Biliary drainage combined with simultaneous 125I seed strand brachytherapy for the treatment of hilar cholangiocarcinoma.

BACKGROUND: To evaluate the clinical efficacy of percutaneous biliary drainage (PBD) combined with 125I seed strand brachytherapy (ISSB) for the treatment of hilar cholangiocarcinoma (HCCA). METHODS: The clinical data of 64 patients with HCCA (median age 62.5, male 29, female 35) treated in our department from April 2017 to April 2021 were retrospectively analyzed. Thirty-four patients in the experimental group (EG) were treated with PBD combined with ISSB, while 30 patients in the control group (CG) were treated with PBD alone. The primary study endpoints were technical success, clinical success and the 2-month local tumor control (LTC) rate. Secondary endpoints were early/late complications, median progression-free survival (mPFS) and overall survival (mOS). RESULTS: The technical and clinical success in the EG and CG showed no significant differences (100 vs. 100%, 94.1 vs. 93.3%, P > 0.05). Both early and late complications showed no significant differences between the two groups (P > 0.05). The 2-month LTC rates were significantly better in the EG versus the CG (94.1% vs. 26.7%, 157.7 ± 115.3 vs. 478.1 ± 235.3 U/ml), respectively (P < 0.05). The mPFS and mOS were 4.3 (95% CI 3.9-4.7) months and 2.8 (95% CI 2.5-3.1) months and 13.5 (95% CI 10.7-16.3) months and 8.8 (95% CI 7.8-9.8) months, respectively, with significant differences (P < 0.05). CONCLUSION: PBD combined with ISSB is a safe and effective treatment for HCCA that can inhibit local tumors and prolong PFS and OS.

[A Case of Pulmonary Metastasis from Hilar Cholangiocarcinoma Treated by Stereotactic Body Radiotherapy].

We report a case of pulmonary metastasis from hilar cholangiocarcinoma successfully treated by stereotactic body radiotherapy. The patient was a 70-year-old woman who underwent extended left hemi-hepatectomy with bile duct reconstruction for hilar cholangiocarcinoma at the age of 67. Pathological diagnosis indicated a well-differentiated adenocarcinoma. We followed up the patient without adjuvant chemotherapy. Nineteen months after the initial resection, a solitary pulmonary metastasis was detected in the right upper lobe. The patient received gemcitabine plus cisplatin(GC)therapy. After 4 courses of GC therapy, the size of the pulmonary metastasis was unchanged. Therefore, we performed a thoracoscopic wedge resection. Pathological diagnosis indicated that the pulmonary metastasis originated from the cholangiocarcinoma. Fifteen months after the pulmonary resection, another solitary pulmonary metastasis was detected in the left lower lobe. As the patient refused further chemotherapy, we performed stereotactic body radiotherapy(SBRT)(50 Gy/4 Fr). An adverse event of Grade 1 radiation pneumonitis was observed. The metastasis disappeared after SBRT. Twenty-eight months after SBRT and 70 months after the initial surgery, the patient is alive without recurrence.

Nutritional prognostic scores in patients with hilar cholangiocarcinoma treated by percutaneous transhepatic biliary stenting combined with 125I seed intracavitary irradiation: A retrospective observational study.

We mainly aimed to preliminarily explore the prognostic values of nutrition-based prognostic scores in patients with advanced hilar cholangiocarcinoma (HCCA).We retrospectively analyzed 73 cases of HCCA, who underwent percutaneous transhepatic biliary stenting (PTBS) combined with I seed intracavitary irradiation from November 2012 to April 2017 in our department. The postoperative changes of total bilirubin (TBIL), direct bilirubin (DBIL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin (ALB) were observed. The preoperative clinical data were collected to calculate the nutrition-based scores, including controlling nutritional status (CONUT), C-reactive protein/albumin ratio (CAR), and prognostic nutritional index (PNI). Kaplan-Meier curve and Cox regression model were used for overall survival (OS) analyses.The serum levels of TBIL, DBIL, ALT, AST, and ALP significantly reduced, and ALB significantly increased at 1 month and 3 months postoperatively. The median survival time of the cohort was 12 months and the 1-year survival rate was 53.1%. Univariate analysis revealed that the statistically significant factors related to OS were CA19-9, TBIL, ALB, CONUT, and PNI. Multivariate analysis further identified CA19-9, CONUT, and PNI as independent prognostic factors.Nutrition-based prognostic scores, CONUT and PNI in particular, can be used as predictors of survival in unresectable HCCA.

Adjuvant Therapy Is Associated With Improved Survival in Resected Perihilar Cholangiocarcinoma: A Propensity Matched Study.

BACKGROUND: There are limited well-controlled studies that conclusively demonstrate a benefit of adjuvant therapy in resected perihilar cholangiocarcinoma. Most studies include all biliary tract tumors as one entity despite the heterogeneity of these diseases. METHODS: We identified patients with resected perihilar cholangiocarcinoma from the National Cancer Database between 2006 and 2013. Patients who received adjuvant therapy (AT) were compared to an observation (OB) cohort by propensity score matching. RESULTS: We identified 1846 patients: 1053 patients (57%) in the OB group, and 793 (43%) in the AT group. Patients who received adjuvant therapy were more likely to be younger, have a higher rate of private insurance, have higher T and N stage tumors, and were more likely to have positive resection margins. After 1:1 propensity score matching, 577 OB group patients were compared with 577 AT group patients. The AT cohort was associated with better overall survival compared with the OB cohort (hazard ratio [HR] 0.73; 95% confidence interval [CI] 0.64-0.83). The median survival was 29.5 and 23.3 months for the AT and OB groups, respectively (P < 0.01). Subgroup analysis demonstrated a survival advantage for adjuvant therapy in disease with positive resection margins (HR 0.53; 95% CI 0.42-0.67). CONCLUSIONS: Adjuvant therapy is associated with improved survival in resected perihilar cholangiocarcinoma, especially in disease with positive resection margins. This study supports the use of adjuvant therapy in high-risk patients.

Benefit of neoadjuvant concurrent chemoradiotherapy for locally advanced perihilar cholangiocarcinoma.

AIM: To clarify the role of neoadjuvant concurrent chemoradiotherapy (NACCRT) followed by surgical resection for localized or locally advanced perihilar cholangiocarcinoma (CCA). METHODS: We retrospectively reviewed 57 patients who underwent surgical resection with or without NACCRT for perihilar CCA; 12 patients received NACCRT and 45 patients did not received NACCRT. Patients with locally advanced perihilar CCA requiring NACCRT were defined as follows: (1) a mass involving unilateral branches of the portal vein or hepatic artery with insufficient volume of the anticipated remnant lobe; or (2) an infiltrating mass in the main portal vein that was too long for reconstruction, identified at preoperative staging. RESULTS: The median disease-free survival (DFS) durations of the neoadjuvant and non-neoadjuvant CCRT groups were 26.0 and 15.1 mo, respectively (P = 0.91). The median overall survival (OS) durations of the neoadjuvant and non-neoadjuvant CCRT groups were 32.9 and 27.1 mo, respectively (P = 0.26). The NACCRT group showed a downstaging tendency compared to the non-NACCRT group as compared with the tumor stage confirmed by histological examination after surgery and the tumor stage confirmed by imaging test at the time of diagnosis (P = 0.01). CONCLUSION: NACCRT does not prolong DFS and OS in localized or locally advanced perihilar CCA. However, NACCRT may allow tumor downstaging and improve tumor resectability.

A pilot study of concurrent chemoradiotherapy with gemcitabine and cisplatin in patients with locally advanced biliary tract cancer.

PURPOSE: Combination chemotherapy with gemcitabine and cisplatin is a standard treatment for patients with advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of gemcitabine- and cisplatin-based concurrent chemoradiotherapy in patients with unresectable biliary tract cancer. METHODS: Patients with pathologically proven, unresectable, non-metastatic biliary tract cancer were enrolled. Gemcitabine was administered intravenously at a dose of 1000 mg/m(2) on days 1, 8, and 15. Cisplatin was administered intravenously at a dose of 70 mg/m(2) on day 1. All the patients underwent concurrent radiotherapy with 45 Gy in 1.8-Gy daily fractions. After treatment completion, tumor response was evaluated by using computed tomography. RESULTS: Eighteen patients were enrolled between June 2007 and October 2011. Their median age was 61 years (range, 38-72 years). Eight patients (44.5 %) were diagnosed with gallbladder cancer, six (33.3 %) with Klatskin's tumor, and four (22.2 %) with distal common bile duct cancer. After treatment completion, partial response was achieved in five patients (27.8 %) and stable disease in 13 patients (72.2 %). The overall response rate was 27.8 %, and the disease stabilization rate was 100 %. No grade 4 adverse events or treatment-related deaths occurred. The most common grade 3 adverse events were thrombocytopenia (33.3 %) and anemia (11.1 %). The median progression-free and overall survival times were 6.8 months (range, 4.5-19.8 months) and 9.6 months (5.4-30.4 months), respectively. CONCLUSIONS: This study shows that gemcitabine- and cisplatin-based concurrent chemoradiotherapy is feasible and tolerable in patients with unresectable and non-metastatic biliary tract cancer.

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.

Successful management of inoperable klatskin's tumour by high dose intra luminal brachytherapy without the need for post radiation stenting.

We present a case of Klatskin's tumour managed by high dose Intra Luminal Brachytherapy without the need for post radiation stenting. We achieved significant reduction in the cost of treatment and avoided complications associated with stenting. We were able to attain a symptom and disease free survival period of 30 months till the patient finally succumbed to metastatic peritoneal disease. We assume that small Klatskin's tumours as in the presented case with a size less than 3 cms when subjected to high dose Intra Luminal Brachytherapy with the help of 3D computed planning ensuring good tumour coverage may not require post radiation assisted biliary drainage.

Defining the role of palliative radiotherapy in bone metastasis from primary liver cancer: an analysis of survival and treatment efficacy.

AIMS AND BACKGROUND: Primary liver cancer is the fourth leading cause of cancer-related death worldwide and is still associated with a poor prognosis. Hepatocellular carcinoma and cholangiocarcinoma are known to cause bone metastasis resulting in pain, neurologic impairment and risk of fracture. Palliative radiotherapy is the treatment of choice in symptomatic bone lesions and is usually performed as percutaneous fractionated radiotherapy. METHODS AND STUDY DESIGN: From June 1987 to December 2009, 41 patients (median age, 64 years) with bone metastasis received radiotherapy in our department. The analyzed patients were treated for 67 sites of bone lesions. We analyzed the applied fractionation schedules and the preferred sites of metastasis and symptoms, evaluated the therapeutic outcome in terms of symptomatic improvement, and described the prognosis of these patients. RESULTS: Main indication for palliative radiotherapy was pain in 94% of all cases. Most frequent radiation protocols were 10 x 3 Gy (20 patients) and 20 x 2 Gy (19 patients). Median applied overall dose was 39 Gy (range, 4-48 Gy) and median single dose was 2.5 Gy (range, 1.8-4 Gy). The median duration of the radiotherapeutic treatment was 15 days (range, 2-24 days) and in 12 cases treatment was discontinuated. The overall response rate to palliative radiotherapy in bone metastasis was 77%. Median overall survival in both cholangiocarcinoma and hepatocellular carcinoma patients was 4.2 months after initiation of radiotherapy (range, 0.2-38.9). CONCLUSIONS: Considering the poor prognosis of patients with bone metastasis in hepatocellular carcinoma and cholangiocarcinoma, with a poor median survival of 3.7-5.0 months according to our study and existing literature, shorter radiotherapy schedules or even single-fraction irradiation can be considered.

Chemoradiation treatment with gemcitabine plus stereotactic body radiotherapy for unresectable, non-metastatic, locally advanced hilar cholangiocarcinoma. Results of a five year experience.

BACKGROUND: Hilar cholangiocarcinoma (Klatskin tumor-KT) accounts for about 0.5-1.5% of all gastrointestinal cancers and for 40-60% of all biliary malignancies. Tumor resection is attainable in about 30-50% of patients. When resection is not possible other treatment options have little or no impact on survival. We present the results of hypofractionated Stereotactic Body Radiotherapy (SBRT) on a small series of non resectable locally advanced KT patients. MATERIALS AND METHODS: Ten patients with histologically proven KT underwent SBRT plus gemcitabine. Radiotherapy (30Gy) was delivered in three fractions. Treatment toxicity was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE v. 3.0). Alive patients with less than 1 year of follow up were excluded from the present study. Local control was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Two grade 1 and Two grade 2 acute toxicities were observed, moreover one grade 2 late toxicity was recorded. The overall local response ratio was 80% (4 PR+2 SD). SBRT showed a good efficacy in achieving local control. Median time to progression was 30 months. Two-year survival was 80% and four-year survival 30%. Six patients developed metastatic disease. Response to treatment and nodal metastases were the only independent indicators of prolonged survival. CONCLUSIONS: The chemoradiation given by SBRT plus gemcitabine is a promising treatment for non-metastatic unresectable KT. High local control rates, even compared to historical data from conventional radiotherapy, can be achieved with minimal toxicity.

Stereotactic fractionated radiotherapy for Klatskin tumours.

BACKGROUND AND PURPOSE: In spite of various efforts perihilar cholangiocellular carcinoma (Klatskin tumour) has still a bad prognosis. The treatment of patients with inoperable Klatskin tumours by stereotactic fractionated radiotherapy (SFRT) was analysed retrospectively. PATIENTS, METHODS AND MATERIALS: In our department 13 patients were treated for Klatskin tumours by SFRT (32-56 Gy, 3 x 4 Gy/week) from 1998 to 2008. The treatment technique was developed from stereotactic body frame radiotherapy to image guided (IGRT) stereotactic radiotherapy with control of patient positioning by cone beam computer tomography (CBCT). 6/13 patients received additional chemotherapy before or after SFRT. RESULTS: A median survival of 33.5 (6.6-60.4) months after diagnosis was reached by SFRT. The median time of freedom from tumour progression was 32.5 (6.1-60.4, last patient died without tumour progression) months. The therapy was tolerated very well. Nausea was the most common side effect. 5/13 patients suffered from recurrent cholangitis caused and enhanced by the primary tumour and drainages or stents in the bile ducts. CONCLUSIONS: In the context of reaching local control being still the main problem of Klatskin tumour patients, SFRT seems to be a very promising method for the treatment of these tumours.

[Palliative locoregional therapy for hilar cholangiocarcinoma: photodynamic therapy and brachytherapy]. / Palliative lokoregionäre Therapie des hilären Gallengangskarzinoms: photodynamische Therapie und Brachytherapie.

In hilar cholangiocarcinoma, only 20-30% of the patients are candidates for curative surgical resection, leaving the majority with merely palliative treatment options. Since the natural history of hilar cholangiocarcinoma is dominated by local complications rather than metastatic disease, local palliative treatment seems a reasonable option. Here, endoluminal photodynamic therapy has emerged as a promising treatment with several prospective observational studies and 2 prospective randomised studies published which included nearly 200 patients. With low complication rate and morbidity, PDT achieves an increased median survival as well as an increased quality of life even in patients with reduced performance status. Radiotherapy is an alternative local treatment option applied as brachytherapy, external beam radiotherapy or combined modality treatment. To date, however, sufficient data from controlled clinical trials are lacking, thus palliative radiotherapy has to be considered an experimental treatment option.

Klatskin tumor treated by inter-disciplinary therapies including stereotactic radiotherapy: a case report.

In view of the poor prognosis of patients with cholangiocarcinoma (CCC), there is a need for new therapeutic strategies. Inter-disciplinary therapy seems to be most promising. Radiotherapy is an effective alternative to surgery for hilar CCC (Klatskin tumors) if an adequate radiation dose can be delivered to the liver hilus. Here, we describe a patient for whom we used a stereotactic radiotherapy technique in the context of an inter-disciplinary treatment concept. We report a 45-year-old patient with a locally advanced Klatskin tumor. Explorative laparotomy showed that the tumor was not resectable. A metallic stent was implanted and the patient was treated by stereotactic radiotherapy using a body frame. A total dose of 48 Gy (3X4 Gy/wk) was administered. Therapy was well tolerated. After 32 mo, local tumor recurrence and a chest wall metastasis developed and were controlled by radio-chemotherapy. After more than 56 mo with a good quality of life, the patient died of advanced neoplastic disease. Stereotactic radiotherapy led to a long-term survival of this patient with a locally advanced Klatskin tumor. In the context of inter-disciplinary treatment concepts, this radiotherapy technique is a promising choice of treatment for patients with hilar CCC.

Concomitant gemcitabine (Gemzar) and extended nodes irradiation in the treatment of pancreatic and biliary carcinoma: a phase I study.

BACKGROUND: The rationale for combining cytotoxic agents, such as gemcitabine, and radiotherapy is based on their ability to act as radiation sensitizers and to improve overall response rate. Several studies on pancreatic or biliary carcinoma evaluated the maximum tolerated dose (MTD) of gemcitabine when combined with irradiation of the macroscopic tumor. However, most of these neoplasms metastasize to the regional lymph nodes. Aim of this report is to determine the MTD of weekly gemcitabine when combined with extended field irradiation (tumor plus nodal irradiation). PATIENTS AND METHOD: 15 patients entered the study. Of these 5 patients were treated with chemoradiation after radical surgical resection. External beam radiation (ERT) was delivered to the tumor (or tumor bed) and regional lymph nodes by using a three-field technique. The initial dose of gemcitabine was 100 mg/m(2) administered as short intravenous infusion once a week. At each dose level 3 patients were treated, and if no grade 3-4 toxicity (considered as dose-limiting toxicity, DLT) was recorded, dose escalation was applied with 50 mg/m(2) increments until the MTD was established. RESULTS: All patients were evaluable for acute toxicity. There were no treatment-related deaths. No DLT occurred at the first 4 dose levels (100-250 mg/m(2)). At the 5th dose level (300 mg/m(2)), 3 patients experienced DLT: 1 had grade 3 gastrointestinal toxicity (painful erosion of gastric mucosa), 1 had uncomplicated grade 3 leukopenia and 1 grade 3 change in liver biochemistry tests. In addition, all 10 unresected patients were evaluated for response, 4 of whom had progressive disease (1 local; 2 distant; 1 local and distant) and 6 had no change. The median follow-up was 21 months. CONCLUSION: Based on this study, the recommended dose for weekly short infusional gemcitabine combined with radiation therapy to the tumor and lymph nodes is 250 mg/m(2). This value is suggestive of a correlation between acute toxicity and inclusion of lymph nodes in the irradiated volume. Moreover, different infusion modalities, as continuous infusion gemcitabine, should be tested more accurately.

Combined external beam and intraluminal radiotherapy for irresectable Klatskin tumors.

BACKGROUND: In most cases of proximal cholangiocarcinoma, curative surgery is not possible. Radiotherapy can be used for palliative treatment. We report our experience with combined external beam and intraluminal radiotherapy of advanced Klatskin's tumors. PATIENTS AND METHODS: 30 patients were treated for extrahepatic proximal bile duct cancer. Our schedule consisted of external beam radiotherapy (median dose 30 Gy) and a high-dose-rate brachytherapy boost (median dose 40 Gy) delivered in four of five fractions, which could be applied completely in twelve of our patients. 15 patients in the brachytherapy and nine patients in the non-brachytherapy group received additional low-dose chemotherapy with 5-fluorouracil. RESULTS: The brachytherapy boost dose improved the effect of external beam radiotherapy by increasing survival from a median of 3.9 months in the non-brachytherapy group to 9.1 months in the brachytherapy group. The effect was obvious in patients receiving a brachytherapy dose above 30 Gy, and in those without jaundice at the beginning of radiotherapy (p < 0.05). CONCLUSIONS: The poor prognosis in patients with advanced Klatskin's tumors may be improved by combination therapy, with the role of brachytherapy and chemotherapy still to be defined. Our results suggest that patients without jaundice should be offered brachytherapy, and that a full dose of more than 30 Gy should be applied.

[Pre- and postoperative irradiation in the treatment of resectable Klatskin tumours]. / Pre- en postoperatieve bestraling bij de behandeling van de resectabele Klatskin-tumor.

Proximal bile duct carcinoma (Klatskin tumour) is infrequent and difficult to treat. In principle, surgery is indicated. The usefulness of irradiation after resection is controversial in the literature. This article describes the experiences gained in the Academic Medical Centre of Amsterdam with pre- and postoperative irradiation of resectable Klatskin tumours. Preoperative irradiation (10.5 Gy) is administered to devitalize detached tumour cells in the bile, to prevent implantation metastases after resection. Postoperative irradiation has been administered since 1986 according to protocol. An analysis of 71 patients, of whom 48 had been irradiated after resection while 23 had not, showed a statistically significant prolongation of survival in the group irradiated postoperatively. Radiotherapy was administered externally (55 Gy) or in combination with internal radiotherapy (45 Gy external, 10 Gy internal). For internal irradiation, the source of radiation (Iridium-192) was introduced along the bile duct anastomoses via the soma formed by the blind end of the Roux-Y jejunal loop used for bile duct reconstruction. Since internal irradiation in combination with external irradiation caused more complications, while there was no difference of survival from patients only irradiated externally, the complete postoperative irradiation is currently being given from the outside. Pre- and postoperative irradiation may contribute to the success of the treatment of the resectable Klatskin tumour.

[Percutaneous treatment of hilar cholangiocarcinoma completed by high-dose rate brachytherapy. Experience in the first 5 cases]. / Trattamento percutaneo del colangiocarcinoma ilare completato con brachiterapia con alto rateo di dose. Esperienza nei primi 5 casi.

Cholangiocarcinoma at the confluence of the hepatic ducts (Klatskin tumor) is a slowly growing malignancy with early onset of symptoms and poor outcome since surgery allows radical resection in only a minority of cases. Percutaneously placed biliary stents offer a good palliation, but tend to obstruct after 6-8 months; then, retreatment requires exchange of the endoprosthesis or establishment of a permanent external-internal biliary drainage which offers, in some patients, a relatively long survival. Percutaneous intraluminal HDR brachytherapy might be a valid alternative as a definitive therapy or as a method to keep metallic stents patent for a long time. Five patients with hilar cholangiocarcinoma, diagnosed by means of ultrasound, Computed Tomography, percutaneous transhepatic cholangiography and transluminal biopsy, underwent double percutaneous external-internal biliary drainage. Dummy sources were introduced into the drainage catheters to allow dose distribution planning. The stepwise progression of the miniaturized high activity Iridium source inside the applicators, introduced into the drainage catheters, was controlled and monitored by a computer equipped with dedicated software. In the radiotherapy bunker, using the remote loading technique, percutaneous intracavitary high dose rate brachytherapy was delivered at the rate of 750 cGy per fraction, prescribed at 1 cm from the center of the catheter, once a week, for 4 weeks. Nevertheless, only 4 of 5 patients underwent the complete treatment. In one case, radiation treatment was discontinued after the first session because of digestive bleeding from a duodenal ulcer, supposingly as a consequence of the decubitus of a catheter tip. CT demonstrated rapid progression of the disease with neoplastic spread to the omentum and gallbladder wall thickening; a gallbladder malignancy was then suspected and the patient was no more eligibile for brachytherapy. Subsequently, Carey-Coons endoprostheses were inserted to prevent post-actinic strictures and removed after three months. After completing radiation therapy, control cholangiograms demonstrated in all cases improvement of neoplastic strictures. The first two patients we treated show no signs of tumor recurrence at 4 and 1 months, respectively, after endoscopic removal of the stents. The third patient is still bearing 2 Carey-Coons endoprostheses to be removed after 3 months. The last patient with supposingly partial success of bracytherapy, was treated with two Strecker nitinol stents.