Actual over 3-year survival after stereotactic body radiation therapy in patients with unresectable intrahepatic cholangiocarcinoma.

PURPOSE: As a non-invasive treatment, stereotactic body radiation therapy (SBRT) has been an emerging and effective option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). The Cyber Knife has an SBRT system, which can realize real-time tracking of tumors during treatment. It can protect the surrounding normal liver tissue while the tumor gets the therapeutic dose. The purpose of this study was to evaluate the factors affecting the local control rate for patients after SBRT treatment, and to predict the factors affecting survival rates, then to report the 3-year actual survival rates after treatment and identify the influencing factors of 3-year survival rate. MATERIALS AND METHODS: We conducted a long-term follow-up of 43 patients with unresectable intrahepatic cholangiocarcinoma who underwent Cyber Knife in our hospital from January 2016 to December 2018. Regular medical check-ups were performed every 2-3 months after SBRT to evaluated the effect of treatment. RESULTS: The median follow-up time was 15 months (4-78 months), and the median progression-free survival (PFS) was 6 months (95% CI, 2.788-9.212) and the median overall survival (OS) was 12 months (95% CI, 3.434-20.566), respectively. Based on modified Response Evaluation and Criteria in Solid Tumor (mRECIST), response rate (RR) and disease control rate (DCR) of SBRT in unresectable ICC were 55.2% and 86%. The 1-, 2- and 3-years OS rate were 51.2%, 32.6% and 23.3%. Multivariate analysis based on competing risk survival analysis identified that patients with multiple nodules, large diameter, high level of CA199 and CEA, poor ECOG performance status had worse overall survival (p < 0.05). Patients who survived ≥3 years had significantly lower levels of CEA, CA199, smaller tumor diameters and lower number of lesions (p < 0.05). CONCLUSION: The SBRT might be a candidate option for patients who unable to perform surgery. The rate of 3-year survival after SBRT for unresectable ICC can be expected with 23.3%.

Stereotactic body radiotherapy in the management of oligometastatic and recurrent biliary tract cancer: single-institution analysis of outcome and toxicity.

INTRODUCTION: Biliary tract cancers (BTC) are rare malignancies arising from biliary system. Systemic therapy is the cornerstone for stage IV disease, with poor overall survival (OS). Evidence is lacking about safety and efficacy of local ablative treatments, such as surgery and stereotactic body radiotherapy (SBRT) in the context of metastatic BTC (mBTC). MATERIALS AND METHODS: We retrospectively analyzed clinical outcomes for a cohort of mBTC patients treated with SBRT for oligometastatic disease. Inclusion criteria were 1-5 distant metastases; SBRT with a dose/fraction of a least 5 Gy to a biological effective dose (BED) of at least 40 Gy considering an α/ß of 10 Gy. Analyzed outcomes included local control (LC), distant progression-free survival (DPFS), PFS, and OS. RESULTS: 51 patients meeting the inclusion criteria. Primary tumor sites were intrahepatic cholangiocarcinoma (35%), extrahepatic cholangiocarcinoma (31%), ampullary adenocarcinoma (20%), gallbladder adenocarcinoma (14%). 21 patients were treated on liver lesions, 17 on nodal metastasis, 5 patients on lung lesions, 4 patients on recurrence along the extrahepatic bile duct. After a median follow-up of 14 months median OS was 13.7 months, 1- and 2-year OS were 58% and 41%, respectively. Node and lung as metastatic sites were associated with a longer OS (p < 0.001). Median LC was 26.8 months, and intrahepatic cholangiocarcinoma was associated with longer LC (p = 0.036). Median DPFS was 11 months, with 1- and 2-year DPFS of 48% and 27.8%, respectively. Ten patients reported grade 1-2 toxicity and 2 cases of acute G3 biliary obstruction. CONCLUSIONS: Stereotactic body radiotherapy (SBRT) is feasible in the context of mBTC. OS and PFS results are promising, considering that our patients were heavily pre-treated with systemic therapy. Patients with nodal or lung relapse have better prognosis. Distant relapses remain the main pattern of failure, but treatment of all metastatic sites seems to improve DMFS.

Stereotactic body radiotherapy dose and its impact on local control and overall survival of patients for locally advanced intrahepatic and extrahepatic cholangiocarcinoma.

PURPOSE: Non-resectable cholangiocarcinoma (CCC) is a significant therapeutic challenge because of bad prognosis. This study analyzed the outcome after SBRT for intra- and extrahepatic CCC. MATERIAL AND METHODS: Sixty-four patients with 82 CCC lesions from a retrospective multicenter database were analyzed. Available parameters were analyzed for local control (LC), overall survival (OS) and toxicity. RESULTS: Median follow-up time for patients alive was 35 months (range 7-91 months). Median overall survival (OS) time was 15 months; 2-year and 3-year OS rates were 32% and 21%. Median prescribed biological effective radiation dose (BED, α/ß = 10) was 67.2 Gy10 (range, 36-115 Gy10; SD: 20 Gy10) in median 8 fractions (range, 3-17; 95% CI: 3-12), median BEDmax was 91 Gy10. BED was the only prognostic factor for LC and OS. Patients receiving BEDmax >91 Gy10 had a median OS of 24 months vs. 13 months for those receiving lower doses (p = 0.008). LC rates at 12 and 24 months were 91% and 80% for BEDmax >91 Gy10 vs. 66% and 39% for lower doses (p = 0.009). Of note, tumor size and PTV were neither predictive nor prognostic for LC and OS. Treatment tolerance was good with 17% of grade 1 gastroduodenitis, 11% of grade 2-3 cholangitis and 4.7% of grade 3 gastrointestinal bleeding. CONCLUSION: This is the largest reported series on SBRT in cholangiocarcinoma. Overall survival and local control were significantly improved after higher doses (BED) and tolerance was excellent.

Repeated Treatment with 90Y-Microspheres in Intrahepatic Cholangiocarcinoma Relapsed After the First Radioembolization.

Background: The aim of this study was to evaluate the safety and efficacy of repeated administration of 90Y-microspheres in intrahepatic cholangiocarcinoma (ICC) relapsed after the first radioembolization (RE). Methods: Nine patients with ICC relapsed after the first 90Y-RE were enrolled. Six patients presented recurrence in the right hepatic lobe, 3 in the left lobe. All subjects underwent a second administration of 90Y-resin microspheres. Toxicity was assessed according to Common Terminology Criteria for Adverse Events (CTCAE, version 4.02). After the repeated treatment, all patients were submitted to follow-up with laboratory, imaging, and clinical examinations. Results: The mean cumulative activity administered considering both treatments was 2.7 ± 0.5 GBq. After the second treatment, 3 patients presented complete metabolic response (33.3%) and 6 had partial response (66.6%). The following adverse events were registered: transient increased levels of liver enzymes (grade 1 = 4; grade 2 = 2), hyperbilirubinemia (grade 1 = 2), ascites (grade 2 = 1), and duodenal ulcer (grade 2 = 1). Two patients developed a significant shrinking of the targeted hepatic lobe, as for radiation lobectomy. No case of RE-induced liver disease was registered. Median overall survival was 16.5 ± 1.4 months after the first RE. Conclusions: The authors' results suggest that repeated administration of 90Y-microspheres may be considered in patients affected by ICC relapsed after the first 90Y-RE.

Dose and Location of Irradiation Determine Survival for Patients with Hepatocellular Carcinoma with Macrovascular Invasion in External Beam Radiation Therapy.

AIM: Prognosis of hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) is extremely poor. However, proper therapeutic strategies have not been established yet. The purpose of this study is to identify the effects of external beam radiation therapy (EBRT) for MVI of HCC. METHODS: We have analyzed and evaluated 80 consecutive patients with HCC with MVI who underwent EBRT, and factors associated with enhanced survival in EBRT were evaluated by univariate and multivariate analysis. RESULTS: The local response rate of radiotherapy for the irradiated MVI was 66.2%. The time to progression of the irradiated MVI was 5.8 months. Univariate and multivariate analyses showed that the higher irradiation dose (over 45 Gy) and the irradiation location (hepatic vein tumor thrombus - HVTT) were significant factors associated with survival benefits of EBRT. The response of EBRT for HVTT was significantly superior to that for portal vein or bile duct tumor thrombus. CONCLUSION: We conclude that a multidisciplinary therapeutic strategy based on EBRT should be proactively selected in the treatment of advanced HCC with MVI.

Individualized Adaptive Stereotactic Body Radiotherapy for Liver Tumors in Patients at High Risk for Liver Damage: A Phase 2 Clinical Trial.

IMPORTANCE: Patients with preexisting liver dysfunction could benefit the most from personalized therapy for liver tumors to balance maximal tumor control and minimal risk of liver failure. We designed an individualized adaptive trial testing the hypothesis that adapting treatment based on change in liver function could optimize the therapeutic index for each patient. OBJECTIVE: To characterize the safety and efficacy of individualized adaptive stereotactic body radiotherapy (SRBT) for liver tumors in patients who have preexisting liver dysfunction. DESIGN, SETTING, AND PARTICIPANTS: From 2010 to 2014, 90 patients with intrahepatic cancer treated with prior liver-directed therapy were enrolled in this large phase 2, single-arm, clinical trial at an academic medical center. All patients had at least 1 year of potential follow-up. INTERVENTIONS: Using indocyanine green retention at 15 minutes (ICGR15) as a direct biomarker of liver function and a Bayesian adaptive model, planned SBRT was individually modified midway through the course of therapy to maintain liver function after the complete course. MAIN OUTCOMES AND MEASURES: The primary outcome was local control; the secondary outcome was safety and overall survival. RESULTS: Patients were 34 to 85 years of age, and 70% (63) were male. Ninety patients (69 [77%] with hepatocellular carcinoma, 4 [4%] with intrahepatic cholangiocarcinoma, and 17 [19%] with metastatic) received treatment to 116 tumors. Sixty-two patients (69%) had cirrhosis, 21 (23%) were Child-Pugh (CP) grade B. The median tumor size was 3 cm; 16 patients (18%) had portal vein involvement. Sixty-two (69%) received all 5 fractions (47 full dose, 15 dose-reduced owing to rising ICGR15). Treatment was well tolerated, with a lower than expected complication rate without adaptation: 6 (7%) experienced a 2-point decline in CP 6 months post-SBRT. The 1- and 2-year local control rates were 99% (95% CI, 97%-100%) and 95% (95% CI, 91%-99%), respectively. CONCLUSIONS AND RELEVANCE: We demonstrated that the treatment strategy of individualized adaptive therapy based on a direct biomarker of liver function can be used to achieve both high rates of local control and a high degree of safety without sacrificing either. Individualized adaptive radiotherapy may represent a new treatment paradigm in which dose is based on individual, rather than population-based, tolerance to treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01522937.

Yttrium-90 microsphere radioembolization in unresectable intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma is increasing in frequency worldwide, but radical surgical treatment is practicable in 30-40% of cases. The median survival without therapy is about 8 months, increased to 12 months in combination with systemic chemotherapy. Therefore, locoregional therapies, such as, radiofrequency ablation or transarterial chemoembolization have been employed. Radioembolization with yttrium-90 microspheres (90Y-TARE) is a novel intrarterial treatment which could be included in the armamentarium of treatment options, having shown higher median survival (up to 22 months) and low complication rates. Evidence-based algorithms for staging and allocation to treatment should be defined in the future, after robust results obtained through randomized controlled trials, thus establishing the exact role and timing of 90Y-TARE in the treatment protocol of unresectable intrahepatic cholangiocarcinoma.

External beam radiation therapy with or without concurrent chemotherapy for patients with unresectable locally advanced hilar cholangiocarcinoma.

BACKGROUND/AIMS: To evaluate the efficacy of concurrent chemoradiotherapy (CCRT) compared to radiotherapy (RT) for unresectable, locally advanced hilar cholangiocarcinoma (HCCA). METHODOLOGY: Between 2001 and 2010, 34 patients with unresectable locally advanced HCCA at our institute were reviewed. Eighteen patients received RT and 16 patients received CCRT. Survivals and multivariate analyses were performed to explore potential variables affecting survivals. RESULTS: There were 18 males and 16 females, with a median age of 72 years and median follow-up time 9.4 months. The median overall survival (OS) was 10.4 months (95% CI, 6.7-13.5) with the 1-year survival rates of 41%. The median OS and progression-free survival (PFS) were 13.5 months and 8.8 months for patients receiving CCRT as compared to 6.7 months and 4.4 months for patients receiving RT alone (p = 0.003 and p = 0.005, respectively). On multivariate analysis demonstrated that Karnofsky performance status (KPS) ≥ 80 (p = 0.001), pretreatment carbohydrate antigen 19-9 (CA 19-9) 200 U/ml (p = 0.045) and CCRT were prognostic factors for OS and PFS. CONCLUSIONS: As compared with RT, CCRT provides longer OS and PFS for patients with unresectable HCCA. The efficacy of adding novel chemotherapeutic to RT needs to be further investigated.

Predictors of toxicity associated with stereotactic body radiation therapy to the central hepatobiliary tract.

PURPOSE: To identify dosimetric predictors of hepatobiliary (HB) toxicity associated with stereotactic body radiation therapy (SBRT) for liver tumors. METHODS AND MATERIALS: We retrospectively reviewed 96 patients treated with SBRT for primary (53%) or metastatic (47%) liver tumors between March 2006 and November 2013. The central HB tract (cHBT) was defined by a 15-mm expansion of the portal vein from the splenic confluence to the first bifurcation of left and right portal veins. Patients were censored for toxicity upon local progression or additional liver-directed therapy. HB toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0. To compare different SBRT fractionations, doses were converted to biologically effective doses (BED) by using the standard linear quadratic model α/ß = 10 (BED10). RESULTS: Median follow-up was 12.7 months after SBRT. Median BED10 was 85.5 Gy (range: 37.5-151.2). The median number of fractions was 5 (range: 1-5), with 51 patients (53.1%) receiving 5 fractions and 29 patients (30.2%) receiving 3 fractions. In total, there were 23 (24.0%) grade 2+ and 18 (18.8%) grade 3+ HB toxicities. Nondosimetric factors predictive of grade 3+ HB toxicity included cholangiocarcinoma (CCA) histology (P<.0001), primary liver tumor (P=.0087), and biliary stent (P<.0001). Dosimetric parameters most predictive of grade 3+ HB toxicity were volume receiving above BED10 of 72 Gy (VBED1072) ≥ 21 cm(3) (relative risk [RR]: 11.6, P<.0001), VBED1066 ≥ 24 cm(3) (RR: 10.5, P<.0001), and mean BED10 (DmeanBED10) cHBT ≥14 Gy (RR: 9.2, P<.0001), with VBED1072 and VBED1066 corresponding to V40 and V37.7 for 5 fractions and V33.8 and V32.0 for 3 fractions, respectively. VBED1072 ≥ 21 cm(3), VBED1066 ≥ 24 cm(3), and DmeanBED10 cHBT ≥14 Gy were consistently predictive of grade 3+ toxicity on multivariate analysis. CONCLUSIONS: VBED1072, VBED1066, and DmeanBED10 to cHBT are associated with HB toxicity. We suggest VBED1072 < 21 cm(3) (5-fraction: V40 < 21 cm(3); 3-fraction: V33.8 < 21 cm(3)), VBED1066 < 24 cm(3) (5-fraction: V37.7 < 24 cm(3); 3-fraction: V32 < 24 cm(3)) as potential dose constraints for the cHBT when clinically indicated.

Placement of ¹²5I seed strands and stents for a type IV Klatskin tumor.

Herein, we report a new technique that consists of placing two (125)I seed strands and two stents in the right and left intrahepatic bile ducts for the treatment of hilar cholangiocarcinoma. A 75-year-old man presented with jaundice and was diagnosed with Bismuth type IV Klatskin tumor. Abdominal computed tomography (CT) showed intrahepatic and extrahepatic bile duct dilatation and a soft tissue mass in the hepatic hilum. Because curative surgical resection was not possible, we placed (125)I seed strands and stents in the right and left intrahepatic bile ducts. Three months later, abdominal CT showed less intrahepatic and extrahepatic bile duct dilatation than before the procedure. This technique was feasible and could be considered for the treatment of patients with Bismuth type IV tumors.

Association between cellular radiosensitivity and G1/G2 checkpoint proficiencies in human cholangiocarcinoma cell lines.

Cholangiocarcinoma is a destructive malignancy with a poor prognosis and lack of effective medical treatment. Radiotherapy is an alternative treatment for patients with unresectable cholangiocarcinoma. However, there are limited data on the radiation responsiveness of individual cholangiocarcinoma cells, which is a key factor that influences radiation treatment outcome. In this study, we found that cholangiocarcinoma cell lines differ remarkably in their radiosensitivity. The variation of radiosensitivity of cholangiocarcinoma cells correlates with their p53 status and existing G1 and/or G2 checkpoint defects. We also demonstrated the potential of checkpoint kinase Chk1/2 inhibition on the enhancement of the radiosensitivity of cholangiocarcinoma cells. Thus, this study provides useful information for predicting radiation response and provides evidence for the enchantment of radiotherapeutic efficiency by targeting checkpoint kinase Chk1/2 in some subpopulations of cholangiocarcinoma patients.

Neoadjuvant chemoradiotherapy followed by liver transplantation for unresectable cholangiocarcinoma: a single-centre national experience.

BACKGROUND: Unresectable cholangiocarcinoma (CCA) has a dismal prognosis. Initial studies of orthotopic liver transplantation (OLT) alone for CCA yielded disappointing outcomes. The Mayo Clinic demonstrated long-term survival using neoadjuvant chemoradiotherapy followed by OLT in selected patients with unresectable CCA. This study reports the Irish National Liver Transplant Programme experience of neoadjuvant therapy and OLT for unresectable CCA. MATERIALS AND METHODS: Twenty-seven patients with CCA were selected for neoadjuvant chemoradiotherapy in a single centre from October 2004 to September 2011. Patients were given brachytherapy, external beam radiotherapy and 5-fluorouracil (5-Fu), followed by liver transplantation if progression free (20 patients). RESULTS: Twenty progression-free patients after neoadjuvant therapy underwent OLT. Hospital mortality was 20%. Of the 16 patients who left hospital, survival rates were 94% and 61% at 1 and 4 years. Seven patients developed recurrent disease and died at intervals of 10-58 months after OLT, whereas 9 are disease free with a median follow-up of 37 months (18-76). Predictors of disease recurrence were a tumour in explant specimen and high CA 19.9 levels. DISCUSSION: In selected patients with unresectable CCA, long-term survival can be achieved using neoadjuvant chemoradiotherapy and OLT although short-term mortality is high. Prospective international registries may aid patient selection and refinement of neoadjuvant regimens.

Neoadjuvant therapy for downstaging of locally advanced hilar cholangiocarcinoma: a systematic review.

BACKGROUND: Hilar cholangiocarcinoma is a rare but highly lethal type of cancer. A minority of patients present with resectable disease. Surgery remains the only treatment modality offering a chance of long-term survival. Unresectable patients are typically offered palliative treatment. The aim of this systematic review was to summarize the evidence for neoadjuvant therapy followed by surgical resection in patients presenting with hilar cholangiocarcinoma. METHODS: Cochrane databases, Medline, PubMed and EMBASE were systematically searched to identify articles describing neoadjuvant therapy and surgical resection or re-assessment of resectability in patients with hilar cholangiocarcinoma. Included were all articles with original research. Study selection and data extraction were performed separately by two reviewers using a standardized protocol. RESULTS: From 732 articles 8 full text articles and 2 abstracts met the inclusion criteria. The 2 abstracts and 1 full text article were case reports, 3 articles were retrospective and 4 were prospective studies (2 phase I and 2 phase II studies). Photodynamic therapy, chemotherapy and radiation therapy were used in various indications in populations that included patients with hilar cholangiocarcinoma, some of which were primarily unresectable. Overall quality of articles was limited. CONCLUSION: Current evidence suggests that neoadjuvant therapy in patients with unresectable hilar cholangiocarcinoma can be performed safely and in a selected group of patients can lead to subsequent surgical R0 resection. Surgical resection of downstaged patients should be assessed in properly designed phase II studies.

Comparison of computed tomography- and positron emission tomography-based radiotherapy planning in cholangiocarcinoma.

INTRODUCTION: The aim of this study was to compare computed tomography (CT)- and positron emission tomography (PET)/CT-based gross tumor volume (GTV) delineation and its subsequent expansion to the planning target volume (PTV), and to analyze the resultant doses of 3-dimensional conformal radiotherapy (3D-CRT) to critical organs. METHODS: 15 patients with unresectable extrahepatic cholangiocarcinoma (EHCC) were enrolled into this study. PTVCT-based plans were initially made, and then PTVPET-CT-based plans were created using the same beam angles and isocenter. The dosimetric parameters analyzed included GTVCT, PTVCT, GTVPET-CT and PTVPET-CT. Prescribed and delivered radiation doses to target volumes and delineated organs at risk were also compared. RESULTS: Mean GTV and PTV were significantly reduced in the PET/CT-based plan compared to the CT-based plan; the mean reductions of GTV and PTV were 28.7% and 15.2%, respectively. The mean value for GTVPET/GTVCT mismatch was 49.5 ± 28.9%, and that for GTVCT/GTVPET was 95.9 ± 19.5%. The mean value for PTVPET-CT/PTVCT mismatch was 21.9 ± 7.0% and that for PTVCT/PTVPET-CT was 39.1 ± 9.2%. Liver doses were significantly reduced (17.1%) in the PET/CT-based plan compared to the CT-based plan; the doses received by at least 30% and 50% of the liver were 30.0%, and 27.3%, respectively. CONCLUSION: The potential benefit of PET/CT is the reduction in geographic misses and regional treatment failures associated with CT-based planning.

Photodynamic therapy for cholangiocarcinoma using low dose mTHPC (Foscan(®)).

BACKGROUND: Photodynamic therapy (PDT) combined with stenting is an effective treatment modality for palliation of nonresectable cholangiocarcinoma (CC). A drawback of standard PDT using Photofrin(®) as photosensitizer is the long lasting skin photosensitivity of up to 3 months. The aim of this study was to show the outcome of PDT of CC, potential side effects and to determine the best drug light interval (DLI) using mTHPC (Foscan(®)) at a low dose. METHODS: 13 patients with nonresectable CC were treated with stenting and PDT (3mg Foscan(®) per treatment, 0.032-0.063 mg/kg body weight, 652 nm, 50 J/cm). Fluorescence measurements were performed with a single bare fiber for 5/13 patients prior to PDT at the tumor site to determine the fluorescence contrast. For another 7/13 patients, long-term fluorescence-kinetics were measured on the oral mucosa to determine the time of maximal relative fluorescence intensity. RESULTS: The results so far indicate a median survival time of 13 months. Side effects such as perforations or skin phototoxicity could not be observed. Foscan(®) fluorescence within the tumor site was clearly detectable but a significant fluorescence contrast of tumor to adjacent healthy tissue could not be found. The fluorescence kinetics measured in the oral mucosa showed a maximum at 3.85 days (median) after drug administration. CONCLUSION: Combined stenting and PDT performed with a low Foscan(®) dose results in equal and potentially longer survival times compared to standard Photofrin(®) PDT, while lowering the risk of side effects strongly. Thus it may improve the quality of life.

Treatment modification of yttrium-90 radioembolization based on quantitative positron emission tomography/CT imaging.

Treatment activity for yttrium-90 ((90)Y) radioembolization when calculated by using the manufacturer-recommended technique is only partially patient-specific and may result in a subtumoricidal dose in some patients. The authors describe the use of quantitative (90)Y positron emission tomography/computed tomography as a tool to provide patient-specific optimization of treatment activity and evaluate this new method in a patient who previously received traditional (90)Y radioembolization. The modified treatment resulted in a 40-Gy increase in absorbed dose to tumor and complete resolution of disease in the treated area within 3 months.

Prognostic factors and prevention of radioembolization-induced liver disease.

UNLABELLED: Radioembolization (RE)-induced liver disease (REILD) has been defined as jaundice and ascites appearing 1 to 2 months after RE in the absence of tumor progression or bile duct occlusion. Our aims were to study the incidence of REILD in a large cohort of patients and the impact of a series of changes introduced in the processes of treatment design, activity calculation, and the routine use of ursodeoxycholic acid and low-dose steroids (modified protocol). Between 2003 and 2011, 260 patients with liver tumors treated by RE were studied (standard protocol: 75, modified protocol: 185). REILD appeared only in patients with cirrhosis or in noncirrhosis patients exposed to systemic chemotherapy prior to RE. Globally, the incidence of REILD was reduced in the modified protocol group from 22.7% to 5.4% and the incidence of severe REILD from 13.3% to 2.2% (P<0.0001). Treatment efficacy was not jeopardized since 3-month disease control rates were virtually identical in both groups (66.7% and 67.2%, P=0.93). Exposure to chemotherapy in the 2-month period following RE and being treated by the standard protocol were independent predictors of REILD among noncirrhosis patients. In cirrhosis, the presence of a small liver (total volume<1.5 L), an abnormal bilirubin (>1.2 mg/dL), and treatment in a selective fashion were independently associated with REILD. CONCLUSION: REILD is an uncommon but relevant complication that appears when liver tissue primed by cirrhosis or prior and subsequent chemotherapy is exposed to the radiation delivered by radioactive microspheres. We designed a comprehensive treatment protocol that reduces the frequency and the severity of REILD.

Determining a minimal safe distance to prevent thermal injury to intrahepatic bile ducts in radiofrequency ablation of the liver: a study in dogs.

PURPOSE: To determine a minimal safe distance between the radiofrequency ablation (RFA) electrode tip and major intrahepatic bile ducts to prevent thermal injury during hepatic RFA in a canine model. MATERIALS AND METHODS: Forty healthy mongrel dogs were randomised equally into four groups based on the distance between the electrode and large intrahepatic bile ducts during RFA of the liver, as follows: 1.0-2.9 mm, 3.0-4.9 mm, 5.0-7.9 mm, or 8.0-10.0 mm. The RFA electrodes were opened uniformly at 2 cm. During RFA, energy was sequentially raised, starting at 5 W and increasing by 5 W increments every minute to a maximum of 95 W. Animals were monitored for a maximum of 14 days post-RFA for complications and by bilirubin testing, after which they were euthanised and their livers were surgically removed for cholangiographic and pathological examination. RESULTS: When the electrodes were less than 5.0 mm from the bile ducts during RFA, either full or partial-thickness bile duct necrosis occurred, leading to a variety of serious complications. In contrast, when the distance was more than 5.0 mm between the RFA electrode and bile ducts, serious complications occurred rarely, with pathological examinations showing either normal bile ducts or vacuolar changes of the biliary ductal epithelium. CONCLUSION: A minimum safe distance of 5.0 mm between the RFA electrode and intrahepatic bile ducts was effective in preventing serious complications secondary to bile duct injury in a canine model.

Transarterial hepatic yttrium-90 radioembolization in patients with unresectable intrahepatic cholangiocarcinoma: factors associated with prolonged survival.

INTRODUCTION: In unresectable intrahepatic cholangiocarcinoma (ICC), systemic chemotherapy often is viewed as the only option, although efficacy is limited. Radioembolization (RE) using yttrium-90 ((90)Y) microspheres is an accepted therapy for patients with hepatocellular-carcinoma or metastatic liver tumors. However, there are limited data on the value of RE in patients with ICC and few data on factors influencing prognosis. The purpose of our retrospective analysis was to establish which factors influenced time-to-progression (TTP) and overall survival (OS). METHODS: Patients with unresectable ICC were treated with (90)Y resin-microspheres and assessed at 3-monthly intervals. Radiologic response was evaluated by using Response Criteria in Solid Tumors (RECIST). Baseline characteristics, biochemical/clinical toxicities, and response were examined for impact on TTP and OS. RESULTS: Thirty-four treatments were administered to 33 patients without major complications. By RECIST, 12 patients had a partial response, 17 had stable disease, and 5 had progressive disease after 3 months. The median OS was 22 months posttreatment and 43.7 months postdiagnosis. Median TTP was 9.8 months. Survival and TTP were significantly prolonged in patients with ECOG 0 (vs. ECOG 1 or 2; median OS: 29.4, 10, and 5.1 months; TTP: 17.5, 6.9, and 2.4 months), tumor burden ≤25% (OS: 26.7 vs. 6 months; TTP: 17.5 vs. 2.3 months), or tumor response (PR or SD vs. PD; OS: 35.5, 17.7 vs. 5.7 months; TTP: 31.9, 9.8 vs. 2.5 months), respectively (P < 0.001). CONCLUSIONS: Radioembolization is an effective and safe option for patients with unresectable ICC. Predictors for prolonged survival are performance status, tumor burden, and RECIST response.

Intrahepatic biliary injuries associated with radiofrequency ablation of hepatic malignancies.

BACKGROUND: Biliary injury after radiofrequency ablation can cause serious consequences including death. However, there are limited data regarding bile duct changes with or without complications associated with radiofrequency ablation of hepatic malignancies. This study aimed to assess the incidence, prognosis and risk factors of intrahepatic biliary injury associated with radiofrequency ablation. METHODS: Between June 2001 and January 2009, 638 patients with hepatic malignancies (405 with hepatocellular carcinoma, and 233 with liver metastasis) who had 955 treatment sessions were enrolled in this study. Imaging and laboratory data, the course of treatment, and patient outcomes were reviewed retrospectively. The risk factors of biliary injury and the impact on overall survival of patients were analyzed. The chi-square test, Fisher's exact test, Kaplan-Meier curves and stepwise Logistic regression model were used for statistical analysis where appropriate. RESULTS: Biliary injury was observed in 17 patients after 17 ablation sessions based on imaging findings. The overall incidence of biliary injury was 1.8% (17/955) with an average onset time of 12 weeks (2-36 weeks). Mild, moderate and severe complications of biliary injury were identified in 9, 6 and 2 cases, respectively. The median survival time after detection of biliary injury was 40 months. There seemed no notable difference in overall survival between patients with and those without biliary injuries. By multivariate analysis, vessel infiltration (P = 0.034) and treatment session ≥ 4 times (P = 0.025) were independent risk factors for biliary injury of hepatocellular carcinoma; while tumor located centrally was the only independent risk factor in the metastasis group (P = 0.043). CONCLUSIONS: The incidence of biliary injury was not frequent (1.8%). Through appropriate treatment, intrahepatic bile duct injuries seemed not affect the patients' long-term survival. Additionally, risk factors may be helpful for selecting radiofrequency ablation candidates and predicting biliary complications.