Surgery Alone Versus Surgery Followed by Chemotherapy and Radiotherapy in Resected Extrahepatic Bile Duct Cancer: Treatment Outcome Analysis of 336 Patients / Journal of the Korean Cancer Association, 대한암학회지

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.

Postoperative radiotherapy appeared to improve the disease free survival rate of patients with extrahepatic bile duct cancer at high risk of loco-regional recurrence

PURPOSE: To investigate the outcomes of postoperative radiotherapy (RT), in patients with extrahepatic bile duct (EHBD) cancer by comparing the survival rate between patients undergoing surgery alone or surgery plus postoperative RT, and to identify the prognostic factors affecting survival. MATERIALS AND METHODS: Between 2000 and 2013, 52 patients with EHBD cancer underwent surgical resection. Of these, 33 patients did not receive postoperative RT (group I), and 19 patients did (group II). R1 resection was significantly more frequent in group II. The median radiation dose was 5,040 cGy. RESULTS: The 3-year overall survival (OS) rate for group I and group II was 38% and 56%, respectively (p = 0.274). The 3-year disease free survival (DFS) rate for group I and group II was 20% and 31%, respectively (p = 0.049), and the 3-year loco-regional recurrence free survival (LRFS) rates were 19% and 58%, respectively (p = 0.002). Multivariate analyses showed that postoperative RT and lymphovascular invasion were independent prognostic factors for DFS and LRFS. Overall, 42 patients (80%) experienced treatment failure. Distant metastasis was the predominant pattern of failure in group II. CONCLUSION: Postoperative RT after surgical resection appeared to improve the loco-regional control and DFS rate. More effort is needed to reduce distant metastasis, the major pattern of failure, in patients who receive postoperative RT.

Molecular biomarkers in extrahepatic bile duct cancer patients undergoing chemoradiotherapy for gross residual disease after surgery

PURPOSE: To analyze the outcomes of chemoradiotherapy for extrahepatic bile duct (EHBD) cancer patients who underwent R2 resection or bypass surgery and to identify prognostic factors affecting clinical outcomes, especially in terms of molecular biomarkers. MATERIALS AND METHODS: Medical records of 21 patients with EHBD cancer who underwent R2 resection or bypass surgery followed by chemoradiotherapy from May 2001 to June 2010 were retrospectively reviewed. All surgical specimens were re-evaluated by immunohistochemical staining using phosphorylated protein kinase B (pAKT), CD24, matrix metalloproteinase 9 (MMP9), survivin, and beta-catenin antibodies. The relationship between clinical outcomes and immunohistochemical results was investigated. RESULTS: At a median follow-up of 20 months, the actuarial 2-year locoregional progression-free, distant metastasis-free and overall survival were 37%, 56%, and 54%, respectively. On univariate analysis using clinicopathologic factors, there was no significant prognostic factor. In the immunohistochemical staining, cytoplasmic staining, and nuclear staining of pAKT was positive in 10 and 6 patients, respectively. There were positive CD24 in 7 patients, MMP9 in 16 patients, survivin in 8 patients, and beta-catenin in 3 patients. On univariate analysis, there was no significant value of immunohistochemical results for clinical outcomes. CONCLUSION: There was no significant association between clinical outcomes of patients with EHBD cancer who received chemoradiotherapy after R2 resection or bypass surgery and pAKT, CD24, MMP9, survivin, and beta-catenin. Future research is needed on a larger data set or with other molecular biomarkers.

Histopathologic Prognostic Factors for Recurrence and Survival after Surgical Resection of Middle and Distal Bile Duct Cancer

PURPOSE: Surgery remains the only curative option for patients with extrahepatic bile duct cancer (EHBD Ca). But, long-term survival is typically not good because of the advanced stage of disease at the time of diagnosis and frequent disease recurrence after surgical resection. The purpose of this study was to evaluate factors that influence survival and recurrence after surgical resection of EHBD Ca. METHODS: A retrospective analysis of 113 patients who had received surgical resection for EHBD Ca between 2004 and 2009 was done. We investigated histopathological features, and survival and recurrence rates, and evaluated prognostic factors affecting survival and disease recurrence after surgical resection. RESULTS: Overall survival rates for 1, 3 and 5 years were 73.2%, 42.8%, and 36.0% respectively. In univariate analysis, prognostic factors influencing survival were histologic differentiation, T stage, lymph node (LN) metastasis, TNM stage, perineural invasion (PNI), lymphovascular invasion (LVI) and resection margin state. Among them, LN metastasis, PNI and resection margin state were found to be independent prognostic factors for overall survival in multivariate analysis. Recurrence occurred in 44 patients (48.9%) and disease-free survival rates were 50.6% at 1 year and 38.3% at 3 year. Univariate analysis revealed that histologic differentiation, T stage, LN metastasis, TNM stage, PNI and LVI were significantly associated with recurrence. In multivariate analysis, only LN metastasis was found to be a significant independent predictor of recurrence. CONCLUSION: LN metastasis, PNI and positive resection margin were significant prognostic factors affecting survival. LN metastasis was found to be a significant independent predictor of recurrence in surgical resection of EHBD Ca.

The effect of curative surgical resection and adjuvant radiotherapy in patients with extrahepatic bile duct cancer / 대한내과학회지

BACKGROUND/AIMS: To evaluate the effect and prognostic factors related to curative surgical resection and adjuvant radiotherapy in patients with extrahepatic bile duct cancer. METHODS: The authors performed a retrospective analysis of 53 patients with extrahepatic bile duct cancer who were treated at Chungnam National University Hospital between 1998 and 2005. 18 patients (Group 1) were managed with percutaneous bile drainage (n=13) or endoscopic bile drainage (n=5), 17 patients (Group 2) underwent only curative resection, and 18 patients (Group 3) received radiotherapy after curative resection. The radio-sensitizer used in these patients was 5-FU. RESULTS: Three-year overall survival was 5.6% in group 1, 64.7% in group 2, and 61.1% in group 3, with no significant difference noted between group 2 and group 3. The disease-free survival rate was 64.7% in group 2 and 66.7% in group 3, with no significant difference noted between the two groups. We evaluated age, sex, differentiation, tumor location, perineural invasion, operative method, lymphovascular tumor emboli, T stage, and N stage as possible prognostic factors. T stage, N stage, and operative method were significant factors in group 2, but age was the only significant factor in group 3. Group 2 patients had longer overall survival than did group 3 patients with well-differentiated cancer, but group 3 patients had longer survival than did group 2 patients with lymph node metastasis. The recurrence rate was 34.3% (mean value) and was no different between group 2 and group 3. Recurrence sites included local tissue, such as liver, and regional lymph nodes. There were no serious complications during radiotherapy. CONCLUSIONS: Patients who underwent curative surgical resection and adjuvant radiotherapy after surgery had no statistically significant difference in survival or recurrent rates. However, curative surgery is considered to be the only method to improve survival. Our results suggest that radiotherapy after curative resection may improve survival in patients with lymph node metastasis.

The Results of Curative Reoperation for Recurrent Cancer of the Extrahepatic Biliary Tract

PURPOSE: Local recurrence, following a resection for cancer of the gallbladder (GB) and bile duct, is usually incurable; with 2nd curative surgery being almost impossible. To determine the feasibility and significance of 2nd curative surgery, our experiences are presented in this study. METHODS: The medical records and clinical outcomes of 4 patients that underwent a re-resection for recurrent cancer of the extrahepatic biliary tract were retrospectively reviewed. RESULTS: The mean age of the four patients was 51.5 years. One patient that had a recurrent disease at the intrahepatic and intrapancreatic bile duct, 66 months after a segmental resection of the bile duct for common bile duct (CBD) cancer, underwent a hepatopancreatoduodenectomy. The second patient had a recurrent tumor mass in the CBD originating from in a cystic duct, 11 months after a cholecystectomy, and underwent a segmental resection of the bile duct. The third patient had a recurrent disease in the distal CBD, 28 months after a right hepatectomy for a Klatskin tumor, and underwent a pylorus-preserving pancreatoduodenectomy. The gross type of the above 3 cases was a papillary tumor. The fourth patient had a recurrent tumor mass of the liver parenchyma, close to the previous resection margin, 16 months after a cholecystectomy and wedge resection of the GB bed at another hospital for GB cancer, and underwent a wider wedge resection of the GB bed. There were no operative mortalities or morbidities. All patient are still alive after 46, 63, 9 and 30 months, respectively, without recurrence after the reoperation. CONCLUSION: It is concluded that a surgical re-resection is possible in selected patients with recurrent bile duct cancer, mostly of the papillary type. A primary operation for bile duct cancer should be performed with a wide surgical margin, and secondary curative surgery should be considered whenever possible in cases of recurrence.

Treatment Outcome of Postoperative Radiotherapy in Extrahepatic Bile Duct Cancer / 대한방사선종양학회지

PURPOSE: To evaluate the efficacy of radiotherapy, and the factors affecting survival in patients of extrahepatic bile duct cancer, by analyzing the results of postoperative radiotherapy. MATERIALS AND METHODS: Between October 1991 and July 2001, 21 patients with extrahepatic bile duct cancer, who received radiotherapy after a radical resection, were retrospectively reviewed. The patients' ages ranged from 39 to 75 years, with a median of 61 years, and a male to female ratio of 16 to 5. The numbers of patients with proximal and distal bile duct cancer were 14 and 7, respectively. From the postoperative pathological examination, 19 of the patients were found to have microscopic residues, and 7 to be lymph node positive. Patients with AJCC stages I, II and III were 10, 10 and 1, respectively. The total radiation dose administered was 4,500~6,300 cGy, with a median dose of 5,040 cGy. The follow up period was 20~81 months, with a median of 57.5 months. RESULTS: The overall and disease free survival rates at 3 and 5 years were 41.0 and 29.3%, and 41.6 and 29.7%, respectively. The influences of age, sex, tumor location, differentiation, microscopic residue, neural invasion, T and N stage, the stage itself, the dose of radiation and chemotherapy, on survival were evaluated. The T stage and the stage itself were found to be significant from a univariate analysis (p< 0.05), but the degree of significance was limited by the small number of patients. A recurrence occurred in 12 patients (57.1%), 5 in locoregional sites, 4 in distant sites and 3 in a combination of locoregional and distant sites, and the sites of distant metastasis were the liver, 6, and the bone, 1. Grade 2 or 3 acute leucopenias occurred in 2 patients and grade 2 chronic peptic ulcers occurred in 4, who were all recovered by conservative management. CONCLUSION: Postoperative radiotherapy is feasible in extrahepatic bile duct cancer, with tolerable toxicity, but prospective studies, with a large patient enrollment, are needed for the evaluation of the effects of postoperative radiotherapy and the related prognostic factors.

Clinical Results in the Treatment of Extrahepatic Bile Duct Cancer and Long-term Survivors' Characteristics after Surgical Resection / 한국간담췌외과학회지

BACKGROUND/AIMS: The objectives of this study were to analyze actual long-term survivors' characteristics and investigate what affect long-term survival after resection for extrahepatic bile duct cancer. METHODS: 151 patients of the total 282 patients with extrahepatic bile duct cancer underwent surgical resection between 1986 and 1996. During study period, 23 cases of hepatobiliary resection (HBR), 25 bile duct resection (BDR), and 103 pancreatoduodenectomy were performed respectively. We analyzed survival results and prognostic factors after surgical resection. We also investigated clinico-pathological features of actual long-term survivors. RESULTS: The 1-,3-,and 5-year survival rates were 72.9%, 41.1%,and 32.5% in the resection group, and the 1-, 3-year survival rates were 35.4% and 1.6% in the non-resection group (p<0.001). The differences of survival rates according to the types of resection were not significant (p=0.083). After surgical resection, tumor histology and lymph node metastasis were the independent prognostic factors in multivariate analysis. CONCLUSION: The prognosis of the extrahepatic bile duct cancer depends on the curative resection. Regardless of the types of resection and tumor location, if tumor histology might be favorable and no lymph node metastasis exist, long-term survival could be expected.

Segmental Resection for Extrahepatic Bile Duct Cancer (excluding GB cancer)

PURPOSE: It is difficult to preoperatively determine the extent of surgery for extrahepatic cholangiocarcinoma due to its proximity to vital structures. Recently the tendency of combined resection of liver and pancreas for the treatment of this appears to be increasing, although, in spite of the expected survival benefit, this radical surgery cannot be applied to all extrahepatic cholangiocarconoma because of the high rate of operative complications. We reviewed patients who had undergone segmental resection of the bile duct vice radical surgery for extrahepatic cholangiocarconoma in order to study their clinical features and to analyze the prognostic factors for survival. METHODS: Thirty-four patients who underwent segmental resection for extrahepatic cholangiocarcinoma, excepting GB cancer, at our center between 1994 to 2000 were included in this study and their medical records were reviewed retrospectively. RESULTS: The mean age of the patients was 63 years and they underwent segmental resection of bile duct and skeletalization of the hepatoduodenal ligament with hepatico-jejunostomy. The mean length of hospital stay after operation was 17.2 days (8~44) and no operative mortality was encountered. Postoperative complications including 5 wound dehiscences, 1 intraperitoneal abscess, 1 pyloric obstruction and 1 case of gastric ulcer bleeding were all improved following conservative management. The mean size of tumors was 2.6 cm and 11 tumors (32%) involved the resection margin. The estimated 2 and 4 year survival rates of the 34 patients following resection was 64% and 22% respectively and the only significant predictive factor for survival following resection was the tumor involvement of resection margin (P=0.045). The 2-year survival rate of the positive margin group was 34%, although that of the free margin group was 74%. CONCLUSION: Segmental resection for extrahepatic cholangiocarconoma may be a reasonable option offering relatively low morbidity and mortality if the resection margin is tumor- free. Additionally, segmental resection may be more beneficial to patients with high operative risk in particular.

Clinical Review of Carcinomas of the Extrahepatic Bile Ducts and Gallbladders

PURPOSE: The poor prognosis of surgery for extrahepatic bile duct and gallbladder carcinomas are at least partialy due to the inadequate extent of resection and the spreading characteristics of the tumor. This study was conducted to evaluate the benefit of a curative resection and extended surgery for extrahepatic bile duct cancer and GB cancer. METHODS: One hundred seventy five patients with extrahepatic bile duct cancer and GB cancer, who were diagnosed between January 1988 and December 1997 at the Hanyang University hospital, were retrospectively analyzed according to the TNM staging system and the extent of resection. RESULTS: A curative resection was performed in 51% of the extrahepatic bile duct cancer cases and 45% of the GB cancer cases. The cummulative survival rate after a curative resection was significantly higher than those after a palliative resection and no operation. The overall one year and three years survival rates were 74% and 48%, respectively after a curative resection compared to 12% and 0% after a palliative resection. Long term survival after a curative resection correlated with the stage of the disease. CONCLUSION: The result of this study shows that as extended curative resection of an extahepatic bile duct carcinoma and GB cancer was associated with a worthwhile improvement of long term survival.

The Effect of Adjuvant Therapy for Curatively Resected Extrahepatic Bile Duct Cancer / 대한암학회지

PURPOSE: This study was attempted to evaluate the effect of adjuvant radiotherapy and chemotherapy after curative resection of extrahepatic bile duct cancer. MATERIALS AND METHODS: The authors performed a retrospective analysis of 57 patients with extrahepatic bile duct cancer not involving the hepatic duct confluence and curatively resected at Seoul National University Hospital between 1990 and 1995. Resection margins of all cases were confirmed pathologically as free of cancer cells. Among 57 patients, 29 received adjuvant therapy. Total 4000 cGy of external beam radiation was delivered to each. 5-fluorouracil (5-FU) was administered as a radiosensitizer. After 4 weeks of radiation therapy, 5-FU maintenance chemotherapy was started and given every 4 weeks up to 12 cycles or until evidence of relapse. RESULTS: The overall median survival of 57 patients was 24 months. I- and 2-year overall survival rate was 73.7 and 52.6%. There was no difference in overall survival rate between adjuvant therapy group (n=29) and operation-only group (n 28). We tried to evaluate the effect on survival of adjuvant therapy according to lymph node status. Patients of Tl stage were excluded from analysis. Adjuvant therapy had no survival benefit in the lymph node positive group. But in the lymph node negative group, 1- and 2-year survival rate of patients who underwent adjuvant therapy were 89.5% and 68.4% whereas 1 and 2-year survival rate of patients in operation-only group were 57.9% and 36.8%, which was statistically significant (p=0.0278, 0.0472). And by multivariate analysis, the survival improvement of 1- and 2-year survival rate in adjuvant therapy group was due to adjuvant therapy itself. CONCLUSION: Our trial of external beam radiotherapy combined with 5-FU chemotherapy after curative resection of extrahepatic bile duct cancer did not show improved overall survival. However the 1- and 2-year survival rate of patients with negative lymph node and advanced T stage ( > T 1) were improved in adjuvant therapy group, so adjuvant therapy may give survival benefit to a certain patient group with negative lymph node.

Significance of EGFR and c-erbB-2 Expression in Extrahepatic Bile Duct Cancer / 한국간담췌외과학회지

Until now, surgical treatment of bile duct carcinoma has been unsatisfactory. There have been few reports dealing with the clinical significance of epidermal growth factor receptor(EGFR) and c-erbB-2 in bile duct cancer. To evaluate epidermal growth factor receptor(EGFR) and c-erbB-2 protein as a marker for prognosis, we analyzed the data and outcome of 32 cases of extrahepatic bile duct carcinoma immunohistologically, as well as clinicopathologically. The expressions of EGFR and c-erbB-2 showed in 71.9%(23/32) and 34.4%(11/32), respectively. The expression of EGFR was closely associated with the expression of c-erbB-2 (p<0.05). The expression rate of EGFR was significantly higher in well-differentiated cancer than in poorly-differentiated cancer (p<0.05), but was not related to stage, or lymph node metastasis. The expression of c-erbB-2 was not related to stage, lymph node metastasis, and differentiation. The expressions of EGFR and c-erbB-2 did not correlate with survival. In conclusion, the expression of EGFR or c-erbB-2 may be used as a tumor marker, but not as a prognostic factor in extrahepatic bile duct cancer.