Role of adjuvant radiotherapy for localized extrahepatic bile duct cancer.

OBJECTIVE: To evaluate the benefit of adjuvant radiotherapy (RT) after surgical resection for extrahepatic bile duct (EHBD) cancer. METHODS: From 1997 to 2015, 59 patients with EHBD cancer were the subject of this study; 36 patients not undergoing adjuvant treatment after surgery (observation group) and 23 patients receiving adjuvant RT (RT group) were compared. Microscopic residual disease (R1) was in 9 (25%) patients and 5 (22%) patients, and macroscopic residual disease (R2) was in 2 (6%) patients and 6 (26%) patients in the observation and RT groups, respectively. Adjuvant RT was delivered to the tumour bed and regional lymph nodes up to 50.4 Gy (range, 45-61 Gy). RESULTS: With a median follow-up of 19 months, local recurrence was observed in 10 (28%) patients and 2 (9%) patients in the observation and RT groups, respectively. On univariate analysis, the 5-year local recurrence-free survival (LRFS) rates were 50% in the observation group and 54% in the RT group (p = 0.401). The 5-year overall survival (OS) rates were 29.3% in the observation group and 26.3% in the RT group (p = 0.602). On multivariable analysis, however, adjuvant RT significantly improved LRFS [hazard ratio (HR), 0.310; 95% confidence interval (CI), 0.100-0.963; p = 0.043] and had a trend towards increased OS (HR, 0.491; 95% CI, 0.219-1.102; p = 0.085). Resection margin (RM) status was also correlated with LRFS (HR for R1 6.134, 95% CI 2.051-18.344; and HR for R2 18.551, 95% CI 3.680-93.520; p < 0.001) and OS (HR for R1 1.816, 95% CI 0.853-3.867; and HR for R2 3.564, 95% CI 1.175-10.809; p = 0.054). CONCLUSION: RM status was a significant prognosticator of EHBD cancer, and adjuvant RT improved local control rate; thereby, survival rate might be increased. Advances in knowledge: The benefit of adjuvant RT in EHBD cancer was demonstrated via comparison with observation group.

Is c-Met oncoprotein expression an adverse prognosticator in extrahepatic bile duct cancer treated with curative resection followed by adjuvant chemoradiotherapy?

Purpose: To analyze the expression of c-Met, and to investigate correlations between the expression of c-Met, clinicopathologic variables, and survival in patients undergoing curative surgery followed by adjuvant chemoradiotherapy for extrahepatic bile duct (EHBD) cancer. Methods: Ninety EHBD cancer patients who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled. Expression of c-Met was assessed with immunohistochemical staining on tissue microarray. The correlation between clinicopathologic variables and survival outcomes was evaluated using Kaplan-Meier method and Cox proportional hazard model. Results: On univariate analysis, 66 patients (76.7 %) showed c-Met expression. c-Met expression had a significant impact on 5-year overall survival (OS) (43.0 % in c-Met(+) vs. 25.0 % in c-Met(-), p = 0.0324), but not on loco-regional relapse-free survival or distant metastasisfree survival (DMFS). However, on multivariate analysis incorporating tumor location and nodal involvement, survival difference was not maintained (p = 0.2940). Tumor location was the only independent prognostic factor predicting OS (p = 0.0089). Hilar location tumors, nodal involvement, and poorly differentiated tumors were all identified as independent prognostic factors predicting inferior DMFS (p = 0.0030, 0.0013, and 0.0037, respectively). Conclusions: This study showed that c-Met expression was not associated with survival outcomes in EHBD cancer patients undergoing curative resection followed by adjuvant chemoradiotherapy. Further studies are needed to fully elucidate the prognostic value of c-Met expression in these patients (AU)

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Surgery Alone Versus Surgery Followed by Chemotherapy and Radiotherapy in Resected Extrahepatic Bile Duct Cancer: Treatment Outcome Analysis of 336 Patients.

PURPOSE: This study analyzed the outcomes of patients with resected extrahepatic bile duct cancer (EHBDC) in order to clarify the role of adjuvant treatments in these patients. MATERIALS AND METHODS: A total of 336 patients with EHBDC who underwent curative resection between 2001 and 2010 were analyzed retrospectively. The treatment types were as follows: surgery alone (n=168), surgery with chemotherapy (CTx, n=90), surgery with radiotherapy (RT) alone (n=29), and surgery with chemoradiotherapy (CRT, n=49). RESULTS: The median follow-up period was 63 months. The 5-year rates of locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) for all patients were 56.5%, 59.7%, 36.6%, and 42.0%, respectively. In multivariate analysis, surgery with RT and CRT was a significant prognostic factor for LRFFS, and surgery with CTx was a significant prognostic factor for DMFS, and surgery with CTx, RT, and CRT was a significant prognostic factor for PFS (p < 0.05). Surgery with CTx and CRT showed association with superior OS (p < 0.05), and surgery with RT had marginal significance (p=0.078). In multivariate analysis of the R1 resection patients, surgery with CRT showed significant association with OS (p < 0.05). CONCLUSION: Adjuvant RT and CTx may be helpful in improving clinical outcomes of patients with resected EHBDC who have a high risk of disease recurrence, particularly R1 resection patients. Conduct of additional prospective, larger-scale studies will be required in order to confirm the benefit of adjuvant RT and CTx in these patients.

Chemoradiotherapy for extrahepatic bile duct cancer with gross residual disease after surgery.

BACKGROUND: The purpose of the present study was to analyze the outcome of chemoradiotherapy for extrahepatic bile duct (EHBD) cancer patients with gross residual disease after surgical resection. PATIENTS AND METHODS: We retrospectively analyzed 30 patients with EHBD adenocarcinoma who underwent chemoradiotherapy after palliative resection (R2 resection). Postoperative radiotherapy was delivered to the tumor bed including residual tumor and regional lymph nodes (range=40-55.8 Gy). Most patients underwent chemoradiotherapy concurrently with 5-fluorouracil (5-FU) or gemcitabine. RESULTS: The 2-year locoregional progression-free, distant metastasis-free and overall survival rates were 33.3%, 42.4% and 44.5%, respectively. High radiation dose≥50 Gy had a marginally significant impact on superior locoregional progression-free survival compared to 40 Gy (p=0.081). One patient developed grade 3 late gastrointestinal toxicity. CONCLUSION: Adjuvant chemoradiotherapy for EHBD cancer patients with gross residual disease after surgery was well-tolerated. There could be a chance for durable locoregional control and even long-term survival in selected patients.

Obstructive component analysis of radioactive stents and common plastic stents in the bile duct.

BACKGROUND: Endoscopic placement of a iodine-125 radioactive stent is useful to treat obstructive jaundice with unresectable periampullary tumors. This study aimed to retrospectively evaluate the obstructive component of biliary radioactive stents and discuss the different obstructive mechanism with common plastic stents. PATIENTS AND METHODS: Twenty consecutive patients with malignant obstruction underwent insertion of stents into the common bile duct, including 10 radioactive stents and 10 polyethylene stents. The radioactive stents were withdrawn after ∼3 months or earlier if clinical signs suggested stent clogging. Polyethylene stents were withdrawn after physical signs suggested stent clogging. Bacteriologic analyses included identification of aerobic and anaerobic bacteria. Stent surfaces were observed by scanning electron microscopy. Stent deposition was identified by Fourier-transformed infrared spectroscopy and pyrolysis derivatization/gas chromatography/mass spectrometry. RESULTS: Radioactive stent group and polyethylene stent group stents were placed for 86 days (interquartile range 62, 114) and 146 days (interquartile range 105, 181) respectively. The placement duration of the two types of stents was statistically significant. A variety of microorganisms were cultured from the stent deposits. Scanning electron microscope images showed a thicker necrotic layer on the external surface of polyethylene stent than the radioactive stent group. The proportions of obstructive components in each stent were different, but none of them were statistically significant. Necrotic tumor tissue was found in the radioactive stent group. CONCLUSION: Similar clogging events occurred in both radioactive stents and polyethylene stents. The median duration time of the radioactive stent was shorter, probably because of the smaller inner diameter, and the radioactive seeds exerted no beneficial effect in inhibiting microorganisms.

Impact of adjuvant radiation therapy for microscopic residual tumor after resection of extrahepatic bile duct cancer.

OBJECTIVES: The effect of adjuvant radiation therapy (RT) in extrahepatic bile duct (EHBD) cancer patients with microscopic-positive resection margins (R1 resection) is still controversial. METHODS: Between January 2000 and March 2010, 52 patients with EHBD cancer underwent surgery at our institution, of whom 36 were subjected to a retrospective analysis. Eleven patients received adjuvant RT after resection [surgery (S)+RT group], which included 9 patients with R1 resection and 2 with para-aortic lymph node metastasis. Their oncological outcomes were analyzed and compared with those of the 25 patients with R0 resection who did not receive adjuvant RT (S group). RESULTS: Patients in the S+RT group had significantly more advanced disease than those in the S group. However, there was no significant difference in disease-free survival or overall survival between the 2 groups. Median survival times for the S+RT and the S groups were 44 and 47 months, respectively, whereas the 5-year survival rates were 38.9% and 46%, respectively (P=0.707). Locoregional recurrence was less frequent in the S+RT group as compared with the S group, but the incidence of distant metastasis was unaffected by the adjuvant RT. CONCLUSIONS: Our results support the beneficial effect of adjuvant RT in EHBD cancer patients with R1 resection. This effect seems to result from an improved control of the locoregional tumor by adjuvant RT.

Chemoradiation may prolong survival of patients with non-bulky unresectable extrahepatic biliary carcinoma. A retrospective analysis.

PURPOSE: . This study compared stenting and chemoradiation (CRT) and attempted to identify factors that are predictive of response to CRT. MATERIAL AND METHODS: . A retrospective analysis identified 98 patients treated. The primary tumor and lymphatics received 45 Gy of three-dimensional conformal radiotherapy. Tumors were boosted to a median total dose of 50.8 Gy. Simultaneous chemotherapy was 5-fluorouracil- (5-FU) and gemcitabine-based. RTOG/NCI-CTC toxicity criteria were applied. RESULTS: . Median survival time was 11.8 months for all patients, 9.3 months for patients with stenting alone and 16.5 months with CRT (p = 0.22). Only tumor diameter was predictive of survival for treatment with CRT. A threshold of 40 mm at diagnosis distinguished two survival profiles (21.4 vs. 8.7 months; p = 0.01). Toxicity was lower for 5-FU-based CRT compared to gemcitabinebased CRT, but a safe schedule for gemcitabine-based CRT was identified. Two patients (2/25) with unresectable tumors at diagnosis had pathohistological complete response at resection after CRT. CONCLUSION: . Inclusion criteria for future CRT trials should be based on tumor size at diagnosis: patients otherwise eligible for CRT should only be included with an inoperable tumor

Intraoperative radiation therapy in liver tissue in a pig model: monitoring with dual-modality PET/CT.

PURPOSE: To assess, in a pig model, the value of dual-modality positron emission tomography (PET)/computed tomography (CT) for monitoring radiation therapy. MATERIALS AND METHODS: Central bile duct resection followed by creation of a biliodigestive anastomosis was performed in nine pigs. Six of these pigs were also treated with intraoperative radiation therapy (IORT) (20 Gy) in the area of the anastomosis. Two, 4, and 8 weeks postoperatively, contrast material-enhanced fluorine 18 fluorodeoxyglucose (FDG) PET/CT of the liver was performed in all of the animals. The radioactive tracer concentration in the region of the anastomosis was quantified, and the values were compared intraindividually with the values at the liver periphery. Histologic evaluation of the liver was performed 8 weeks postoperatively. The PET/CT images were assessed for changes in liver volume and bile duct diameter over time. RESULTS: In all nine pigs, the region of the anastomosis could be clearly defined on the fused PET/CT images. PET/CT revealed a decreased concentration of FDG in the irradiated field 2 and 4 weeks after IORT. At 8 weeks, however, the distribution of the tracer in the irradiated pigs did not differ from that in the nonirradiated pigs. Homogeneous tracer uptake in all liver regions was observed in the nonirradiated animals. The CT images showed an increase in liver volume in all pigs and bile duct dilatation that increased over time in the irradiated pigs. CONCLUSION: The morphologic and functional changes due to IORT in liver tissue can be accurately monitored with dual-modality PET/CT. By enabling the integration of functional and morphologic data, PET/CT may have an important role in monitoring radiation treatment.

Clinical efficacy of brachytherapy combined with external-beam radiotherapy and repeated arterial infusion chemotherapy in patients with unresectable extrahepatic bile duct cancer.

The objective of this study was to evaluate the clinical efficacy of brachytherapy combined with external-beam radiotherapy and repeated arterial infusion chemotherapy in improving stent patency and prognosis in patients with unresectable bile duct cancer as compared with brachytherapy alone. Seventeen patients were treated. Five patients received brachytherapy alone before stent placement. Twelve patients received brachytherapy combined with external-beam radiotherapy (n=5), repeated hepatic arterial infusion chemotherapy using an implanted catheter and port (n=1), or both (n=6). Mean survival was significantly improved in the group that received combined therapy as compared with the group that received brachytherapy alone (16.2 months vs. 4.6 months, p<0.01). Although stent occlusion rates were similar in the two groups (42% vs. 40%), there was a trend towards longer stent patency in the combined therapy group than in the brachytherapy group (22 months vs. 3.6 months, p<0.2). Radiation gastritis necessitating gastrectomy developed in 1 patient who received external-beam radiotherapy at more than 50 Gy. Brachytherapy combined with external-beam radiotherapy and repeated hepatic arterial infusion chemotherapy increases survival compared with brachytherapy alone in patients with unresectable bile duct cancer.

The experiences of hilar skeletonization for the treatment of locally advanced proximal bile duct cancer.

BACKGROUND/AIMS: Because proximal bile duct cancer easily involves the surrounding tissue, tumor cells often remain after apparent macroscopically complete radical resection. We evaluated the effect of resective modality of these tumors on prognosis and the effect of postoperative radiotherapy on survival of patients with microscopic residual tumor following local resection in locally advanced proximal bile duct cancer. METHODOLOGY: From November, 1990 to October, 1993, 45 proximal bile duct cancer patients who received local excision were entered onto this prospective, nonrandomized study. The patients were divided into three groups after operation, 16 patients with curative resection; 15 noncurative resection; and 14 nonresection. Patients who had positive lymph nodes or microscopic cancer cells in resection margin or adjacent major vessels, were treated with postoperative external radiotherapy, 5040 cGy for 40 days. RESULTS: The overall 1-, 2-, and 5-year survival of the patients was 62.2%, 24.4%, and 15.6%, respectively. The overall mean and median survival of patients was 24.1 +/- 3.98 (mean +/- SE) months and 13 +/- 0.74 months, respectively. Survival rates between resection and nonresection showed a statistically significant difference (P < 0.05). However, survival rates between curative resection and noncurative resection with postoperative radiotherapy were not statistically significant (P > 0.05). CONCLUSIONS: The resection is the treatment of choice for locally advanced proximal bile duct cancer, if resectable and the noncurative resection followed by postoperative external radiotherapy may be beneficial to the patients with locally advanced proximal bile duct cancer.

Cholangiocarcinoma: clinical significance of tumor location along the extrahepatic bile duct.

PURPOSE: To define the criteria for resection and/or radiation therapy (RT) of extrahepatic bile duct cancer. MATERIALS AND METHODS: Of 81 patients with extrahepatic bile duct cancer treated from 1983 to 1992, those with proximal duct lesions (n = 56) underwent RT and/or resection or palliative care, and those with distal lesions (n = 25) underwent resection with or without RT. Follow-up was available 3-114 months (median, 28 months). RESULTS: Patients with distal bile duct cancer lived longer than patients with proximal bile duct cancer (survival with Kaplan-Meier analysis, 53% vs 13% at 5 years, respectively, P < .01). Median survival in patients with proximal cancer after RT was more than double that without RT (17 months vs 6 months, respectively, regardless of stage [P = .01]); survival was not significantly different after resection. In patients with distal cancer, RT after resection made no significant difference in median survival (68 months). CONCLUSION: Patients with proximal cancer should undergo primary RT, and expectations should be limited. Patients with distal cancer should undergo resection, and RT may not be needed.

Late effects of intraoperative radiation therapy on retroperitoneal tissues, intestine, and bile duct in a large animal model.

PURPOSE: The late histopathological effects of intraoperative radiotherapy (IORT) on retroperitoneal tissues, intestine, and bile duct were investigated in dogs. METHODS AND MATERIALS: Fourteen adult foxhounds were subjected to laparotomy and varying doses (0-45 Gy) of IORT (11 MeV electrons) delivered to retroperitoneal tissues including the great vessels and ureters, to a loop of defunctionalized small bowel, or to the extrahepatic bile duct. One control animal received an aortic transection and reanastomosis at the time of laparotomy; another control received laparotomy alone. This paper describes the late effects of single-fraction IORT occurring 3-5 years following treatment. RESULTS AND CONCLUSION: Dogs receiving IORT to the retroperitoneum through a 4 x 15 cm portal showed few gross or histologic abnormalities at 20 Gy. At doses ranging from 30-45 Gy, radiation changes in normal tissues were consistently observed. Retroperitoneal fibrosis with encasement of the ureters and great vessels developed at doses > or = 30 Gy. Radiation changes were present in the aorta and vena cava at doses > or = 40 Gy. A 30 Gy dog developed an in-field malignant osteosarcoma at 3 years which invaded the vertebral column and compressed the spinal cord. A 40 Gy animal developed obstruction of the right ureter with fatal septic hydronephrosis at 4 years. Animals receiving IORT through a 5 cm IORT portal to an upper abdominal field which included a defunctionalized loop of small bowel, showed a few gross or histologic abnormalities at a dose of 20 Gy. At 30 Gy, hyaline degeneration of the intestinal muscularis layer of the bowel occurred. At a dose of 45 Gy, internal intestinal fistulae developed. One 30 Gy animal developed right ureteral obstruction and hydronephrosis at 5 years. A dog receiving 30 Gy IORT through a 5 cm portal to the extrahepatic bile duct showed diffuse fibrosis through the gastroduodenal ligament. These canine studies contribute to the area of late tissue tolerance to IORT.