Won Il Jang

High-dose stereotactic body radiotherapy correlates increased local control and overall survival in patients with inoperable hepatocellular carcinoma

BackgroundRecent studies using stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) have reported high tumor response and local control. However, the optimal SBRT dose remains unknown, and it is still not clear whether a dose response relationship for local control (LC) and overall survival (OS) exist or not. We performed this study to determine whether a dose response relationship for LC and OS is observed in SBRT for inoperable HCC.MethodsBetween 2003 and 2011, 108 patients with HCC were treated with SBRT. All patients were unsuitable for surgery or local ablation and had incomplete response to transarterial chemoembolization. Eighty-two patients with a longest tumor diameter (LD) less than or equal to 7.0 cm who were treated with 3-fraction SBRT and were analyzed. This cohort comprised 74 Child-Turcotte-Pugh (CTP) class A patients and 8 CTP class B7 patients. The median LD was 3.0 cm (range, 1.0–7.0 cm), and the median dose was 51 Gy (range, 33–60 Gy).ResultsLC and OS rates at 2 years after SBRT were 87% and 63%, respectively, with a median follow-up duration of 30 months for all patients. The 2-year LC/OS rates for patients treated with doses of > 54, 45–54, and < 45 Gy were 100/71, 78/64, and 64%/30%, respectively (p = .009/p < .001). Multivariate analysis revealed that the SBRT dose (p = .005) and Barcelona Clinic Liver Cancer stage (p = .015) were significant prognostic factors for OS. Correlation analysis revealed a positive linear relationship between the SBRT dose and LC (p = .006, R = .899)/OS (p = .002, R = .940) at 2 years. Based on the tumor-control probability model, a dose of 54.8 Gy provides 2-year LC with a 90% probability. Five patients experienced grade 3 or higher gastrointestinal toxicity, and 6 had deteriorating of CTP score by greater than or equal to 2 within 3 months of SBRT.ConclusionsThis study demonstrated a dose response relationship for LC and OS with SBRT for HCC. Higher LC rates resulting from an increased dose may translate into survival benefits for patients with HCC.

Outcomes of stereotactic body radiotherapy for unresectable primary or recurrent cholangiocarcinoma

Purpose To report the results of stereotactic body radiotherapy (SBRT) for unresectable primary or recurrent cholangiocarcinoma. Materials and Methods From January 2005 through August 2013, 58 patients with unresectable primary (n = 28) or recurrent (n = 30) cholangiocarcinoma treated by SBRT were retrospectively analyzed. The median prescribed dose was 45 Gy in 3 fractions (range, 15 to 60 Gy in 1-5 fractions). Patients were treated by SBRT only (n = 53) or EBRT + SBRT boost (n = 5). The median tumor volume was 40 mL (range, 5 to 1,287 mL). Results The median follow-up duration was 10 months (range, 1 to 97 months). The 1-year, 2-year overall survival rates, and median survival were 45%, 20%, and 10 months, respectively. The median survival for primary group and recurrent group were 5 and 13 months, respectively. Local control rate at 1-year and 2-year were 85% and 72%, respectively. Disease progression-free survival rates at 1-year and 2-year were 26% and 23%, respectively. In univariate analysis, ECOG performance score (0-1 vs. 2-3), treatment volume (<50 vs. ≥50 mL), and pre-SBRT CEA level (<5 vs. ≥5 ng/mL) were significant in overall survival rate. In multivariate analysis, ECOG score (p = 0.037) and tumor volume (p = 0.030) were statistically significant. In the recurrent tumor group, patients with >12 months interval from surgery to recurrence showed statistically significant higher overall survival rate than those with ≤12 months (p = 0.026). Six patients (10%) experienced ≥grade 3 complications. Conclusion SBRT can be considered as an effective local modality for unresectable primary or recurrent cholangiocarcinoma.

Dosimetric comparison of volumetric modulated arc therapy with robotic stereotactic radiation therapy in hepatocellular carcinoma.

Purpose To compare volumetric modulated arc therapy of RapidArc with robotic stereotactic body radiation therapy (SBRT) of CyberKnife in the planning and delivery of SBRT for hepatocellular carcinoma (HCC) treatment by analyzing dosimetric parameters. Materials and Methods Two radiation treatment plans were generated for 29 HCC patients, one using Eclipse for the RapidArc plan and the other using Multiplan for the CyberKnife plan. The prescription dose was 60 Gy in 3 fractions. The dosimetric parameters of planning target volume (PTV) coverage and normal tissue sparing in the RapidArc and the CyberKnife plans were analyzed. Results The conformity index was 1.05 ± 0.02 for the CyberKnife plan, and 1.13 ± 0.10 for the RapidArc plan. The homogeneity index was 1.23 ± 0.01 for the CyberKnife plan, and 1.10 ± 0.03 for the RapidArc plan. For the normal liver, there were significant differences between the two plans in the low-dose regions of V1 and V3. The normalized volumes of V60 for the normal liver in the RapidArc plan were drastically increased when the mean dose of the PTVs in RapidArc plan is equivalent to the mean dose of the PTVs in the CyberKnife plan. Conclusion CyberKnife plans show greater dose conformity, especially in small-sized tumors, while RapidArc plans show good dosimetric distribution of low dose sparing in the normal liver and body.

Association between metformin use and mortality in patients with type 2 diabetes mellitus and localized resectable pancreatic cancer: a nationwide population-based study in korea

Background Preclinical studies support an antitumor effect of metformin. However, clinical studies have conflicting results and metformins effect remains controversial. The aim of this study was to evaluate metformins effect on clinical outcomes in diabetic patients with pancreatic cancer treated with curative resection. Results A total of 764 patients underwent curative resection, met none of the exclusion criteria, and were prescribed oral hypoglycemic agents. The cancer-specific survival (5-year, 31.9% vs. 22.2%, p < 0.001) was significantly higher in the 530 metformin users than in the 234 diabetic metformin non-users. After multivariable adjustments, metformin users had significantly lower cancer-specific mortality as compared with metformin non-users (hazard ratio, 0.727; 95% confidence interval, 0.611–0.868). Cubic spline regression analysis demonstrated significantly decreased cancer-specific mortality with increasing dose of metformin (p = 0.0047). Materials and Methods Data were provided from the Korea Central Cancer Registry and the National Health Insurance Service in the Republic of Korea. The study cohort consisted of 28,862 patients newly diagnosed with pancreatic cancer between 2005 and 2011. Metformin exposure was determined from prescription information from 6 months before the first diagnosis of pancreatic cancer to last follow-up. The main outcome was cancer-specific survival. Conclusions This large study indicates that metformin might decrease cancer-specific mortality rates in localized resectable pancreatic cancer patients with pre-existing diabetes, independently of other factors, with a dose-response relationship.

Treatment of Patients with Clinically Lymph Node-negative Squamous Cell Carcinoma of the Oral Cavity

OBJECTIVE To evaluate treatment outcome and to determine optimal treatment strategy for patients with clinically lymph node-negative (N0) oral cavity squamous cell carcinoma (SCC). METHODS Two hundred and twenty-seven patients with oral cavity SCC received radiotherapy with curative intent. We retrospectively analyzed 69 patients with clinically N0 disease. Forty-three patients were treated with surgery followed by radiotherapy (S+EBRT) and 26 with radiotherapy alone (EBRT). The median doses administered were 63.0 Gy for S+EBRT and 70.2 Gy for EBRT. RESULTS The rates of occult metastasis were 60% for T1, 69% for T2, 100% for T3 and 39% for T4, respectively, among patients who underwent neck dissection. A contralateral occult metastasis occurred only in two patients. The median follow-up was 39 months (range, 6-170 months). The 5-year overall survival (OS), disease-free survival (DFS), local control (LC) and regional control (RC) rates for all patients were 56, 50, 66 and 79%, respectively. The 5-year OS, DFS, LC and RC rates were 67/39% (P < 0.01), 66/24% (P < 0.01), 87/30% (P < 0.01) and 73/89% (P = 0.11) for S+EBRT/EBRT, respectively. CONCLUSIONS The risk for occult neck metastasis is high in patients with oral cavity SCC; therefore, elective neck treatment should be considered. Excellent RC for subclinical disease can be achieved with radiotherapy alone. However, external beam radiotherapy alone to primary tumor resulted in poor LC and combined treatment with surgery and radiotherapy appeared to be a better treatment strategy.

Low Hepatic Toxicity in Primary and Metastatic Liver Cancers after Stereotactic Ablative Radiotherapy Using 3 Fractions.

This study evaluated the incidence of hepatic toxicity after stereotactic ablative radiotherapy (SABR) using 3 fractions to the liver, and identified the predictors for hepatic toxicity. We retrospectively reviewed 78 patients with primary and metastatic liver cancers, who underwent SABR using 3 fractions between 2003 and 2011. To examine the incidence of hepatic toxicity, we defined newly developed hepatic toxicity≥grade 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 within 3 months after the end of SABR as a significant adverse event. To identify the predictors for hepatic toxicity, we analyzed several clinical and dosimetric parameters (rV5Gy-rV35Gy: normal liver volume receiving <X Gy, reverse VXGy). Hepatic toxicity≥grade 2 occurred in 10 patients (13%): grade 2 in 9 patients and grade 3 in 1 patient. On univariate analysis, baseline Child-Pugh (CP) score (5 vs. 6-8), normal liver volume, and planning target volume were the significant clinical predictors. All dosimetric parameters were significant: rV20Gy was the most significant predictor. On multivariate analysis, baseline CP score (hazard ratio, 0.026; P=0.001) was the only significant predictor. In conclusion, SABR using 3 fractions in primary and metastatic liver cancers produces low hepatic toxicity, especially in patients with a baseline CP score of 5. However, further studies are needed to minimize hepatic toxicity in patients with baseline CP scores≥6. Graphical Abstract

Association of Metformin Use With Cancer-Specific Mortality in Hepatocellular Carcinoma After Curative Resection: A Nationwide Population-Based Study.

AbstractMany preclinical reports and retrospective population studies have shown an anticancer effect of metformin in patients with several types of cancer and comorbid type 2 diabetes mellitus (T2DM). In this work, the anticancer effect of metformin was assessed in hepatocellular carcinoma (HCC) patients with T2DM who underwent curative resection.A population-based retrospective cohort design was used. Data were obtained from the National Health Insurance Service and Korea Center Cancer Registry in the Republic of Korea, identifying 5494 patients with newly diagnosed HCC who underwent curative resection between 2005 and 2011. Crude and adjusted hazard ratios (HRs) were calculated using Cox proportional hazard models to estimate effects. In the sensitivity analysis, we excluded patients who started metformin or other oral hypoglycemic agents (OHAs) after HCC diagnosis to control for immortal time bias.From the patient cohort, 751 diabetic patients who were prescribed an OHA were analyzed for HCC-specific mortality and retreatment upon recurrence, comparing 533 patients treated with metformin to 218 patients treated without metformin. In the fully adjusted analyses, metformin users showed a significantly lower risk of HCC-specific mortality (HR 0.38, 95% confidence interval [CI] 0.30–0.49) and retreatment events (HR 0.41, 95% CI 0.33–0.52) compared with metformin nonusers. Risks for HCC-specific mortality were consistently lower among metformin-using groups, excluding patients who started metformin or OHAs after diagnosis.In this large population-based cohort of patients with comorbid HCC and T2DM, treated with curative hepatic resection, metformin use was associated with improvement of HCC-specific mortality and reduced occurrence of retreatment events.

A Survey of Stereotactic Body Radiotherapy in Korea

Purpose The purpose of this study is to investigate the current status of stereotactic body radiotherapy (SBRT) in Korea. A nationwide survey was conducted by the Korean Stereotactic Radiosurgery Group of the Korean Society for Radiation Oncology (KROG 13-13). Materials and Methods SBRT was defined as radiotherapy with delivery of a high dose of radiation to an extracranial lesion in ≤ 4 fractions. A 16-questionnaire survey was sent by e-mail to the chief of radiation oncology at 85 institutions in June 2013. Results All institutions (100%) responded to this survey. Of these, 38 institutions (45%) have used SBRT and 47 institutions (55%) have not used SBRT. Regarding the treatment site, the lung (92%) and liver (76%) were the two most common sites. The most common schedules were 60 Gy/4 fractions for non-small cell lung cancer, 48 Gy/4 fractions for lung metastases, 60 Gy/3 fractions for hepatocellular carcinoma, and 45 Gy/3 fractions or 40 Gy/4 fractions for liver metastases. Four-dimensional computed tomography (CT) was the most common method for planning CT (74%). During planning CT, the most common method of immobilization was the use of an alpha cradle/vacuum-lock (42%). Conclusion Based on this survey, conduct of further prospective studies will be needed in order to determine the appropriate prescribed doses and to standardize the practice of SBRT.

Definitive radiotherapy for treatment of primary vaginal cancer: effectiveness and prognostic factors.

Objective This study was performed to evaluate treatment outcomes and define prognostic factors for primary vaginal cancer treated with definitive radiotherapy. Materials and Methods We retrospectively analyzed 38 patients with primary vaginal cancer who received radiotherapy with curative intent between January 1981 and August 2008. Of these 38 patients, 6 were excluded from this analysis because of other uncontrolled malignancy (n = 1), uncommon histology (n = 4), or insufficient medical records (n = 1). Twenty-three patients (72%) presented with early-stage disease (International Federation of Gynecology and Obstetrics stages 0, I, or II). Eleven patients (34%) were treated with external beam radiotherapy (EBRT) alone and 21 patients (66%) with EBRT plus brachytherapy (BT). Low–dose rate cesium-137 was used with intracavitary technique for most of the patients who received BT. Five patients received chemotherapy. The median total dose in patients who received EBRT and EBRT+BT was 50.4 Gy (range, 39.6–70.4 Gy) and 78.9 Gy (range, 72.0–87.0 Gy), respectively. Results The median duration of follow-up was 38 months. Five-year overall survival, cause-specific survival, disease-free survival, local control, and regional control rates for the analyzed patients were 75%, 88%, 58%, 62% and 90%, respectively. Thirteen patients had treatment failure as follows: local (n = 7), distant (n = 1), local plus regional (n = 1), local plus distant (n = 2), and local plus regional plus distant (n = 2). Primary tumor size was a significant prognostic factor for disease-free survival (P = 0.039). Conclusions Definitive radiotherapy is an effective treatment modality for primary vaginal cancer. Local failure was the major failure pattern, and achievement of local control is important for disease control and survival.

Definitive treatment of primary vaginal cancer with radiotherapy: multi-institutional retrospective study of the Korean Radiation Oncology Group (KROG 12-09).

Objective To assess the outcome of the treatment of primary vaginal cancer using definitive radiotherapy (RT) and to evaluate the prognostic factors of survival. Methods The medical records of nine institutions were retrospectively reviewed to find the patients with vaginal cancer treated with definitive RT with or without chemotherapy. A total of 138 patients met the inclusion criteria. None had undergone curative excision. Results The median follow-up time of the survivors was 77.6 months and the median survival time was 46.9 months. The 5-year overall survival, cancer-specific survival (CSS), and progression-free survival (PFS) rates were 68%, 80%, and 68.7%, respectively. In the survival analysis, the multivariate analysis showed that a lower the International Federation of Gynecology and Obstetrics (FIGO) stage and prior hysterectomy were favorable prognostic factors of CSS, and a lower FIGO stage and diagnosed prior to year 2000 were favorable prognostic factors of PFS. In the subgroup analysis of the patients with available human papillomavirus (HPV) results (n=27), no statistically significant relationship between the HPV status and recurrence or survival was found. Grade 3 or 4 acute and late toxicity were present in 16 and 9 patients, respectively. The FIGO stage and the tumor size were predictors of severe late toxicity. Conclusion The data clearly showed that a higher FIGO stage was correlated with a worse survival outcome and higher severe late toxicity. Therefore, precise RT and careful observation are crucial in advanced vaginal cancer. In this study, the HPV status was not related to the survival outcome, but its further investigation is needed.