Comparison of the methods for tumor response assessment in patients with hepatocellular carcinoma undergoing transarterial chemoembolization

doi:10.1016/j.jhep.2013.01.039

Journal of Hepatology

Volume 58, Issue 6, June 2013, Pages 1181-1187

https://doi.org/10.1016/j.jhep.2013.01.039 Get rights and content

Background & Aims

Recently, new methods, including the concept of viable enhancing tumor such as EASL and mRECIST, have been proposed for substitution of the conventional WHO and RECIST criteria in hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE). Herein, we evaluated the differences of four methods and compared the association of these methods with the prognosis of HCC patients undergoing TACE.

Methods

We retrospectively reviewed 114 consecutive newly diagnosed HCC patients who underwent TACE as initial treatment. We evaluated the intermethod agreement (κ values) between the methods and compared their association with the prognosis of HCC patients.

Results

The κ values for EASL vs. WHO, EASL vs. RECIST, mRECIST vs. WHO, and mRECIST vs. RECIST were low, of 0.102, 0.088, 0.112, and 0.122, respectively. However, good correlations were observed for WHO vs. RECIST and EASL vs. mRECIST (κ = 0.883, κ = 0.759, respectively p <0.001). The median OS was 32.3 months. Hazard ratios (HR) for survival in responders compared with non-responders were 0.21 (95% CI; 0.12–0.37, p <0.001) for EASL and 0.27 (95% CI; 0.15–0.48, p <0.001) for mRECIST. The mean survival of responders was significantly longer than that of non-responders in both EASL (40.8 vs. 16.9 months, p <0.001) and mRECIST (41.1 vs. 20.7 months, p <0.001). In multivariate analysis, EASL response (HR 0.21, 95% CI 0.11–0.40, p <0.001) and mRECIST response (HR; 0.31, 95% CI, 0.17–0.59, p <0.001) were independently associated with survival.

Conclusions

The response assessment by EASL and mRECIST could reliably predict the survival of HCC patients undergoing TACE and could be applicable in practice in preference to the conventional WHO and RECIST criteria.

Introduction

Primary liver cancers, most of which consist of hepatocellular carcinomas (HCC), are increasing globally [1], [2]. However, fewer than 20% of HCC patients could be candidates for curative therapy at the time of diagnosis, due to asymptomatic progression, underlying chronic liver disease, and specific tumor biologic characters, making this disease one of the poorest prognostic cancers.

Locoregional therapy, such as radiofrequency ablation or transarterial chemoembolization (TACE), is widely used to treat HCC as curative or palliative treatment. Although TACE has been the optimal therapy for patients with intermediate Barcelona Clinic Liver Cancer (BCLC) stage [3], TACE can be applied to patients in the early stage, who are ineligible for surgery due to poor residual liver function and/or co-morbidities, and for ablation due to tumor location. TACE is also a palliative treatment option for patients with advanced stage. In this respect, TACE is a widely applicable therapeutic option in the treatment of HCC and thus produces various results according to patient conditions. Nevertheless, TACE showed a survival benefit and became the standard treatments in HCC patients with BCLC intermediate stage [4], [5].

Objective response assessment is important in the evaluation of the effect of anticancer treatment. The most important end point for approved anticancer therapy is overall survival (OS), but radiologic responses have been widely used as surrogate end points in phase II trials and as short-term decision guides to continue or change the ongoing therapy [6]. However, it has not been well evaluated whether object radiologic response could properly reflect prolonged survival of HCC patients undergoing TACE.

For the purpose of radiologic response evaluation, the World Health Organization (WHO) response criteria were introduced in 1979. The WHO criteria are based on the sum of bidimensional perpendicular products [7]. However, because of some limitations of the WHO criteria, the Response Evaluation Criteria in Solid Tumors (RECIST) were introduced in 2000 to unify and standardize the response assessment criteria [8]. The RECIST criteria, which were revised to version 1.1 in 2009 [9], are based on the sum of the unidimensional longest diameters. However, the WHO and RECIST criteria were designed for the evaluation of cytotoxic agents. In the case of molecular targeted therapy or locoregional therapy such as TACE, clinical benefit is not always correlated with shrinkage of tumor size, but could be correlated with necrosis of a viable tumor. TACE induces tumor necrosis with or without change in tumor size. Since the WHO and RECIST criteria are based on tumor size measurement, they have been considered as suboptimal methods for tumor response assessment in HCC patients, especially for those undergoing TACE. Therefore, recently, the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Disease (AASLD) have proposed new methods, including the concept of viable enhancing lesion modifying WHO (EASL) [10] and RECIST (mRECIST) [11], [12] criteria, respectively. However, EASL and mRECIST methods should be extensively validated by investigating their correlation with the survival in HCC patients undergoing TACE.

Herein, we investigated the differences among WHO, RECIST, EASL, and mRECIST and evaluated the optimal method for predicting radiologic end point of time to progression (TTP) and clinical benefits of OS.

Section snippets

Materials and methods

We retrospectively reviewed the medical records of 141 consecutive newly diagnosed HCC patients who underwent TACE as initial treatment between the period from August 2005 to November 2006. Diagnosis of HCC was confirmed by biopsy or radiologic imaging studies according to the guidelines [13]. Among the 141 patients, we excluded 43 patients due to early follow-up loss after 1st TACE (n = 6), no measurable enhancing lesions >1 cm (n = 8), other co-existing cancers (n = 4), main portal vein thrombosis (n

Results

The baseline characteristics of 98 enrolled patients are summarized in Table 1. 86.7% of the patients were male and the mean age was 59.6 ± 9.4 years. The etiology of HCC was mostly hepatitis B in 68 patients (69.4%). 77 patients (78.6%) were Child-Pugh class A and 21 (21.4%) Child-Pugh class B. Liver cirrhosis was documented in 72 patients (73.5%). ECOG performance status was 0 in 24 patients (24.5%), 1 in 66 (67.3%) and 2 in 8 (8.2%). Concerning the tumor characteristics, 24 patients (24.5%)

Discussion

Survival has a key role in the assessment of treatment efficacy in solid tumors, but objective radiologic response has been widely accepted as an auxillary surrogate end point. In conventional cytotoxic chemotherapy aimed at reducing tumor size, two response assessment methods, the WHO and RECIST criteria, have been proven as valuable response assessment methods to well reflect patient survival [7], [8]. In contrast with other solid tumors, various locoregional therapies, such as local

Financial support

This study was supported by the GlaxoSmithKline Research Fund of the Korean Association for the Study of the Liver.

Conflict of interest

The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

References (22)

F.X. Bosch et al.
Epidemiology of hepatocellular carcinoma
Clin Liver Dis
(2005)
F.X. Bosch et al.
Primary liver cancer: worldwide incidence and trends
Gastroenterology
(2004)
J. Bruix et al.
Chemoembolization for hepatocellular carcinoma
Gastroenterology
(2004)
J.M. Llovet et al.
Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival
Hepatology
(2003)
E.A. Eisenhauer et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009)
J. Bruix 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)
R. Gillmore et al.
EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization
J Hepatol
(2011)
J.M. Llovet et al.
Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial
Lancet
(2002)
C.M. Lo et al.
Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma
Hepatology
(2002)
J.M. Llovet et al.
Prognosis of hepatocellular carcinoma: the BCLC staging classification
Semin Liver Dis
(1999)

J.R. Johnson et al.

End points and United States Food and Drug Administration approval of oncology drugs

J Clin Oncol

(2003)

Cited by (109)

Phase I Dose-Escalation Study of Tirapazamine Chemoembolization for Unresectable Early- and Intermediate-Stage Hepatocellular Carcinoma
2022, Journal of Vascular and Interventional Radiology
To investigate the safety of replacing doxorubicin with tirapazamine in conventional transarterial chemoembolization (TACE) in an Asian population with hepatocellular carcinoma (HCC), and to determine the optimal tirapazamine dose for phase II studies.
This was a phase I, 3 + 3 dose-escalation study for patients with unresectable early- and intermediate-stage HCC who received 5, 10, or 20 mg/m² of intra-arterial (IA) tirapazamine followed by ethiodized oil/gelatin sponge-based embolization. Key eligibilities included HCCs no more than 10 cm in diameter, prior embolization allowed, Eastern Cooperative Oncology Group performance status of 0 or 1, Child-Pugh score of 5–7, and platelet count of ≥60,000 μL. Dose-limiting toxicity (DLT) was defined as any grade 3 nonhematological or grade 4 hematological toxicity, with the exception of transient elevation of aminotransferase levels after the procedure.
Seventeen patients were enrolled, 59% of whom had progression from a prior HCC therapy and 35% of whom had progression or recurrence after TACE. All patients tolerated the tirapazamine TACE well without any DLT or serious adverse event. Using the modified Response Evaluation Criteria in Solid Tumors, the complete response (CR) rate was 47%, and the CR + partial response rate was 65%. The median duration of response was not reached. The median time to progression was 12.6 months (95% confidence interval, 5.1–not reached). The median overall survival was 29.3 months. The selected phase II dose was set at a fixed dose of 35 mg of IA tirapazamine.
IA tirapazamine with transarterial embolization was well tolerated and showed promising efficacy signals in intermediate-stage HCC, justifying pursuit of a phase II study.
Comparison of MRI-based response criteria and radiomics for the prediction of early response to transarterial radioembolization in patients with hepatocellular carcinoma
2022, Diagnostic and Interventional Imaging
The purpose of this study was to evaluate the capabilities of radiomics using magnetic resonance imaging (MRI) data in the assessment of treatment response to ⁹⁰yttrium transarterial radioembolization (TARE) in patients with locally advanced hepatocellular carcinoma (HCC) by comparison with predictions based on European Association for the Study of the Liver (EASL) criteria.
Twenty-two patients with HCC (19 men, 3 women; mean age: 66.7 ± 9.8 [SD]; age range: 37–82 years) who underwent contrast-enhanced MRI 4 ± 1 weeks before and 4 ± 4 weeks after TARE, were enrolled in this retrospective study. Regions of interest were placed manually along the contours of the treated tumor on each axial slice of arterial and portal phase images using the ITK-SNAP post-processing software. For each MRI, the Pyradiomics Python package was used to extract 107 radiomics features on both arterial and portal phases, and resulting delta-features were computed. The Mann-Whitney U test with Bonferroni correction was used to select statistically different features between responders and non-responders (i.e., those with progressive or stable disease) at 6-month follow-up, according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Finally, for each selected feature, univariable logistic regression with leave-one-out cross validation procedure was used to perform receiver operating characteristic (ROC) curve analysis and compare radiomics parameters with MRI variables.
According to mRECIST, 14 patients (14/22; 64%) were non-responders and 8 (8/22; 36%) were responders. Four radiomics parameters (long run emphasis, minor axis length, surface area, and gray level non-uniformity on arterial phase images) were the only predictors of early response. ROC curve analysis showed that long run emphasis was the best parameter for predicting early response, with 100% sensitivity (95% CI: 68–100) and 100% specificity (95% CI: 78–100). EASL morphologic criteria yielded 75% sensitivity (95% CI: 41–96%) and 93% specificity (95% CI: 69–100%).
Radiomics allows identify marked differences between responders and non-responders, and could aid in the prediction of early treatment response following TARE in patients with HCC.
Clinical Significance of the Initial and Best Responses after Chemoembolization in the Treatment of Intermediate-Stage Hepatocellular Carcinoma with Preserved Liver Function
2020, Journal of Vascular and Interventional Radiology
Citation Excerpt :
From their results, Kim et al concluded that achievement of an objective response at an early time point is still the most robust predictor for favorable outcomes in HCC patients undergoing transarterial chemoembolization (4). However, the patient sample sizes in previous studies were relatively small (n = 83–314), and the study patient cohorts consisted of somewhat heterogeneous stages (from BCLC A to BCLC C) (1,4,21,22). On the basis of the present findings using data from a large single-stage homogeneous cohort (BCLC stage B with good liver function) for whom transarterial chemoembolization was considered a standard of care, transarterial chemoembolization should be repeated on demand in cases with residual tumors, no progression, and stable liver function, until CR is achieved.
To evaluate the clinical implications of initial and best responses during repeated transarterial chemoembolization procedures for hepatocellular carcinoma (HCC).
This study included 726 patients who received a diagnosis of intermediate-stage HCC with Child-Pugh class A liver function between 2007 and 2016, and who were treated with transarterial chemoembolization as the first-line treatment. Evaluation of treatment response was based on the modified response evaluation criteria in solid tumors. Overall survival (OS) was compared between response categories after implementation of landmark analysis.
Of the 726 patients, an objective response (complete response [CR] or partial response [PR]) was observed as the initial response in 78.1% of patients. Regarding the best response during the transarterial chemoembolization series, 87.2% of patients were overall responders. The median OS of initial responders (n = 483) was not significantly different from that of subsequent responders at the 1-year landmark (stable disease [SD] after first transarterial chemoembolization but CR or PR after repeated transarterial chemoembolization; n = 61; 46.2 vs 40.1 months, respectively; P = .145). Likewise, the median OS of initial CR patients (n = 326) was not significantly different from that of the subsequent CR group (n = 126) at the 1-year landmark (PR or SD after first transarterial chemoembolization but CR after repeated transarterial chemoembolization; 53.4 vs 46.3 months, respectively; P = .455). Multivariate Cox analyses showed that the objective responses, the initial responses (hazard ratio [HR], 0.638; P = .001), and the best responses (HR, 0.304; P < .001) had the significant prognostic significance for OS.
Both the initial and best responses during repeated transarterial chemoembolization were significantly associated with OS in patients with intermediate-stage HCC and preserved liver function.
Temperature sensitive hydrogel for preoperative treatment of renal carcinoma
2020, Materials Science and Engineering C
Surgical resection has been suggested as an effective and first-line treatment of renal cell carcinoma (RCC). However, operation is quite difficult for the patients with stage of middle-late or hypervascularized tumors. Transarterial chemoembolization (TACE) plays an important role in decreasing the size of tumors before surgery. In this work, we prepared an injectable drug-delivery system of doxorubicin-loaded temperature sensitive hydrogel for transarterial chemoembolization in RCC. The sol–gel transition behavior and rheologic analysis showed that the doxorubicin-loaded temperature sensitive hydrogel had good temperature sensitivity. Then, The X-ray experiment of hydrogel showed excellent visibility under the digital subtraction angiography and computed tomography scans in vitro and in vivo. Moreover, the studies of embolization in beagle's right kidney showed good properties in embolizing of renal arteries. In TACE therapy studies of rabbit VX₂ renal tumors, angiography, computed tomography and histopathological analysis verified that TACE therapy of doxorubicin-loaded temperature sensitive hydrogel had excellent embolic efficiency as a result of repressing the tumor growth. This hydrogel could provide valuable option in the treatment of renal cell carcinoma before surgery.
mRECIST for HCC: Performance and novel refinements
2020, Journal of Hepatology
In 2010, modified RECIST (mRECIST) criteria were proposed as a way of adapting the RECIST criteria to the particularities of hepatocellular carcinoma (HCC). We intended to overcome some limitations of RECIST in measuring tumour shrinkage with local and systemic therapies, and also to refine the assessment of progression that could be misinterpreted with conventional RECIST 1.1, due to clinical events related to the natural progression of chronic liver disease (development of ascites, enlargement of lymph nodes, etc.). mRECIST has served its purpose since being adopted or included in clinical practice guidelines (European, American and Asian) for the management of HCC; it has also been instrumental for assessing response and time-to-event endpoints in several phase II and III investigations. Nowadays, mRECIST has become the standard tool for measurement of radiological endpoints at early/intermediate stages of HCC. At advanced stages, guidelines recommend both methods. mRECIST has been proven to capture higher objective response rates in tumours treated with molecular therapies and those responses have shown to be independently associated with better survival. With the advent of novel treatment approaches (i.e. immunotherapy) and combination therapies there is a need to further refine and clarify some concepts around the performance of mRECIST. Similarly, changes in the landscape of standard of care at advanced stages of the disease are pointing towards progression-free survival as a potential primary endpoint in some phase III investigations, as effective therapies applied beyond progression might mask overall survival results. Strict recommendations for adopting this endpoint have been reported. Overall, we review the performance of mRECIST during the last decade, incorporating novel clarifications and refinements in light of emerging challenges in the study and management of HCC.
Current strategies for the treatment of intermediate and advanced hepatocellular carcinoma
2020, Cancer Treatment Reviews
Hepatocellular carcinoma (HCC) ranks among the most common cancers worldwide and remains to be a major global health care problem. Until 2007, no effective therapies were available for patients after failure of locoregional approaches, and the approval of sorafenib as the first systemic agent with efficacy in patients suffering from advanced HCC marked a new era in the treatment of this deadly disease. However, it took nearly 10 years until the portfolio of effective drugs finally expanded and additional substances showed activity in both first and further lines of treatment. Since their recent approval, these novel substances have substantially changed the field of palliative treatment strategies in patients with advanced HCC, and their sequential application has demonstrated their potential to significantly prolong patient survival in the palliative setting. With the recently communicated data from the first positive immuno-oncology trial in HCC, it appears highly likely that the implementation of IO concepts will result in a further improvement of patient prognosis. Although locoregional approaches remain an integral component of meaningful treatment concepts for patients with BCLC-B stage HCC, repetitive interventions bear the risk of a progressive deterioration of liver function. More than ever, in order to implement long-term therapeutic concepts and exploit the full potential of systemic treatment strategies, it is of utmost importance to maintain a fine balance between anti-tumor activity and toxicity.
With an emphasis on the systemic treatment options, this review provides a summary of the most recent results from large phase III clinical trials and discusses their clinical implications.

View all citing articles on Scopus

View full text

Research ArticleComparison of the methods for tumor response assessment in patients with hepatocellular carcinoma undergoing transarterial chemoembolization

Background & Aims

Methods

Results

Conclusions

Introduction

Section snippets

Materials and methods

Results

Discussion

Financial support

Conflict of interest

Clin Liver Dis

Gastroenterology

Gastroenterology

Hepatology

Eur J Cancer

J Hepatol

J Hepatol

Lancet

Hepatology

Prognosis of hepatocellular carcinoma: the BCLC staging classification

Semin Liver Dis

End points and United States Food and Drug Administration approval of oncology drugs

J Clin Oncol

Research Article
Comparison of the methods for tumor response assessment in patients with hepatocellular carcinoma undergoing transarterial chemoembolization