is that of providing simple, inexpen-
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sive, and universally available biomarkers whose accuracy has been repeatedly tested in large cohorts of patients diagnosed with a variety of tumor types.11,15,35,36 In addition to holding prognostic value, some of the inflammatory scores may predict toxicity15 and efficacy of systemic anticancer treatments.17 The clinical onset of HCC is related to chronic inflammation, with 70% to 80% of the cases arising in the setting of end-stage liver disease.37 The dissection of the molecular pathways sustaining the neoplastic potential of HCC has revealed a connection between several proinflammatory mediators, such as interleukin (IL)-1, IL-6, and IL-8, and the clinical progression of HCC.38 Moreover, there is a recognized role in tumor promotion and sustained angiogenesis in HCC played by the peritumoral stroma through the activation of innate immunity.39 An increased NLR reflects a condition of combined neutrophilia and relative lymphopenia, both sustained by tumor-secreted cytokines or as part of the host’s immune response against neoplastic cells. Lymphocyte depletion is not only an adverse prognostic trait21 but also the likely reflection of an impaired T-lymphocyte– mediated antitumor response40 and a dysfunctional cytotoxic CD81 lymphocyte subpopulation.41 On the other hand, neutrophilia is functionally related to the systemic release of chemokines and ILs, which in addition to holding proinflammatory activity can also influence disease progression by increasing tumor proliferation and angiogenesis.39,42 We have provided evidence that systemic inflammation is a dynamic and potentially reversible process affecting the prognosis of unresectable HCC and that a simple, universally available and inexpensive biomarker such as the NLR can stratify patients into different clinical and biological categories, with diverse survival outcomes. In the specific setting of TACE, the translational relevance of our results seems multifaceted. To date there is no consensus as to the optimal treatment schedule, with some centers performing sequential sessions of TACE at fixed intervals, whereas others choose ‘‘a la demande’’ protocols.43 In addition, it is the opinion of some investigators that patients who do not achieve an adequate response after 2 sessions of TACE should be switched to systemic treatment with sorafenib.44 However, this opinion is not shared by others who have shown that a selected subset of patients may benefit from sequential retreatment.9 Our results are provocative in suggesting that the presence of a persistently elevated NLR after treatment may support the clinicians in formulating better tailored treatment decisions after the first session of TACE. Because poor NLR response is associated with worse outcome, clinicians may omit retreatment TACE and consider systemic therapy, a concept that needs to be evaluated in any
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future studies. A number of limitations applying to our study need to be considered, including the retrospective and single-institution nature of our study and the small sample size tested. Therefore, we believe that crossvalidation in independent and that larger patient cohorts, possibly in a prospective setting, should be mandatory before the NLR can be confidently incorporated as a validated biomarker to guide treatment decisions. CONCLUSIONS
The results of the present study suggest that the presence of a systemic inflammatory response, as indicated by NLR, is a useful tool in the assessment of survival benefit in patients undergoing TACE. As described, the NLR may reflect the complex interplay between inflammatory mediators and angiogenic factors that are known to influence patients’ survival. Unlike other more complex molecular markers, the NLR is easy to compute and universally available because it is derived from laboratory measures that are routinely assessed in patients before treatment. The NLR therefore should be further evaluated not only as a prognostic marker in patients with HCC at diagnosis but also as a surrogate marker of outcome after locoregional treatments of HCC. We would like to acknowledge Ms. Lynn Maslen for her critical revision of this manuscript and Dr Harpreet Wasan for the kind support he offered to this study.
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