MOLECULAR AND CLINICAL ONCOLOGY 4: 515-522, 2016
Comparison of five staging systems in hepatocellular carcinoma treated with sorafenib: A single-center experience MASATSUGU ENDO*, HIROKI NISHIKAWA*, RYUICHI KITA, TORU KIMURA, YOSHIAKI OHARA, AZUSA SAKAMOTO, SUMIO SAITO, NORIHIRO NISHIJIMA, AKIHIRO NASU, HIDEYUKI KOMEKADO and YUKIO OSAKI Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka 543-0027, Japan Received March 13, 2015; Accepted October 9, 2015 DOI: 10.3892/mco.2016.755 Abstract. To the best of our knowledge, none of the prognostic staging systems for hepatocellular carcinoma (HCC) patients who underwent sorafenib therapy is universally adopted or preferred. In the present study, we aimed to compare prognostic ability among five prognostic systems, including the Japan Integrated Staging (JIS) system, the Barcelona Clinic Liver Cancer classification system, the tumor‑node‑metastasis classification system, the Cancer of the Liver Italian Program scoring system and the Chinese University Prognostic Index (CUPI) scoring system for HCC patients who received sorafenib therapy. A total of 143 HCC patients treated with sorafenib were analysed. We compared prognostic ability among the five prognostic systems using the likelihood ratio (LR) χ2 test, linear trend χ2 test and concordance index (c-index). Our cohort included 114 men and 29 women. The median patient age was 71 years (range, 45-89 years). A total of 102 patients were classified as Child-Pugh A and 41 as Child‑Pugh B, whereas 31 patients (21.7%) had portal vein invasion and 63 (44.1%) extrahepatic metastases. The median survival time was 6.9 months. In the LR χ2 test, the CUPI scoring system had the highest value (35.804), followed by the JIS system (17.469). In the linear trend χ2 test, the CUPI scoring system had the highest value (17.523), followed by the JIS system (15.819). In addition, the JIS system had the highest value in the 6‑month c-index (0.659) as well as in the 1‑year c-index (0.674). However, the CUPI classification system had the lowest value in the 1-year c-index (0.590). In conclusion, the JIS system may be an appropriate staging system for HCC patients undergoing sorafenib therapy.
Correspondence
to: Dr Hiroki Nishikawa, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, 5-30 Fudegasaki-cho, Tennoji-ku, Osaka, Osaka 543-0027, Japan E-mail: [email protected] *
Contributed equally
Key words: hepatocellular carcinoma, sorafenib, prognostic systems, predictability
Introduction The design of a tumor staging system depends on the identification of individual predictors of survival in cancer patients (1-15). The staging of hepatocellular carcinoma (HCC) differs significantly from that of other malignancies, as the underlying liver disease, apart from the biology of the tumor itself, may significantly affect patient prognosis (1-15). Based on the identification of relevant predictors for tumor burden and liver functional reserve, several staging systems for HCC including both aspects have been proposed in different parts of the world (1-15). Of these prognostic systems for HCC, the Japan Integrated Staging (JIS) system, the Barcelona Clinic Liver Cancer (BCLC) classification system, the tumor‑node‑metastasis (TNM) classification system, the Cancer of the Liver Italian Program (CLIP) scoring system and the Chinese University Prognostic Index (CUPI) scoring system are currently used in daily clinical practice, with an ongoing debate between Western and Eastern countries regarding their prognostic ability in HCC (2,6,10-12,14). Sorafenib (Nexavar; Bayer Healthcare Pharmaceuticals, Montville, NJ, USA), a multikinase inhibitor that blocks tumor growth and cell proliferation, was the first systemic chemotherapeutic agent found to significantly improve the survival of patients with advanced HCC in the Sorafenib HCC Assessment Randomised Protocol (SHARP) trial and in the Asian Pacific trial, and it is currently approved for use as first‑line systemic chemotherapy in these patients (16,17). In order to optimize the beneficial effects of sorafenib, combination or sequential therapies comprising sorafenib and other HCC therapies, such as transcatheter arterial chemoembolization (TACE), were recently investigated (18). However, to the best of our knowledge, predictive factors of responders to sorafenib among HCC patients have not been well established, and none of the prognostic staging systems for HCC patients who underwent sorafenib therapy is yet universally adopted or preferred (19,20). Thus, there is an urgent need for determining the prognostic ability of staging systems in patients with advanced HCC receiving sorafenib therapy. The aim of the present study was to compare prognostic ability among the five aforementioned well‑known prognostic systems (JIS, BCLC, TNM, CLIP and CUPI systems) for HCC patients who received sorafenib therapy.
516
ENDO et al: SORAFENIB FOR HCC AND STAGING SYSTEMS
Patients and methods Patients. A total of 143 HCC patients were treated with sorafenib monotherapy at the Osaka Red Cross Hospital (Osaka, Japan) between June, 2009 and 2014. Subjects participating in clinical trials of novel molecular targeted agents or sequential or combination therapies with TACE and sorafenib were excluded from the present analysis. Sorafenib therapy was indicated in patients with unresectable HCC determined by dynamic computed tomography (CT): i) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0‑2; ii) presence of extrahepatic metastases; iii) HCC refractory to previous therapies, such as TACE; iv) unsuitability for TACE due to anatomical reasons; or v) vascular invasion, such as tumor thrombus in the portal vein (19,21). The disease was staged for all analysed patients by means of five staging systems, including the JIS, BCLC, TNM, CLIP and CUPI systems (2,6,10,11,14). We investigated the prognostic ability of each prognostic system. Furthermore, we investigated prognostic factors associated with overall survival (OS) using univariate and multivariate analyses. The following data were used for the analyses: gender, age, tumor burden, presence of portal vein invasion, presence of extrahepatic metastases, Child-Pugh classification, ECOG PS, cause of liver disease, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase (ALP), platelet count, tumor markers and initial dose of sorafenib [recommended (800 mg̸day) or reduced dose]. Prior to sorafenib therapy for HCC, written informed consent for HCC therapy was obtained from all the subjects. The Ethics Committee of our department approved the study protocol. The present study comprised a retrospective analysis of patients' medical records in our database and all the treatments were performed in an open-label manner. Diagnosis of HCC and sorafenib therapy. HCC was diagnosed based on the results of the abdominal ultrasound and dynamic CT scan (hyperattenuation during the arterial phase in the entire or part of the tumor, and hypoattenuation in the portal venous phase) and̸or magnetic resonance imaging (MRI), mainly as recommended by the American Association for the Study of Liver Diseases (22). Arterial and portal phase dynamic CT images were obtained ~30 and 120 sec after injection of contrast material. In our hospital, abdominal angiography combined with CT (angio‑CT) was routinely performed prior to therapy for HCC after obtaining informed consent from the patients. This was performed based on the fact that this technique was useful for detecting small satellite nodules, as reported by Yamasaki et al (23). Subsequently, HCC was confirmed using CT during hepatic arteriography and during arterial portography. Patients who presented with atypical liver tumors underwent ultrasound‑guided tumor biopsy. Vascular invasion was determined using dynamic CT and/or angio‑CT. During initial evaluation for HCC, a chest X-ray was performed and, if abnormal, it was followed by a chest CT scan. Bone scintigraphy, brain CT or MRI was performed if there were any symptoms or clinical indications. The response to sorafenib was assessed every 4‑8 weeks after the initiation of sorafenib therapy, using the modified Response Evaluation Criteria in Solid Tumors (mRECIST)
and̸or tumor markers (24). Sorafenib therapy was continued until disease progression, unacceptable drug-related toxicity, or the patient's wish to discontinue treatment. After discontinuation of sorafenib therapy for any reason, any additional therapies, such as TACE or systemic chemotherapy, were allowed based on the status of each patient (19,21). As regards the initial dose of sorafenib, for patients without risk factors, we introduced the recommended initial dose of 400 mg twice a day (800 mg/day) of sorafenib (16,17,19,21,25,26). Considering previous studies on dose reduction of sorafenib, the initial dose was reduced based on clinical factors such as age, body weight, ECOG PS and liver functional reserve (19,21,27). During sorafenib therapy, each attending physician decided to reduce the daily dose of sorafenib according to the grades of adverse events or ECOG PS. Sorafenib‑related toxicities, including hand‑foot skin reaction (HFSR), rash, diarrhea, fever, hypertension, fatigue, liver injury, gastrointestinal bleeding and lung injury were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (http://ctep.cancer.gov). Statistical analysis. In this study, OS was the only endpoint. Data were analysed using univariate and multivariate methods. To analyse the significance of prognostic predictors, continuous variables were divided by the median values for all cases (n=143) and treated as dichotomous covariates. The cumulative OS rate was calculated by the Kaplan-Meier method and tested by the log-rank test. A Cox proportional hazards model via a stepwise forward method was used for multivariate analyses of factors with a P-value of 52 vs. 34 vs. 405 vs. 11.5 vs. 139.1 vs. 1,341 vs.
Comparison of five staging systems in hepatocellular carcinoma treated with sorafenib: A single-center experience MASATSUGU ENDO*, HIROKI NISHIKAWA*, RYUICHI KITA, TORU KIMURA, YOSHIAKI OHARA, AZUSA SAKAMOTO, SUMIO SAITO, NORIHIRO NISHIJIMA, AKIHIRO NASU, HIDEYUKI KOMEKADO and YUKIO OSAKI Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka 543-0027, Japan Received March 13, 2015; Accepted October 9, 2015 DOI: 10.3892/mco.2016.755 Abstract. To the best of our knowledge, none of the prognostic staging systems for hepatocellular carcinoma (HCC) patients who underwent sorafenib therapy is universally adopted or preferred. In the present study, we aimed to compare prognostic ability among five prognostic systems, including the Japan Integrated Staging (JIS) system, the Barcelona Clinic Liver Cancer classification system, the tumor‑node‑metastasis classification system, the Cancer of the Liver Italian Program scoring system and the Chinese University Prognostic Index (CUPI) scoring system for HCC patients who received sorafenib therapy. A total of 143 HCC patients treated with sorafenib were analysed. We compared prognostic ability among the five prognostic systems using the likelihood ratio (LR) χ2 test, linear trend χ2 test and concordance index (c-index). Our cohort included 114 men and 29 women. The median patient age was 71 years (range, 45-89 years). A total of 102 patients were classified as Child-Pugh A and 41 as Child‑Pugh B, whereas 31 patients (21.7%) had portal vein invasion and 63 (44.1%) extrahepatic metastases. The median survival time was 6.9 months. In the LR χ2 test, the CUPI scoring system had the highest value (35.804), followed by the JIS system (17.469). In the linear trend χ2 test, the CUPI scoring system had the highest value (17.523), followed by the JIS system (15.819). In addition, the JIS system had the highest value in the 6‑month c-index (0.659) as well as in the 1‑year c-index (0.674). However, the CUPI classification system had the lowest value in the 1-year c-index (0.590). In conclusion, the JIS system may be an appropriate staging system for HCC patients undergoing sorafenib therapy.
Correspondence
to: Dr Hiroki Nishikawa, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, 5-30 Fudegasaki-cho, Tennoji-ku, Osaka, Osaka 543-0027, Japan E-mail: [email protected] *
Contributed equally
Key words: hepatocellular carcinoma, sorafenib, prognostic systems, predictability
Introduction The design of a tumor staging system depends on the identification of individual predictors of survival in cancer patients (1-15). The staging of hepatocellular carcinoma (HCC) differs significantly from that of other malignancies, as the underlying liver disease, apart from the biology of the tumor itself, may significantly affect patient prognosis (1-15). Based on the identification of relevant predictors for tumor burden and liver functional reserve, several staging systems for HCC including both aspects have been proposed in different parts of the world (1-15). Of these prognostic systems for HCC, the Japan Integrated Staging (JIS) system, the Barcelona Clinic Liver Cancer (BCLC) classification system, the tumor‑node‑metastasis (TNM) classification system, the Cancer of the Liver Italian Program (CLIP) scoring system and the Chinese University Prognostic Index (CUPI) scoring system are currently used in daily clinical practice, with an ongoing debate between Western and Eastern countries regarding their prognostic ability in HCC (2,6,10-12,14). Sorafenib (Nexavar; Bayer Healthcare Pharmaceuticals, Montville, NJ, USA), a multikinase inhibitor that blocks tumor growth and cell proliferation, was the first systemic chemotherapeutic agent found to significantly improve the survival of patients with advanced HCC in the Sorafenib HCC Assessment Randomised Protocol (SHARP) trial and in the Asian Pacific trial, and it is currently approved for use as first‑line systemic chemotherapy in these patients (16,17). In order to optimize the beneficial effects of sorafenib, combination or sequential therapies comprising sorafenib and other HCC therapies, such as transcatheter arterial chemoembolization (TACE), were recently investigated (18). However, to the best of our knowledge, predictive factors of responders to sorafenib among HCC patients have not been well established, and none of the prognostic staging systems for HCC patients who underwent sorafenib therapy is yet universally adopted or preferred (19,20). Thus, there is an urgent need for determining the prognostic ability of staging systems in patients with advanced HCC receiving sorafenib therapy. The aim of the present study was to compare prognostic ability among the five aforementioned well‑known prognostic systems (JIS, BCLC, TNM, CLIP and CUPI systems) for HCC patients who received sorafenib therapy.
516
ENDO et al: SORAFENIB FOR HCC AND STAGING SYSTEMS
Patients and methods Patients. A total of 143 HCC patients were treated with sorafenib monotherapy at the Osaka Red Cross Hospital (Osaka, Japan) between June, 2009 and 2014. Subjects participating in clinical trials of novel molecular targeted agents or sequential or combination therapies with TACE and sorafenib were excluded from the present analysis. Sorafenib therapy was indicated in patients with unresectable HCC determined by dynamic computed tomography (CT): i) Eastern Cooperative Oncology Group performance status (ECOG PS) of 0‑2; ii) presence of extrahepatic metastases; iii) HCC refractory to previous therapies, such as TACE; iv) unsuitability for TACE due to anatomical reasons; or v) vascular invasion, such as tumor thrombus in the portal vein (19,21). The disease was staged for all analysed patients by means of five staging systems, including the JIS, BCLC, TNM, CLIP and CUPI systems (2,6,10,11,14). We investigated the prognostic ability of each prognostic system. Furthermore, we investigated prognostic factors associated with overall survival (OS) using univariate and multivariate analyses. The following data were used for the analyses: gender, age, tumor burden, presence of portal vein invasion, presence of extrahepatic metastases, Child-Pugh classification, ECOG PS, cause of liver disease, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase (ALP), platelet count, tumor markers and initial dose of sorafenib [recommended (800 mg̸day) or reduced dose]. Prior to sorafenib therapy for HCC, written informed consent for HCC therapy was obtained from all the subjects. The Ethics Committee of our department approved the study protocol. The present study comprised a retrospective analysis of patients' medical records in our database and all the treatments were performed in an open-label manner. Diagnosis of HCC and sorafenib therapy. HCC was diagnosed based on the results of the abdominal ultrasound and dynamic CT scan (hyperattenuation during the arterial phase in the entire or part of the tumor, and hypoattenuation in the portal venous phase) and̸or magnetic resonance imaging (MRI), mainly as recommended by the American Association for the Study of Liver Diseases (22). Arterial and portal phase dynamic CT images were obtained ~30 and 120 sec after injection of contrast material. In our hospital, abdominal angiography combined with CT (angio‑CT) was routinely performed prior to therapy for HCC after obtaining informed consent from the patients. This was performed based on the fact that this technique was useful for detecting small satellite nodules, as reported by Yamasaki et al (23). Subsequently, HCC was confirmed using CT during hepatic arteriography and during arterial portography. Patients who presented with atypical liver tumors underwent ultrasound‑guided tumor biopsy. Vascular invasion was determined using dynamic CT and/or angio‑CT. During initial evaluation for HCC, a chest X-ray was performed and, if abnormal, it was followed by a chest CT scan. Bone scintigraphy, brain CT or MRI was performed if there were any symptoms or clinical indications. The response to sorafenib was assessed every 4‑8 weeks after the initiation of sorafenib therapy, using the modified Response Evaluation Criteria in Solid Tumors (mRECIST)
and̸or tumor markers (24). Sorafenib therapy was continued until disease progression, unacceptable drug-related toxicity, or the patient's wish to discontinue treatment. After discontinuation of sorafenib therapy for any reason, any additional therapies, such as TACE or systemic chemotherapy, were allowed based on the status of each patient (19,21). As regards the initial dose of sorafenib, for patients without risk factors, we introduced the recommended initial dose of 400 mg twice a day (800 mg/day) of sorafenib (16,17,19,21,25,26). Considering previous studies on dose reduction of sorafenib, the initial dose was reduced based on clinical factors such as age, body weight, ECOG PS and liver functional reserve (19,21,27). During sorafenib therapy, each attending physician decided to reduce the daily dose of sorafenib according to the grades of adverse events or ECOG PS. Sorafenib‑related toxicities, including hand‑foot skin reaction (HFSR), rash, diarrhea, fever, hypertension, fatigue, liver injury, gastrointestinal bleeding and lung injury were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (http://ctep.cancer.gov). Statistical analysis. In this study, OS was the only endpoint. Data were analysed using univariate and multivariate methods. To analyse the significance of prognostic predictors, continuous variables were divided by the median values for all cases (n=143) and treated as dichotomous covariates. The cumulative OS rate was calculated by the Kaplan-Meier method and tested by the log-rank test. A Cox proportional hazards model via a stepwise forward method was used for multivariate analyses of factors with a P-value of 52 vs. 34 vs. 405 vs. 11.5 vs. 139.1 vs. 1,341 vs.
