Chul Seung Kay

2014 Korean Liver Cancer Study Group-National Cancer Center Korea practice guideline for the management of hepatocellular carcinoma

The guideline for the management of hepatocellular carcinoma (HCC) was first developed in 2003 and revised in 2009 by the Korean Liver Cancer Study Group and the National Cancer Center, Korea. Since then, many studies on HCC have been carried out in Korea and other countries. In particular, a substantial body of knowledge has been accumulated on diagnosis, staging, and treatment specific to Asian characteristics, especially Koreans, prompting the proposal of new strategies. Accordingly, the new guideline presented herein was developed on the basis of recent evidence and expert opinions. The primary targets of this guideline are patients with suspicious or newly diagnosed HCC. This guideline provides recommendations for the initial treatment of patients with newly diagnosed HCC.

Serum interleukin-6 and C-reactive protein as a prognostic indicator in hepatocellular carcinoma

The development of hepatocellular carcinoma (HCC) is often associated with chronic inflammation, suggesting a strong relationship between inflammation and carcinogenesis. This study evaluated the prognostic values of inflammatory and T-helper (Th) cytokines in the clinical outcome and survival of HCC. The study included 110 patients with HCC undergoing loco-regional therapy and 24 healthy controls. Five Th1/Th2 cytokines and C-reactive protein (CRP) were quantified before and after loco-regional treatment, using enzyme-linked immunosorbent assays. Levels of CRP, interleukin (IL)-4, and IL-6 were higher in patients with HCC than those in healthy subjects. Tumor characteristics, Child-Pugh class, and CRP, IL-6, and IL-10 levels were associated with HCC survival (all P<0.05). With multivariate analysis, higher IL-6 levels were identified as the independent cytokine for shorter survival (P=0.010). Higher CRP and IL-6 levels correlated well with larger tumor size, poor Child-Pugh function, and shorter survival, with a significant inter-correlation (r=0.667). On serial measurements, the association of CRP with tumor response was stronger than that of α-fetoprotein or other cytokines. IL-6 and CRP are strong inflammatory indicators predictive of outcome in patients with HCC receiving loco-regional therapy. This study suggests that inflammatory activation of the IL-6/CRP network may be a potential therapeutic target and biomarker for HCC.

Prognostic value of C-reactive protein and neutrophil-to-lymphocyte ratio in patients with hepatocellular carcinoma

BackgroundAccumulating evidence indicates that components of the systemic inflammatory response, such as C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR), have been associated with prognosis of various cancers. We aimed to elucidate whether CRP and NLR could serve as potential surrogate markers for response and survival in patients with hepatocellular carcinoma (HCC).MethodsThe study population consisted of 318 consecutive patients with HCC. CRP and NLR were measured at baseline with follow-up measurements.ResultsWith the mean follow-up of 13.9 months, the median survival time was 13.8 months. Child-Pugh class, tumor size > 5 cm, tumor multiplicity, presence of portal vein thrombosis, α-fetoprotein > 200 ng/mL, CRP > 6.3 mg/L and NLR > 2.3 were identified as independent factors for worse survival of HCC (all p < 0.05). Patients with elevated CRP (> 6.3 mg/L) and elevated NLR (> 2.3) had a significantly shorter overall survival than those with low CRP and low NLR (all p < 0.001). The combined use of CRP and NLR provided incremental prognostic information. With significant inter-correlations, levels of CRP and NLR escalated with aggravating Child-Pugh class from A to C or progressing tumor stage from I to IV. CRP and NLR on baseline and serial measurements were well predictive of treatment response (p < 0.001).ConclusionsCRP and NLR are independent indicators for survival in HCC patients, reflecting tumor burden and hepatic reserve. Their role in predicting tumor response and survival is more enhanced when used in combination. This study suggests that CRP and NLR are important prognostic biomarkers for HCC.

Simultaneous Multitarget Irradiation Using Helical Tomotherapy for Advanced Hepatocellular Carcinoma With Multiple Extrahepatic Metastases

PURPOSE The prognosis of hepatocellular carcinoma (HCC) patients with extrahepatic metastases is extremely poor. Helical tomotherapy, an image-guided, intensity-modulated radiotherapy system, can allow for simultaneous and precise targeting of multiple cancerous lesions, while sparing normal tissues. This study evaluated the feasibility and outcome of tomotherapy for advanced HCC with metastases. PATIENTS AND METHODS A total of 42 consecutive HCC patients with metastases were treated with tomotherapy using the Hi-Art system. A total of 152 intra- and extrahepatic lesions (3.5 lesions/patient) were treated simultaneously, with a dose of 51.03 Gy (range, 30-57.61) in 10 fractions. Transarterial chemolipiodolization using epirubicin (50 mg) and cisplatin (60 mg) was repeated in patients with intrahepatic HCC (mean size, 9.0 cm) after tomotherapy. RESULTS An objective response (complete response and partial response) was achieved in 45.2% of patients with intrahepatic tumors, 68.4% of patients with pulmonary lesions, 60.0% of patients with lymph node/adrenal lesions, and 66.7% of patients with soft-tissue metastases. The complete response rate for those with pulmonary and lymph node/adrenal metastases was 26.3% and 5.0%, respectively. The overall survival rate at 1 and 2 years was 50.1% and 14.9%, respectively, with a median survival of 12.3 months. The actuarial in-field tumor control rate for < or =1 year was 79.0%. No cases of Grade 4-5 acute toxicity occurred. CONCLUSION The results of this study have shown that helical tomotherapy is safe and feasible without major toxicities for the treatment of advanced HCC and results in excellent tumor control and a potential survival benefit. This approach is expected to be a useful palliative option for selected HCC patients with metastases.

Helical Tomotherapy for Simultaneous Multitarget Radiotherapy for Pulmonary Metastasis

PURPOSE To retrospectively evaluate our experience with tomotherapy for simultaneous multitarget radiotherapy in patients with pulmonary metastases. METHODS AND MATERIALS Thirty-one patients were treated with tomotherapy for pulmonary metastases. We defined gross tumor volume (GTV) in computed tomography scans, and the margin of the planning target volume was 1 to 1.5 cm from the GTV. The median doses prescribed were 50 Gy and 40 Gy delivered in 10 fractions over 2 weeks to the 95% isodose volume of the GTV and planning target volume, respectively. Prior to each treatment, online corrections were made in the three axes, and rotation was done after registration of the megavoltage and simulation computed tomography scans. Survival was calculated from the completion of tomotherapy, using the Kaplan-Meier method and log rank test. RESULTS The overall survival rate at 12 months was 60.5%, and the median survival time was 16.0 months. A rating of 1 or below on the Eastern Cooperative Oncology Group scale, a breast or colon cancer as the primary cancer, primary lesions that were completely controlled, and a response maintained at 3 months after tomotherapy were shown by univariate analysis to be statistically significant favorable prognostic factors. Progression-free survival rates at 1 and 2 years were 39.6% and 27.7%, respectively. The posttreatment failure rate was 64.5%, the local failure rate was 9.7%, the regional failure rate was 51.6%, and the synchronous local and regional failure rate was 3.2%. Grades I and II radiation-related toxicity levels were observed in 41.9% and 16.0% of patients, respectively. There were no treatment-related deaths. CONCLUSIONS Tomotherapy could be offered to patients as a safe and effective treatment in select patients with lung metastases. However, large-scale, prospective clinical trials should be done to confirm our results.

Role of intrahepatic tumor control in the prognosis of patients with hepatocellular carcinoma and extrahepatic metastases.

Background and Aim:  There has been little information about the long‐term outcome and prognostic factors in patients with hepatocellular carcinoma (HCC) and extrahepatic metastases. The purpose of this study was to investigate the clinical factors affecting survival after extrahepatic metastasis and to determine the survival benefit of controlling intrahepatic HCC.

A Customized Bolus Produced Using a 3-Dimensional Printer for Radiotherapy

Objective Boluses are used in high-energy radiotherapy in order to overcome the skin sparing effect. In practice though, commonly used flat boluses fail to make a perfect contact with the irregular surface of the patient’s skin, resulting in air gaps. Hence, we fabricated a customized bolus using a 3-dimensional (3D) printer and evaluated its feasibility for radiotherapy. Methods We designed two kinds of bolus for production on a 3D printer, one of which was the 3D printed flat bolus for the Blue water phantom and the other was a 3D printed customized bolus for the RANDO phantom. The 3D printed flat bolus was fabricated to verify its physical quality. The resulting 3D printed flat bolus was evaluated by assessing dosimetric parameters such as D1.5 cm, D5 cm, and D10 cm. The 3D printed customized bolus was then fabricated, and its quality and clinical feasibility were evaluated by visual inspection and by assessing dosimetric parameters such as Dmax, Dmin, Dmean, D90%, and V90%. Results The dosimetric parameters of the resulting 3D printed flat bolus showed that it was a useful dose escalating material, equivalent to a commercially available flat bolus. Analysis of the dosimetric parameters of the 3D printed customized bolus demonstrated that it is provided good dose escalation and good contact with the irregular surface of the RANDO phantom. Conclusions A customized bolus produced using a 3D printer could potentially replace commercially available flat boluses.

Re-irradiation of unresectable recurrent head and neck cancer: using Helical Tomotherapy as image-guided intensity-modulated radiotherapy

Purpose Re-irradiation (re-RT) is considered a treatment option for inoperable locoregionally recurrent head and neck cancer (HNC) after prior radiotherapy. We evaluated the efficacy and safety of re-RT using Helical Tomotherapy as image-guided intensity-modulated radiotherapy in recurrent HNC. Materials and Methods Patients diagnosed with recurrent HNC and received re-RT were retrospectively reviewed. Primary endpoint was overall survival (OS) and secondary endpoints were locoregional control and toxicities. Results The median follow-up period of total 9 patients was 18.7 months (range, 4.1 to 76 months) and that of 3 alive patients was 49 months (range, 47 to 76 months). Median dose of first radiotherapy and re-RT was 64.8 and 47.5 Gy10. Median cumulative dose of the two courses of radiotherapy was 116.3 Gy10 (range, 91.8 to 128.9 Gy10) while the median interval between the two courses of radiation was 25 months (range, 4 to 137 months). The response rate after re-RT of the evaluated 8 patients was 75% (complete response, 4; partial response, 2). Median locoregional relapse-free survival after re-RT was 11.9 months (range, 3.4 to 75.1 months) and 5 patients eventually presented with treatment failure (in-field failure, 2; in- and out-field failure, 2; out-field failure, 1). Median OS of the 8 patients was 20.3 months (range, 4.1 to 75.1 months). One- and two-year OS rates were 62.5% and 50%, respectively. Grade 3 leucopenia developed in one patient as acute toxicity, and grade 2 osteonecrosis and trismus as chronic toxicity in another patient. Conclusion Re-RT using Helical Tomotherapy for previously irradiated patients with unresectable locoregionally recurrent HNC may be a feasible treatment option with long-term survival and acceptable toxicities.

Dosimetric parameter predicting the deterioration of hepatic function after helical tomotherapy in patients with unresectable locally advanced hepatocellular carcinoma

BackgroundThe purpose of this study was to identify parameters capable of predicting the deterioration of hepatic function after helical tomotherapy in patients with unresectable locally advanced hepatocellular carcinoma.MethodsBetween March 2006 and February 2012, 72 patients were eligible for this study. All patients received hypofractionated radiotherapy using the TomoTherapy Hi-Art (TomoTherapy, Madison, WI, USA) at Seoul St. Marys Hospital and Incheon St. Marys Hospital, the Catholic University of Korea. The radiation dose was a median 50 Gy (range: 40–50 Gy) in 10 fractions to 95% of the planning target volume. Radiation-induced hepatic toxicity was defined as an increase of at least 2 points in the Child-Pugh (CP) score within 3 months after completion of helical tomotherapy.ResultsAn increase of at least 2 points in the CP score occurred in 32 of the 72 patients (44.4%). Multivariate logistic regression analysis revealed that pretreatment CP class and V15Gy were significant parameters associated with an increase in CP score (p = 0.009 and p < 0.001, respectively). The area under receiver operating characteristic curve was 0.863 for V15Gy (p < 0.001). For V15Gy, with a cutoff value of 43.2%, the accuracy was 0.806 (58/72) with a sensitivity of 0.938 and a specificity of 0.725.ConclusionsAn increase of at least 2 points in the CP score is a radiation dose-limiting factor, and the non-target normal liver receiving a dose more than 15 Gy (V15Gy) should be <43.2% to reduce the risk of the deterioration of hepatic function.

Determination of the α/β ratio for the normal liver on the basis of radiation-induced hepatic toxicities in patients with hepatocellular carcinoma

BackgroundThe purpose of this study was to determine the α/β ratio for normal liver with hepatitis by analyzing the toxicity data from patients with unresectable hepatocellular carcinoma treated with helical tomotherapy.MethodsBetween March 2006 and February 2012, 98 patients were eligible for this study. 66 patients received 45–50 Gy in 4.5-5 Gy fractions (Group A) and 32 patients received 36–60 Gy in 2.5-3 Gy fractions (Group B). Radiation-induced hepatic toxicity was defined as an increase of at least 2 points in the Child-Pugh score within 4 months of completing helical tomotherapy. We attempted to find the statistically significant parameters in the 2 groups using α/β ratios of 2, 4, 6, 8, or 10, and compared the estimated probability curves of each significant parameter. We hypothesized that the α/β ratio associated with the best matches for the curves between the 2 groups would be equivalent to the α/β ratio for the normal liver.ResultsWhen using an α/β ratio of 2 or 4, different parameters were found to be statistically significant in a multivariate analysis (Group A: VBED30 for α/β ratio = 2 and VBED25 for α/β ratio = 4, Group B: VBED25 for α/β ratio = 2 and VBED20 for α/β ratio = 4). When using an α/β ratio of 6, 8, or 10, VBED20 was found to be a statistically significant parameter in both groups. Comparison of the estimated probability curve of each significant parameter between the groups revealed that an α/β ratio of 8 resulted in the best matches.ConclusionsWe suggest that the α/β ratio of the normal liver with hepatitis is 8. We hope that previously reported parameters and their values can be effectively used in different fractionation schemes by calculating the biologically effective dose using an α/β ratio of 8.