Adverse hepatic events caused by radiotherapy for advanced hepatocellular carcinoma

BACKGROUND: Radiotherapy is often used to treat patients with unresectable advanced hepatocellular carcinoma (HCC). The present study examines the nature and frequency of adverse events with respect to liver function in such patients after radiotherapy. METHODS: Forty-six patients with HCC who underwent radiotherapy were retrospectively examined. Radiotherapy was applied using coplanar 2-3-beam arrangements to a target dose of 50 Gy/5 weeks. The adverse hepatic events were evaluated according to the National Cancer Institute Common Toxicity Criteria and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme during the acute phase and the late phase by following the patients for up to 1 year. The influence on survival by adverse hepatic events and other factors was analyzed. RESULTS: The full irradiation dose of 50 Gy was given to 40 patients (87.0%). Grade 3 or 4 toxicity was observed in 18 (39.1%) within 3 months after radiotherapy and in 11 (33.3%) of 33 thereafter, respectively. The most frequent and serious adverse events were hyperbilirubinemia, hypoalbuminemia, and ascites. The independent adverse prognostic factors for survival were portal vein tumor thrombus (P = 0.0012), tumor response (P = 0.011), acute adverse hepatic event (P = 0.012), and late adverse hepatic event (P = 0.015). CONCLUSIONS: Hypoalbuminemia, hyperbilirubinemia, and ascites were important hepatic adverse events that developed after applying radiotherapy to treat advanced HCC. These adverse events seriously affected survival.     

Radiation-induced hepatic toxicity after radiotherapy combined with chemotherapy for hepatocellular carcinoma

Aim: The purpose of the present study was to analyze hepatic toxicity following radiotherapy combined with regional chemotherapy for hepatocellular carcinoma (HCC). Methods: From 2001 to 2003, a total of 132 patients with HCC received 3-D conformal radiation therapy (3D-CRT) combined with chemotherapy. Patients were divided into two groups based on drug localization: the transcatheter arterial chemoembolization (TACE) group, where the chemotherapeutic drug (adriamycin) was localized within the tumor, and the non-TACE group, where the drugs (adriamycin, cisplatin, 5-fluorouracil) were diffusely spread over the entire liver. Results: Patients were evaluated by biochemical parameters for any hepatic toxicity prior to, during, and until 12 months after 3D-CRT. Hepatic toxicity was defined as radiation-induced liver disease (RILD) or combined modality-induced liver disease (CMILD), which is defined as RILD with abnormal elevation of total bilirubin levels. In the TACE group, three patients developed RILD (5.6%) and none developed CMILD. In the non-TACE group, three patients (3.7%) and seven patients (8.8%) developed RILD and CMILD, respectively. Conclusion: Hepatic toxicity following radiotherapy combined with regional chemotherapy for HCC might be influenced by the distribution of the chemotherapeutic drugs. A more precise understanding of hepatic toxicity from chemoradiotherapy will help design optimal treatments for HCC.     

三维适形放射治疗原发性肝癌患者发生放射性肝损伤相关因素分析*

目的 研究三维适形放射治疗原发性肝癌患者发生放射性肝损伤（RILD)的相关危险因素。方法 对2009年3月至2015年12月期间收治的三维适形放射治疗的原发性肝癌患者的临床资料进行归纳整理,以假设检验筛选相关危险因素,并进行多因素非条件Logistic回归分析。结果 本组纳入研究的原发性肝癌患者39例,在完成放射治疗后发生RILD 14例（35.9%);各类别单因素的假设检验提示肝癌患者的年龄和肝功能CTP评分与放疗后RILD的发生相关（P<0.05）;进一步的非条件多因素Logistic回归分析显示,年龄≥60岁（OR:15.72,P=0.020）和肝功能CTP评分≥6（OR:24.95,P=0.005）是三维适形放射治疗原发性肝癌后发生RILD的2个独立危险因素。结论 通过对三维适形放射治疗原发性肝癌患者发生RILD的研究,初步识别了肝癌患者接受放疗后发生RILD的相关危险因素,为日后制定治疗计划时减少RILD的发生,或建立适当的干预措施提供了科学依据。     

Conformal radiotherapy for hepatocellular carcinoma

Technical advancements in radiation therapy (RT) have facilitated the safe delivery of conformal, dose-escalated radiation to a wide spectrum of hepatocellular carcinoma (HCC) patients. A variety of doses and RT fractionation schemes have been used, and RT has been used in combination with transarterial chemoembolization (TACE). Compared to untreated historical controls or those treated with TACE alone, outcomes following RT alone or TACE and RT are better. Despite advances in RT delivery, liver toxicity following RT remains a dose-limiting factor, and investigations to better understand the pathophysiology of RT-induced liver toxicity are warranted. For most tumors, RT can provide sustained local control. However, HCC tends to recur within the liver away from the irradiated volume, providing rationale for combining RT with systemic or regional therapies. There is a particular interest in combining RT with anti-VEGF-targeted agents for their independent activity in HCC as well as their radiation sensitization properties. Randomized trials of RT are warranted.     

A simple, noninvasively determined index predicting hepatic failure following liver resection for hepatocellular carcinoma

Background

A novel index, the serum aspartate aminotransferase activity/platelet count ratio index (APRI), has been identified as a biochemical surrogate for histological fibrogenesis and fibrosis in cirrhosis. We evaluated the ability of preoperative APRI to predict hepatic failure following liver resection for hepatocellular carcinoma.

Methods

Potential preoperative risk factors for postoperative hepatic failure (hepatic coma with hyperbilirubinemia, four patients; intractable pleural effusion or ascites, 30 patients; and variceal bleeding, one patient) as well as APRI were evaluated in 366 patients undergoing liver resection for hepatocellular carcinoma. Prognostic significance was determined by univariate and multivariate analyses.

Results

Hepatic failure developed postoperatively in 30 patients, causing death in four. APRI correlated with histological intensity of hepatitis activity and degree of hepatic fibrosis, and was significantly higher in patients who developed postoperative hepatic failure than in others without failure. Risk of postoperative hepatic failure increased as the serum albumin concentration and platelet count decreased and as indocyanine green retention rate at 15 min, aspartate and alanine aminotransferase activities, and APRI increased. Only APRI was an independent preoperative factor on multivariate analysis. Of the four patients who died of postoperative hepatic failure, three had an APRI of at least 10.

Conclusions

Preoperative APRI independently predicted hepatic failure following liver resection for hepatocellular carcinoma. Patients with an APRI of 10 or more have a high risk of postoperative hepatic failure.     

Long‐term outcome of stereotactic body radiotherapy for patients with small hepatocellular carcinoma

Aim

To evaluate the long‐term outcome of stereotactic body radiotherapy in patients with small hepatocellular carcinoma who were ineligible for resection or ablation therapies.

Methods

A total of 65 patients with 74 hepatocellular carcinomas (median tumor size 16 mm) were enrolled in the present study. They were treated with the prescribed dose of 48 Gy in four fractions at the isocenter. We extended the observation period and analyzed long‐term outcomes, including overall survival, progression‐free survival, local control, and various prognostic factors, in these patients.

Results

The median follow‐up period was 41 months for all patients and 62 months for surviving patients. The 3‐ and 5‐year overall survival rates were 56.3% (95% confidence interval, 44.1–68.5%) and 41.4% (95% confidence interval, 28.7–54.1%), respectively. The 3‐ and 5‐year progression‐free survival rates were 25.4% (95% confidence interval, 14.0–36.8%) and 10.6% (95% confidence interval, 1.5–19.8%), respectively. The 3‐ and 5‐year local control rates were both 100% (95% confidence interval 100%). Liver toxicities exceeding grade 3 were observed in 15 patients (23.1%). The proportion of patients who had grade ≥3 toxicities did not increase. Adverse effects (grade ≤2) presented as significant prognostic factors of overall survival, while TNM stage (T1N0M0) was a significant prognostic factor of progression‐free survival after multivariate analysis.

Conclusions

Stereotactic body radiotherapy was effective for patients with small hepatocellular carcinomas who were ineligible for resection or ablation therapies. The incidence of grade ≥3 adverse effects did not increase, even after longer follow‐up times.     

Hypofractionated stereotactic radiotherapy with and without transarterial chemoembolization for small hepatocellular carcinoma not eligible for other ablation therapies: Preliminary results for efficacy and toxicity

Aim: To investigate the efficacy and toxicity of hypofractionated stereotactic radiotherapy for the treatment of patients presenting with hepatocellular carcinoma (HCC) in a single institutional setting. Methods: Sixteen patients who presented with solitary HCC, including two patients with a tumor thrombus of the portal veins, were treated with stereotactic radiotherapy with or without transarterial chemoembolization. The criteria for stereotactic radiotherapy were existence of technical difficulties for other ablation therapies, inoperable disease or refusal to undergo surgery, tumor staged as Grade A or B according to the Child-Pugh classification, and solitary tumor distant from the gastrointestinal tract and kidney with a tumor volume <100 cm(3). In 14 of 16 patients, a total dose of 35- 50 Gy was delivered in 5-7 fractions over 5-9 days. Results: At the end of a mean follow-up of 612 days (median 611 days; range 244-994 days), all patients were alive. Eight of 16 patients had complete responses and seven others were judged as stable with lipiodol accumulation. In one patient, local recurrence developed after 489 days. Intrahepatic recurrences developed outside the treated volume in six patients and no extrahepatic metastases developed during follow-up. No serious treatment-related toxic manifestations developed. Conclusions: Stereotactic radiotherapy for HCC with or without transarterial chemoembolization is feasible therapy and provides good local control with a short treatment period. Stereotactic radiotherapy may be of clinical benefit in patients who are inoperable or for whom there are difficulties in other ablation therapies.     

Effects of branched-chain amino acids-enriched nutrient support for patients undergoing liver resection for hepatocellular carcinoma

Background and Aims: Most patients with hepatocellular carcinoma (HCC) have underlying liver cirrhosis that is frequently associated with a state of protein energy malnutrition. The aim of this study was to evaluate the clinical benefit of perioperative supplementation of a branched‐chain amino acid–enriched nutrient‐mixture for patients undergoing liver resection for HCC. Methods: A total of 112 patients with HCC who underwent hepatic resection were enrolled in this study. These patients were divided into two groups: 40 patients received perioperative supplementation of branched‐chain amino acid–enriched nutrient‐mixture (AEN group) and 72 patients did not (control group). Laboratory data, postoperative complications, duration of hospitalization, and survival were assessed for each group and compared. Results: The overall incidence of postoperative complications was lower in the AEN group (17.5%) than in the control group (44.4%) (P = 0.01). Among the postoperative complications, surgical site infection and bile leakage was observed in 5% of patients in the AEN group and in 15.3% and 12.5% of patients in the control group, respectively. Ascites appeared after the surgery in 7.5% of patients in the AEN group and in 16.7% of patients in the control group. The duration of hospitalization was significantly shorter in the AEN group was than in the control group (P < 0.05). Conclusions: This study strongly suggests that perioperative supplementation of a branched‐chain amino acid–enriched nutrient‐mixture is clinically beneficial in reducing the morbidity associated with postoperative complications and in shortening the duration of hospitalization of patients with chronic liver disease who undergo liver resection for HCC.     

A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma

BACKGROUND: The purpose of this study was to determine the potential role of three-dimensional (3-D) conformal radiotherapy (RT) in treatment of unresectable hepatocellular carcinoma (HCC). METHODS: Thirteen patients were included in this study, which was conducted between 1993 and 1996. Nine patients (group A) were treated with 3-D conformal RT alone because of main portal vein thrombosis, inferior vena cava thrombosis, obstructive jaundice and failure of previous transcatheter arterial chemoembolization (TACE) to control the disease. The remaining four patients (group B) were treated with a combination of TACE and 3-D conformal RT. RESULTS: The greatest dimension of the main tumour in the whole group of patients ranged from 6 to 25 cm (median 15 cm). The radiation dose ranged from 40 to 60 Gy. The tumour response was evaluated by computed tomography scans of the liver 6-8 weeks after completion of radiotherapy. Partial response was observed in 58% of the patients (seven of 12) and minimal response in another 25% of patients (three of 12). One patient could not be evaluated because of the development of hepatic failure 1 month after completion of RT. All patients in group B lived for more than 1 year (range 16-40 months). In group A, one patient who had a large tumour (11 x 10 x 21 cm) with portal vein thrombosis was converted to become resectable after 45 Gy of radiation. The resection specimen revealed no residual cancer cells. This patient is alive longer than 15 months after treatment without the evidence of disease. CONCLUSIONS: Our experience indicates that HCC is more radiosensitive than it was traditionally expected. Three-dimensional reconstruction of tumour and surrounding organs helps to avoid excessive exposure of the liver and adjacent organs to RT and makes it a safer treatment modality for unresectable HCC. Our preliminary data show promise and are worthy of further study to explore the potential role of radiotherapy in the treatment strategy for HCC at various stages of involvement.     

Laparoscopic hepatectomy for hepatocellular carcinoma in cirrhotic patients

Introduction

We have used laparoscopic hepatectomy as a surgical treatment for HCC in patients with cirrhosis. We describe the indications, evaluate invasiveness and analyze the outcomes of laparoscopic hepatectomy.

Methods and Results

With respect to operative method, laparoscopic hepatectomy involving either partial hepatectomy or left lateral sectionectomy is a less invasive procedure in patients with cirrhosis than conventional hepatectomy. Among our laparoscopic hepatectomy cases, operative time was shorter and bleeding was less in recent, as compared to earlier, cases. Furthermore, laparoscopic hepatectomy was less invasive than conventional hepatectomy, as determined by the E-PASS scoring system. Patients also recovered more quickly, which resulted in shorter hospital stays even for patients with cirrhosis. Both the 5-year survival rate and the rate of survival without recurrence of HCC were nearly identical to those of open conventional hepatectomy.

Conclusion

These findings indicate that laparoscopic hepatectomy avoids the disadvantages of standard hepatectomy for HCC in properly selected patients with cirrhosis and that its minimal invasiveness improves patients’ quality of life.     

Role of adjuvant treatment in liver transplantation for advanced hepatocellular carcinoma

The results of liver transplantation for advanced hepatocellular carcinoma have been disappointing because of high recurrence rates, leading to low long-term survival; this indication remains controversial in an era of organ shortage. To continue to offer this treatment possibility, efforts were made to reduce recurrence and improve survival. The first approach is to maintain a strict selection policy excluding patients with extraheptic disease. The second approach is to test the efficacy of perioperative adjuvant therapies in patients selected for transplantation. The reasons for recurrence include: (1) undetected preoperative micrometastases, (2) intraoperative dissemination by surgical manipulation, and (3) acceleration of tumor growth by immunosuppression. Preoperative treatment, which may include systemic chemotherapy or arterial chemoembolization, seems necessary to limit tumor progression during the waiting period. Systemic chemotherapy has been tested pre-, intra-, and postoperatively. It is considered essential postoperatively and should be used as soon as possible after surgery (i.e., in the 1st postoperative week). Several teams have performed pilot studies that included rather limited numbers of patients, and the results were compared with those for historic controls. Published results show that chemoembolization creates tumor necrosis in most instances. This is efficient in limiting tumor progression but the effect on recurrence and survival is unknown. All authors who used postoperative chemotherapy reported improved survival over controls, with 50%—60% 3-year survival and up to 50% 5-year survival. However, recent results suggest that late recurrence may occur. Chemotherapy was usually well tolerated, although leukopenia, sometimes severe, was observed in most patients. The use of granulocyte colony-stimulating factor seems useful to overcome this problem. Perioperative adjuvant treatments seem to prolong survival in patients undergoing liver transplantation for advanced hepatocellular carcinoma, but delayed recurrence remains possible. Further studies are necessary; these should ideally be multicentric, prospective, and randomized.     

A better method for assessment of hepatic function in hepatocellular carcinoma patients treated with radiofrequency ablation: Usefulness of albumin–bilirubin grade

Aim

To evaluate the efficacy of the newly proposed albumin–bilirubin (ALBI) grade for therapy selection, clinical features of patients treated with radiofrequency ablation (RFA) were elucidated.

Methods

From 2000 to 2015, 1101 patients with HCC (<3 cm, ≤3 tumors) treated with RFA were enrolled, with the following clinical features: 734 men and 367 women; 779 with hepatitis C virus, 153 with hepatitis B virus, 5 with hepatitis C and B, and 164 others; and Child–Pugh classification (CP) A : B ratio of 842:259. Liver damage classification (LD) using the indocyanine green retention rate at 15 min and ALBI‐grade were compared in regard to the prognoses of those patients.

Results

Median tumor size was 1.7 cm (interquartile range, 1.4–2.2 cm) and single tumors were found in 802 cases (72.8%) (tumor–node–metastasis stage of the Liver Cancer Study Group of Japan I : II : III = 536:454:111). In the LD‐A group, the number of cases with ALBI‐grade 1, 2, and 3 were 294, 224, and 1, respectively, while those in the LD‐B group were 47, 490, and 12, respectively. In the LD‐C group, 19 and 14 patients were ALBI‐2 and ‐3, respectively. Akaike Information Criterion values for CP, LD‐grade, and ALBI‐grade were 6015.4, 5988.8, and 5990.7, respectively. However, there was no significant difference regarding prognosis between LD‐A/B (n = 228) and C (n = 31) (median survival time, 4.8 vs. 3.9 years, P = 0.0818) in CP‐B, whereas a significant difference was observed regarding prognosis for ALBI‐1/2 (n = 232) and ALBI‐3 (n = 27) (median survival time, 4.8 vs. 2.7 years, P = 0.0168).

Conclusion

Albumin–bilirubin grade showed an assessment ability similar to that of LD‐grade. Furthermore, there was a small improvement in prognosis following RFA in patients with an ALBI‐grade of 3. Although only two serological parameters, albumin and total bilirubin, are used, assessment with ALBI‐grade may be more useful than with LD‐grade for avoiding a non‐beneficial RFA procedure.     

Assessment of liver function for successful hepatectomy in patients with hepatocellular carcinoma with impaired hepatic function

Background/Purpose

This study aimed to construct a formula for assessing liver function in order to prevent post-hepatectomy liver failure.

Methods

A formula was constructed by analyzing data from 28 patients with hepatocellular carcinoma (HCC) with liver cirrhosis operated on between 1981 and 1984. Next, we evaluated the validity of this formula in 207 hepatectomy patients operated on from 1985 to 1999. For 145 hepatectomy patients operated on from 2000 to 2006, this formula was calculated before surgery in order to assess their risk of hepatectomy.

Results

The formula for liver functional evaluation, constructed from preoperative hepatic function parameters, was: liver failure score = 164.8 ? 0.58 × Alb ? 1.07 × HPT + 0.062 × GOT ? 685 × K. ICG ? 3.57 × OGTT. LI + 0.074 × RW, where Alb is albumin (g/dl); HPT, hepaplastin test (%); GOT, glutamate oxaloacetate transaminase (U/l); K. ICG, K value of indocyanine green clearance test; OGTT. LI, 60-min/120-min glucose level in 75-g oral glucose tolerance test. linearity index of OGTT; and RW, weight of resected liver (g). We decided that a score below 25 would be safe for hepatectomy.

Conclusions

The mortality rate decreased from 3.9% in 1985–1999 to 1.3% in 2000–2006. This finding allows us to conclude that the formula is valid for assessing the risk of post-hepatectomy liver failure.