Partial irradiation of the liver

The use of three-dimensional radiotherapy (RT) and the prospective follow-up of patients for radiation-induced liver disease (RILD) have led to a more quantitative understanding of the partial organ tolerance of the liver compared with previous estimates based on clinical judgment alone. Parameters of both the Lyman normal tissue complication probability (NTCP) model and a local damage-organ injury (D-I) NTCP model have been fit to clinical data from patients who have received hepatic radiation. Based on analyses of over 180 patients, the liver exhibits a large volume effect and a low threshold volume for RILD. Mean liver dose is associated with RILD, and no cases of RILD have been reported in patients with a mean liver dose of less than 31 Gy. Most recent estimates of the partial liver tolerance to RT suggest that if less than 25% of the normal liver is treated with RT, then there may be no upper limit on dose associated with RILD. Estimates of the liver doses associated with a 5% risk of RILD for uniform irradiation of one third, two thirds, and the whole liver are 90 Gy, 47 Gy, and 31 Gy, respectively.     

Analysis of radiation-induced liver disease using the Lyman NTCP model

PURPOSE: To describe the dose-volume tolerance for radiation-induced liver disease (RILD) using the Lyman-Kutcher-Burman (LKB) normal tissue complication probability (NTCP) model. METHODS AND MATERIALS: A total of 203 patients treated with conformal liver radiotherapy and concurrent hepatic arterial chemotherapy were prospectively followed for RILD. Normal liver dose-volume histograms and RILD status for these patients were used as input data for determination of LKB model parameters. A complication was defined as Radiation Therapy Oncology Group Grade 3 or higher RILD < o r =4 months after completion of radiotherapy. A maximal likelihood analysis yielded best estimates for the LKB NTCP model parameters for the liver for the entire patient population. A multivariate analysis of the potential factors associated with RILD was also completed, and refined LKB model parameters were obtained for patient subgroups with different risks of RILD. RESULTS: Of 203 patients treated with focal liver irradiation, 19 developed RILD. The LKB NTCP model fit the complication data for the entire group. The "n" parameter was larger than previously described, suggesting a strong volume effect for RILD and a correlation of NTCP with the mean liver dose. No cases of RILD were observed when the mean liver dose was <31 Gy. Multivariate analysis demonstrated that in addition to NTCP and the mean liver dose, a primary hepatobiliary cancer diagnosis (vs. liver metastases), bromodeoxyuridine hepatic artery chemotherapy (vs. fluorodeoxyuridine chemotherapy), and male gender were associated with RILD. For 169 patients treated with fluorodeoxyuridine, the refined LKB model parameters were n = 0.97, m = 0.12, tolerance dose for 50% complication risk for whole organ irradiated uniformly [TD50(1)] = 45.8 Gy for patients with liver metastases, and TD50(1) = 39.8 Gy for patients with primary hepatobiliary cancer. CONCLUSION: These data demonstrate that the liver exhibits a large volume effect for RILD, suggesting that the mean liver dose may be useful in ranking radiation plans. The inclusion of clinical factors, especially the diagnosis of primary hepatobiliary cancer vs. liver metastases, improves the estimation of NTCP over that obtained solely by the use of dose-volume data. These findings should facilitate the application of focal liver irradiation in future clinical trials.     

Radiation-induced liver disease after three-dimensional conformal radiotherapy for patients with hepatocellular carcinoma: dosimetric analysis and implication

PURPOSE: To analyze the correlation of radiation-induced liver disease (RILD) with patient-related and treatment-related dose-volume factors and to describe the probability of RILD by a normal tissue complication probability (NTCP) model for patients with hepatocellular carcinoma (HCC) treated with three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: Between November 1993 and December 1999, 93 patients with intrahepatic malignancies were treated with 3D-CRT at our institution. Sixty-eight patients who were diagnosed with HCC and had complete 3D dose-volume data were included in this study. Of the 68 patients, 50 had chronic viral hepatitis before treatment, either type B or type C. According to the Child-Pugh classification for liver cirrhosis, 53 patients were in class A and 15 in class B. Fifty-two patients underwent transcatheter arterial chemoembolization with an interval of at least 1 month between transcatheter arterial chemoembolization and 3D-CRT to allow adequate recovery of hepatic function. The mean dose of radiation to the isocenter was 50.2 +/- 5.9 Gy, in daily fractions of 1.8-2Gy. No patient received whole liver irradiation. RILD was defined as Grade 3 or 4 hepatic toxicity according to the Common Toxicity Criteria of the National Cancer Institute. All patients were evaluated for RILD within 4 months of RT completion. Three-dimensional treatment planning with dose-volume histogram analysis of the normal liver was used to compare the dosimetric difference between patients with and without RILD. Maximal likelihood analysis was conducted to obtain the best estimates of parameters of the Lyman NTCP model. Confidence intervals of the fitted parameters were estimated by the profile likelihood method. RESULTS: Twelve of the 68 patients developed RILD after 3D-CRT. None of the patient-related variables were significantly associated with RILD. No difference was found in tumor volume (780 cm(3) vs. 737 cm(3), p = 0.86), normal liver volume (1210 cm(3) vs. 1153 cm(3), p = 0.64), percentage of normal liver volume with radiation dose >30 Gy (V(30 Gy); 42% vs. 33%, p = 0.05), and percentage of normal liver volume with >50% of the isocenter dose (V(50%); 45% vs. 36%, p = 0.06) between patients with and without RILD. The mean hepatic dose was significantly higher in patients with RILD (2504 cGy vs. 1965 cGy, p = 0.02). The probability of RILD in patients could be expressed as follows: probability = 1/[1 + exp(-(0.12 x mean dose - 4.29))], with coefficients significantly different from 0. The best estimates of the parameters in the Lyman NTCP model were the volume effect parameter of 0.40, curve steepness parameter of 0.26, and 50% tolerance dose for uniform irradiation of whole liver [TD(50)(1)] of 43 Gy. Patients with RILD had a significantly higher NTCP than did those with no RILD (26.2% vs. 15.8%; p = 0.006), using the best-estimated parameters. CONCLUSION: Dose-volume histogram analysis can be effectively used to quantify the tolerance of the liver to RT. Patients with RILD had received a significantly higher mean dose to the liver and a significantly higher NTCP. The fitted volume effect parameter of the Lyman NTCP model was close to that from the literature, but much lower in our patients with HCC and prevalent chronic viral hepatitis than that reported in other series with patients with normal liver function. Additional efforts should be made to test other models to describe the radiation tolerance of the liver for Asian patients with HCC and preexisting compromised hepatic reserve.     

Biologic susceptibility of hepatocellular carcinoma patients treated with radiotherapy to radiation-induced liver disease

PURPOSE: To identify the factors associated with radiation-induced liver disease (RILD) and to describe the difference in normal tissue complication probability (NTCP) between subgroups of hepatocellular carcinoma patients undergoing three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: A total of 89 hepatocellular carcinoma patients who completed 3D-CRT for local hepatic tumors were included. The average isocenter dose was 49.9 +/- 6.2 Gy. Logistic regression analysis was used for the association between statistically significant factors and RILD (defined as Grade 3 or 4 hepatic toxicity of elevated transaminases or alkaline phosphatase within 4 months of completing 3D-CRT) in multivariate analysis. Maximal likelihood analysis was conducted to obtain the best estimates of the NTCP model parameters. RESULTS: Of the 89 patients, 17 developed RILD. In univariate analysis, hepatitis B virus (HBV)-positive status and the mean radiation dose to the liver were the two factors significantly associated with the development of RILD. Of the 65 patients who were HBV carriers, 16 had RILD compared with 1 of 24 non-carrier patients (p = 0.03). The mean radiation dose to liver was significantly greater in patients with RILD (22.9 vs. 19.0 Gy, p = 0.05). On multivariate analysis, HBV carrier status (odds ratio, 9.26; p = 0.04) and Child-Pugh B cirrhosis of the liver (odds ratio, 3.65; p = 0.04) remained statistically significant. The best estimates of the NTCP parameters were n = 0.35, m = 0.39, and TD(50)(1) = 49.4 Gy. The n, m, TD(50)(1) specifically estimated from the HBV carriers was 0.26, 0.40, and 50.0 Gy, respectively, compared with 0.86, 0.31, and 46.1 Gy, respectively, for non-carrier patients. CONCLUSION: Hepatocellular carcinoma patients who were HBV carriers or had Child-Pugh B cirrhosis presented with a statistically significantly greater susceptibility to RILD after 3D-CRT.     

Radiation-induced liver disease in three-dimensional conformal radiation therapy for primary liver carcinoma: the risk factors and hepatic radiation tolerance

PURPOSE: To identify risk factors relevant to radiation-induced liver disease (RILD) and to determine the hepatic tolerance to radiation. METHODS AND MATERIALS: The data of 109 primary liver carcinomas (PLC) treated with hypofractionated three-dimensional conformal radiation therapy (3D-CRT) were analyzed. Seventeen patients were diagnosed with RILD and 13 of 17 died of it. RESULTS: The risk factors for RILD were late T stage, large gross tumor volume, presence of portal vein thrombosis, association with Child-Pugh Grade B cirrhosis, and acute hepatic toxicity. Multivariate analyses demonstrated that the severity of hepatic cirrhosis was a unique independent predictor. For Child-Pugh Grade A patients, the hepatic radiation tolerance was as follows: (1) Mean dose to normal liver (MDTNL) of 23 Gy was tolerable. (2) For cumulative dose-volume histogram, the tolerable volume percentages would be less than: V5 of 86%, V10 of 68%, V15 of 59%, V20 of 49%, V25 of 35%, V30 of 28%, V35 of 25%, and V40 of 20%. (3) Tolerable MDTNL could be estimated by MDTNL (Gy) = -1.686 + 0.023 * normal liver volume (cm3). CONCLUSION: The predominant risk factor for RILD was the severity of hepatic cirrhosis. The hepatic tolerance to radiation could be estimated by dosimetric parameters.     

Prediction of radiation-induced liver disease by Lyman normal-tissue complication probability model in three-dimensional conformal radiation therapy for primary liver carcinoma

PURPOSE: To describe the probability of RILD by application of the Lyman-Kutcher-Burman normal-tissue complication (NTCP) model for primary liver carcinoma (PLC) treated with hypofractionated three-dimensional conformal radiotherapy (3D-CRT). METHODS AND MATERIALS: A total of 109 PLC patients treated by 3D-CRT were followed for RILD. Of these patients, 93 were in liver cirrhosis of Child-Pugh Grade A, and 16 were in Child-Pugh Grade B. The Michigan NTCP model was used to predict the probability of RILD, and then the modified Lyman NTCP model was generated for Child-Pugh A and Child-Pugh B patients by maximum-likelihood analysis. RESULTS: Of all patients, 17 developed RILD in which 8 were of Child-Pugh Grade A, and 9 were of Child-Pugh Grade B. The prediction of RILD by the Michigan model was underestimated for PLC patients. The modified n, m, TD50 (1) were 1.1, 0.28, and 40.5 Gy and 0.7, 0.43, and 23 Gy for patients with Child-Pugh A and B, respectively, which yielded better estimations of RILD probability. The hepatic tolerable doses (TD5) would be MDTNL of 21 Gy and 6 Gy, respectively, for Child-Pugh A and B patients. CONCLUSIONS: The Michigan model was probably not fit to predict RILD in PLC patients. A modified Lyman NTCP model for RILD was recommended.     

Inclusion of biological factors in parallel-architecture normal-tissue complication probability model for radiation-induced liver disease

PURPOSE: To include biologic factors in parallel-architecture normal-tissue complication probability (NTCP) model for radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy (3D-CRT) for gastric or hepatic cancer. METHODS AND MATERIALS: A total of 151 patients (89 with hepatocellular carcinoma and 62 with gastric cancer) who received 3D-CRT to the liver were included (isocenter dose range 33.0 to 66.0 Gy; mean 48.0 Gy). RILD was defined as grade 3 or higher liver toxicity according to Common Toxicity Criteria Version 2.0 of the National Cancer Institute within 4 months after 3D-CRT. Possible correlations of patient-related or dosimetric factors with RILD were tested. Maximum-likelihood analysis estimated NTCP model parameters for group and subgroups. Goodness-of-fit analysis estimated deviance of NTCP model parameters between subgroups. RESULTS: RILD developed in 25 patients. Hepatitis B virus carrier status (p < 0.001) was the only significant independent factor. The 4 parallel NTCP model parameters, mean functional reserve (V(50)), width of functional reserve distribution (sigma), dose damage to 50% of liver subunits (D(50)), and slope parameter for subunit dose-response (k), were respectively, 0.54, 0.14, 50 Gy, 0.18 (group); 0.53, 0.07, 50 Gy, 4.6 x 10(-7) (carriers); 0.59, 0.12, 25 Gy, 59.8 (noncarriers). In carrier-state subgroups, goodness-of-fit deviance with 1 subgroup's parameter set would have been worse in the other group. Across subgroups, patients with RILD all had liver fraction damage (f) greater than 0.4 compared with wider distribution for the whole group. CONCLUSIONS: RILD is described with a parallel-architecture NTCP model for HBV carriers and noncarriers with a threshold effect greater than 0.4. The main difference is in slope parameter for subunit dose-response.     

Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description.

Twelve patients with hepatocellular carcinoma and chronic hepatitis developed radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy. Six patients died of RILD and six recovered. Mean prescribed dose was 50.6+/-4.3Gy, in a daily fraction of 1.8-2.0Gy. Commonly used dosimetric parameters, such as fraction volume of normal liver with radiation dose >30Gy, prediction score, and normal tissue complication probability, failed to differentiate the fatality and clinical types of this complication. Elevated transaminases are more frequently seen than ascites and elevated alkaline phosphamide are seen in patients with RILD.     

Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer.

PURPOSE: To determine the relationships between the three-dimensional dose distributions in parotid glands and their saliva production, and to find the doses and irradiated volumes that permit preservation of the salivary flow following irradiation (RT). METHODS AND MATERIALS: Eighty-eight patients with head and neck cancer irradiated with parotid-sparing conformal and multisegmental intensity modulation techniques between March 1994 and August 1997 participated in the study. The mean dose and the partial volumes receiving specified doses were determined for each gland from dose-volume histograms (DVHs). Nonstimulated and stimulated saliva flow rates were selectively measured from each parotid gland before RT and at 1, 3, 6, and 12 months after the completion of RT. The data were fit using a generalized linear model and the normal tissue complication probability (NTCP) model of Lyman-Kutcher. In the latter model, a "severe complication" was defined as salivary flow rate reduced to < or =25% pre-RT flow at 12 months. RESULTS: Saliva flow rates data were available for 152 parotid glands. Glands receiving a mean dose below or equal to a threshold (24 Gy for the unstimulated and 26 Gy for the stimulated saliva) showed substantial preservation of the flow rates following RT and continued to improve over time (to median 76% and 114% of pre-RT for the unstimulated and stimulated flow rates, respectively, at 12 months). In contrast, most glands receiving a mean dose higher than the threshold produced little saliva with no recovery over time. The output was not found to decrease as mean dose increased, as long as the threshold dose was not reached. Similarly, partial volume thresholds were found: 67%, 45%, and 24% gland volumes receiving more than 15 Gy, 30 Gy, and 45 Gy, respectively. The partial volume thresholds correlated highly with the mean dose and did not add significantly to a model predicting the saliva flow rate from the mean dose and the time since RT. The NTCP model parameters were found to be TD50 (the tolerance dose for 50% complications rate for whole organ irradiated uniformly) = 28.4 Gy, n (volume dependence parameter) = 1, and m (the slope of the dose/response relationship) = 0.18. Clinical factors including age, gender, pre-RT surgery, chemotherapy, and certain medical conditions were not found to be significantly associated with the salivary flow rates. Medications (diuretics, antidepressants, and narcotics) were found to adversely affect the unstimulated but not the stimulated flow rates. CONCLUSIONS: Dose/volume/function relationships in the parotid glands are characterized by dose and volume thresholds, steep dose/response relationships when the thresholds are reached, and a maximal volume dependence parameter in the NTCP model. A parotid gland mean dose of < or =26 Gy should be a planning goal if substantial sparing of the gland function is desired.     

原发性肝癌三维适形放疗致乙型肝炎病毒再激活相关研究

目的：探讨原发性肝癌患者中三维适形放疗（three dimensional conformal radiotherapy,3D-CRT）致乙型肝炎病毒（HBV）再激活的相关因素。方法入组56例接受3D-CRT治疗的原发性肝癌患者为研究对象,并按放疗后是否接受抗病毒治疗分为A组（抗病毒治疗组,32例）和B组（未接受抗病毒治疗组,24例）。统计HBV再激活率、HBV再激活危险因素、HBV再激活相关性肝炎、丙氨酸氨基转移酶（alanine aminotransferase, ALT）升高情况、肝功能损伤程度、放射性肝损伤（radiation-induced liver disease,RILD）发生率及转归等情况。结果3D-CRT治疗后12周,A组患者的HBV再激活率低于B组（13.64%vs 41.67%）,差异有统计学意义（P＜0.05）;两组ALT升高2倍的患者比例的差异无统计学意义（P＞0.05）;A组再激活相关性肝炎发生率低于B组（6.25% vs 25.0%）,差异有统计学意义（P＜0.05）;两组患者的肝功能损伤程度的差异无统计学意义（P＞0.05）;随访3个月时A组和B组的RILD发生率（6.25%vs 16.67%）的差异无统计学意义（P＞0.05）。B组患者中,HBV再激活患者和HBV未激活患者的Child-Pugh分级构成、HBV DNA水平的差异差异均具有统计学意义（均P＜0.05）。结论3D-CRT技术是治疗肝癌的重要方案,HBV再激活及RILD是肝癌3D-CRT治疗时较为常见的并发症,3D-CRT治疗后的抗病毒治疗可以降低HBV再激活率及HBV再激活相关性肝炎的发生率。     

Dosimetric predictor identification for radiation-induced liver disease after hypofractionated conformal radiotherapy for primary liver carcinoma patients with Child-Pugh Grade A cirrhosis

Purpose

Radiation-induced liver disease (RILD) is the most severe complication in liver cancer treatment. The aim of this study was to identify dosimetric predictors for RILD in primary liver carcinoma (PLC) patients with Child-Pugh Grade A cirrhosis after hypofractionated conformal radiotherapy (CRT).

Methods and materials

A total of 114 eligible patients (mean age 45 years old) were enrolled and treated. The mean gross tumor volume (GTV) was (378.3 ± 308.1) cm³. A median dose of 53 Gy was delivered to the PLC by hypofractionated CRT (three fractions/week) with a median fraction size of 4.6 Gy (range: 4-6 Gy).

Results

Patients were followed up for 1-79 months (median 19 months) after the completion of irradiation. RILD was diagnosed in nine (7.9%) patients. Univariate analyses revealed that GTV and the percentage of normal liver volume receiving more than 5-40 Gy irradiations (V_5-40) were related to the risk of developing RILD. Multivariate analyses demonstrated that only GTV and V₂₀ were independent predictors. Using V₂₀ as the predictor for RILD, the accuracy, sensitivity, and specificity was 76.3%, 88.9%, and 75.2%, respectively.

Conclusions

Our data suggest that V₂₀ is the unique significant dosimetric predictor for RILD risks in PLC patients with Child-Pugh Grade A cirrhosis after hypofractionated CRT.     

Radiotherapy of liver malignancies. From whole liver irradiation to stereotactic hypofractionated radiotherapy

AIMS AND BACKGROUND: Until recently radiotherapy of hepatic malignancies has played a limited role due to the well-known limited radiotolerance of the liver. The aim of this paper is to review the available data on the risk of radiation-induced liver disease (RILD) and to define the modern role of radiotherapy in the management of patients with metastatic or primary liver malignancies. METHODS: The advent of three-dimensional conformal treatment planning with dose-volume histogram analysis has made the study of partial liver irradiation possible. Limited portions of the liver may withstand high doses of radiation with minimal risk of RILD. Patients with solitary unresectable liver tumors may be treated with high-dose radiotherapy with curative intent. Recently, the feasibility of stereotactically guided treatment techniques with a single fraction or few treatment sessions has been explored in numerous institutions. RESULTS: The radiation tolerance of the whole liver found by several investigations is in the order of approximately 30 Gy, which seriously restricts its clinical application. The role of whole liver irradiation therefore appears of limited benefit in the palliation of patients with multiple liver metastases. The use of three-dimensional conformal techniques has made partial liver irradiation possible to doses in the 70-80 Gy range with conventional fractionation. At least two published series have reported improved local control and survival rates with dose escalation with three-dimensional conformal radiotherapy in patients with unresectable liver metastases. Similar outcomes have been recently reported with single dose (or hypofractionated) stereotactic radiotherapy both in metastatic and primary hepatic malignancies with minimal morbidity. Accurate target delineation and treatment reproducibility are the key to the success of this novel treatment approach, and specific treatment planning techniques and patient setup procedures must be developed to implement it. CONCLUSIONS: Stereotactic high-dose radiotherapy is technically feasible for the treatment of inoperable liver malignancies, with the potential of high local control and low morbidity. Definitive evidence on the clinical advantages of this technique over other more established treatments can only be gathered from well-designed clinical studies.     

Hepatic toxicity resulting from cancer treatment

Radiation-induced liver disease (RILD), often called radiation hepatitis, is a syndrome characterized by the development of anicteric ascites approximately 2 weeks to 4 months after hepatic irradiation. There has been a renewed interest in hepatic irradiation because of two significant advances in cancer treatment: three dimensional radiation therapy treatment planning and bone marrow transplantation using total body irradiation. RILD resulting from liver radiation can usually be distinguished clinically from that resulting from the preparative regime associated with bone marrow transplantation. However, both syndromes demonstrate the same pathological lesion: veno-occlusive disease. Recent evidence suggests that elevated transforming growth factor β levels may play a role in the development of veno-occlusive disease. Three dimensional treatment planning offers the potential to determine the radiation dose and volume dependence of RILD, permitting the safe delivery of high doses of radiation to parts of the liver. The chief therapy for RILD is diuretics, although some advocate steroids for severe cases. The characteristics of RILD permit the development of a grading system modeled after the NCI Acute Common Toxicity Criteria, which incorporates standard criteria of hepatic dysfunction.     

Hepatic radiation toxicity: avoidance and amelioration

The refinement of radiation therapy and radioembolization techniques has led to a resurgent interest in radiation-induced liver disease (RILD). The awareness of technical and clinical parameters that influence the chance of RILD is important to guide patient selection and toxicity minimization strategies. "Classic" RILD is characterized by anicteric ascites and hepatomegaly and is unlikely to occur after a mean liver dose of approximately 30 Gy in conventional fractionation. By maintaining a low mean liver dose and sparing a "critical volume" of liver from radiation, stereotactic delivery techniques allow for the safe administration of higher tumor doses. Caution must be exercised for patients with hepatocellular carcinoma or pre-existing liver disease (eg, Child-Pugh score of B or C) because they are more susceptible to RILD that can manifest in a nonclassic pattern. Although no pharmacologic interventions have yet been proven to mitigate RILD, preclinical research shows the potential for therapies targeting transforming growth factor-β and for the transplantation of stem cells, hepatocytes, and liver progenitor cells as strategies that may restore liver function. Also, in the clinical setting of veno-occlusive liver disease after high-dose chemotherapy, agents with fibrinolytic and antithrombotic properties can reverse liver failure, suggesting a possible role in the setting of RILD.     

Radiation Tolerance of the Liver in Relation to the Preserved Functional Capacity

The radiation tolerance of the liver was investigated in 12 patients, 11 of them with liver cirrhosis, treated for hepatocellular carcinoma by partial liver irradiation with doses between 50 and 77 Gy. The tolerance was assessed by the complication probability (Lyman's model), which concerned the injured tissue itself, and by a prediction score used for postsurgical liver failure, which concerned the preserved functional capacity, assuming that the ≥ 30 Gy volume was equivalent to the resected volume. The prediction score corresponded better with the observed risk of fatal liver failure than the complication probability. The liver volume after radiotherapy correlated largely with the untreated volume and the low-dose volume. Thus the preserved functional capacity gives a better expression of the radiation tolerance than direct measures of the extent of injured tissue.     

A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases

PURPOSE: To determine the maximum tolerated dose (MTD) of stereotactic body radiation therapy (SBRT) for liver metastases. METHODS AND MATERIALS: A multicenter Phase I clinical trial was conducted. Eligible patients had one to three liver metastases, tumor diameter <6 cm, and adequate liver function. The first cohort received 36 Gy to the planning target volume (PTV) in three fractions (F). Subsequent cohorts received higher doses up to a chosen maximum of 60 Gy/3F. At least 700 mL of normal liver had to receive a total dose <15 Gy. Dose-limiting toxicity (DLT) included acute Grade 3 liver or intestinal toxicity or any acute Grade 4 toxicity. The MTD was exceeded if 2/6 patients in a cohort experienced DLT. RESULTS: Eighteen patients were enrolled (10 male, 8 female): median age, 55 years (range, 26-83 years); most common primary site, colorectal (6 patients); median aggregate gross tumor volume, 18 ml (range, 3-98 ml). Four patients had multiple tumors. No patient experienced a DLT, and dose was escalated to 60 Gy/3F without reaching MTD. CONCLUSIONS: Biologically potent doses of SBRT are well tolerated in patients with limited liver metastases. Results of this study form the basis for an ongoing Phase II SBRT study of 60 Gy over three fractions for liver metastases.     

Risk factors for hepatitis B virus reactivation after conformal radiotherapy in patients with hepatocellular carcinoma

This study investigated whether conformal radiotherapy affects hepatitis B virus (HBV) reactivation, and the risk factors for HBV reactivation in patients with HBV‐related hepatocellular carcinoma (HCC). Sixty‐nine patients with HCC were included in this retrospective study. Before radiotherapy (RT), all patients underwent imaging examinations and some baseline examinations, including CBC, liver function test, renal function test, α‐fetoprotein level, hepatitis B (HB) surface antigen, HB surface Ab, HB e antigen, HB e Ab, and serum HBV DNA quantification. During the period of RT and at least 16 weeks after the end of RT, CBCs were carried out weekly and the other tests were monitored monthly or more frequently if necessary. The clinical features and dosimetric parameters of RT were recorded. Univariate and multivariate logistic regression algorithms were used to analyze the risk factors of HBV reactivation. The incidence of complications in the study population was as follows: radiation‐induced liver disease, 17.4%; HBV reactivation, 24.6%; and HBV reactivation‐induced hepatitis, 21.7%. The HBV DNA level and dose volume parameters including normal liver volume, V20, and mean dose were associated with HBV reactivation. There was a relatively high incidence of HBV reactivation in HCC patients after the end of conformal RT. The serum HBV DNA level and some dosimetric parameters related to normal liver, including normal liver volume, V20, and mean dose, were the prognosis factors of HBV reactivation and should be carefully considered before conformal RT.