however , the incidence of btc appears to be increasing worldwide over the last few decades , particularly in latin america and east asia ( 1 ) . btc is currently the sixth leading cause of cancer - related mortality in japan , and patients with btc have a poor prognosis ( 2 ) . however , the majority of patients are diagnosed at an advanced stage , when curative resection is no longer feasible ; in addition , even in cases where surgery may be performed , there is a significant likelihood of relapse ( 3 ) . patients with unresectable or recurrent disease appear to be clinical candidates for systemic chemotherapy ( 4,5 ) . after the abc-02 study reported that gemcitabine / cisplatin ( gc ) combination therapy significantly prolonged median survival time ( mst ) from 8.1 to 11.7 months over gemcitabine monotherapy in patients with advanced btc ( 6 ) , this combination therapy has become the standard treatment for btc worldwide . recently , kanai et al determined the optimal dose of gc / s-1 ( gcs ) combination therapy for patients with advanced btc in a phase i study ( 7 ) and reported a promising mst of > 15 months in a phase ii study ( 8) . based on these results , a phase iii randomized trial is underway to demonstrate the superiority of gcs therapy compared with gc in patients with unresectable btc ( umin000014371/nct02182778 ) . we herein report the case of a patient with unresectable intrahepatic cholangiocarcinoma ( icc ) who underwent conversion surgery and ultimately achieved a pathologically complete response using gcs combination therapy . a 68-year - old woman was referred to toyonaka municipal hospital with increased levels of biliary enzymes in march , 2015 . the patient suffered from hypertension and rheumatoid arthritis , which were controlled with oral medication . a physical examination revealed no abdominal abnormalities , but the laboratory tests revealed abnormal liver function , including an elevated serum alkaline phosphatase level of 839 u / l [ upper limit of normal ( uln ) , 328 u / l ) , a -glutamyltranspeptidase level of 324 u / l ( uln , 64 u / l ) and an alanine aminotransferase level of 82 u / l ( uln , 40 u / l ) . additionally , the serum carcinoembryonic antigen ( cea ) and carbohydrate antigen ( ca ) 19 - 9 levels were 9.8 ng / ml ( uln , 5.0 ng / ml ) and 32,806 u / ml ( uln , 37 u / ml ) , respectively . computed tomography ( ct ) revealed a 3-cm mass in the 1/8 segment of the liver , resulting in dilated bile ducts in both hepatic lobes , enlarged para - aortic and regional lymph nodes , and invasion of the portal vein ( pv ) ( fig . 1a ) . magnetic resonance imaging ( mri ) revealed an intrahepatic mass as a hypointense lesion compared with normal liver tissue in t1-weighted images . t2-weighted images revealed mild hyperintensity compared with the liver parenchyma . furthermore , diffusion - weighted mri revealed high signal intensity ( fig . 1b ) . positron emission tomography with f - fluoro - d - deoxyglucose ( f - fdg pet)/ct revealed abnormal uptake of the primary tumor and para - aortic lymph nodes , with an suvmax of 5.8 and 2.5 , respectively ( fig . the patient was diagnosed with unresectable intrahepatic btc with para - aortic and hilar lymph node metastasis [ ct3n1m1 , cstage ivb according to the union for international cancer control classification system ( http://www.uicc.org/sites/main/files/private/tnm_classification_of_malignant_tumours_website_15%20may2011.pdf ) ] . endoscopic retrograde cholangiopancreatography ( ercp ) revealed a 2-cm irregular stricture of the hilar bile duct with a lobulated tumor ( fig . the brush cytology specimens revealed atypical cells in a three - dimensional cluster and an isolated pattern strongly suggestive of adenocarcinoma ( fig . , the patient was diagnosed with unresectable icc with para - aortic lymph node metastasis and , therefore , systemic chemotherapy was considered . the patient underwent endoscopic biliary drainage using plastic stent placement for the biliary stricture prior to therapy . endobiliary stents ( 7f 12- and 7-cm at a light angle ) were successfully placed through the narrowed lumen at initial ercp , resulting in successful biliary decompression . the patient was subsequently enrolled in a phase iii randomized trial ( umin000014371/nct02182778 ) and randomly assigned to receive gcs combination therapy . / m on day 1 , and oral s-1 was administered daily at a dose of 80 mg / m on days 17 every 2 weeks . the patient received 12 cycles of the regimen for 6 months . on the first day of the 8th cycle , the patient presented with grade 3 malaise after receiving chemotherapy . this adverse effect was , however , manageable and improved within 2 days by fluid replacement therapy . after the scheduled 12 cycles of the regimen , ct revealed a marked reduction of the primary tumor and metastatic lymph nodes . f - fdg - pet / ct also revealed diminished abnormal uptake of the primary lesion and para - aortic lymph nodes ( fig . 3b ) . additionally , the serum cea and ca19 - 9 levels decreased to within the normal range ( 1.5 ng / ml and 11 u / ml , respectively ) . the patient achieved a good partial response to gcs therapy and was allowed to undergo conversion surgery . therefore , the patient underwent extended right hepatic lobectomy , lymph node dissection and left hepaticojejunostomy . the resected specimen exhibited almost complete occlusion of the right hepatic duct immediately before the junction ( fig . histological examination revealed scattered pigmented macrophages in the fibrotic tissue , suggesting that necrotic cells were scavenged from this location . although atypical epithelia in the bile duct were identified , invasive carcinoma and intraepithelial carcinoma components were not found , even following thorough examination . there were no viable carcinoma cells in the dissected nodes , but some contained fibrotic foci ( fig . a patient with unresectable icc at presentation achieved a pathologically complete response after undergoing preoperative gcs combination chemotherapy . at the last follow - up , 9 months after the operation ( september , 2016 ) , the patient remained alive and recurrence - free , without adjuvant therapy . btc , which originates in the intrahepatic and extrahepatic bile ducts , is a relatively uncommon type of cancer , comprising ~3% of all gastrointestinal malignancies ( 9,10 ) . the majority of btc patients are diagnosed at an advanced stage due to the lack of abdominal symptoms , and the prognosis is generally poor ( 1,2 ) . therefore , surgery is the optimal therapeutic approach , although systemic chemotherapy is considered for patients with unresectable btc . in the abc-02 study , valle et al reported that gc combination therapy was associated with a significant survival advantage compared with gemcitabine alone , with a overall mst of 11.7 months compared with 8.1 months , respectively ( hazard ratio = 0.64 ; p<0.001 ) ( 6 ) . based on that study , gc combination therapy has been the standard palliative chemotherapy for patients with advanced btc worldwide . the bt-22 study used the same regimen as the abc-02 study and evaluated the efficacy and safety for patients with advanced btc in a japanese population ; the study revealed that its outcome was similar to that of the abc-02 study , as the mst for gc combination therapy and g alone was 11.2 and 7.7 months , respectively , and the adverse events did not significantly differ between the two groups , although the incidence of hematotoxicity was higher with gc combination therapy compared with g alone ( gc vs. g : leukopenia , 29.3 vs. 19.0% ; neutropenia , 56.1 vs. 38.1% ; thrombocytopenia , 39.0 vs. 7.2% ; and decreased hemoglobin level , 36.6 vs. 16.6% , respectively ) ( 11 ) . therefore , this indicates that the new regimen exhibited a higher efficacy and fewer adverse events . s-1 is an oral fluoropyrimidine prodrug that is widely used for various solid tumors ( 1215 ) , and it is approved in japan as a chemotherapeutic agent for btc ( 16 ) . s-1 monotherapy has shown promising outcomes associated with mild toxicity in btc patients ( 13 ) . additionally , in combination with gemcitabine , s-1 has also achieved favorable response rates ( 3034% ) and mst ( 11.612.7 months ) ( 14,15 ) . on the basis of these reports , kanai et al expected that the addition of s-1 would exert an additive or synergistic effect with gc combination therapy to improve treatment results with respect to efficacy and safety . in a phase i study , the regimen described below had the fewest grade 34 adverse events ( maculopapular rash , vasovagal reaction and anemia ) . based on the incidental rates of adverse events in the phase i study , kanai et al established a recommended dose of the gcs combination therapy , which consisted of intravenous administration of gemcitabine ( 1,000 mg / m ) and cisplatin ( 25 mg / m ) on day 1 and oral administration of s-1 ( 80 mg / m ) on days 17 , every 2 weeks ( 7 ) a phase ii study demonstrated significantly prolonged mst ( 16.2 months , 95% confidence interval 10.222.2 months ) without uncontrollable adverse events compared with that of the abc-02 study ( 11.7 months , hazard ratio = 0.64 ; p<0.001 ) . interestingly , two patients ( 4% ) were able to achieve curative secondary resection after tumor downstaging following chemotherapy ( 8) . thus , gcs combination therapy should not only be considered to be a standard first - line chemotherapy , but also a  conversion surgery or neoadjuvant chemotherapy. on the basis of these findings , a randomized phase iii study has now been launched ( umin000014371/nct02182778 ) . conversion surgery is radical resection performed for previously unresectable cases that become resectable as a result of regression following chemotherapy ; it should be distinguished from neoadjuvant chemotherapy , although a strict distinction between these two strategies is occasionally clinically difficult , as the definition of unresectable cancer varies among physicians . conversion surgery or neoadjuvant chemotherapy for unresectable cancers , including gastric , colorectal and pancreatic cancer , has been frequently reported ( 1719 ) . kim et al demonstrated that clinically curative conversion therapy resulted in the highest survival rate and best prognosis in gastric cancer patients with peritoneal seeding ( cstage iv ) . the mst of patients undergoing clinically curative conversion therapy and non - curative resection was 37 and 18 months , respectively , and the 3-year survival rates were 50 and 0% , respectively ( 17 ) . for colorectal and pancreatic cancer , several recent reports also demonstrated a clinical advantage with neoadjuvant chemotherapy ( 18,19 ) . however , the feasibility and efficacy of neoadjuvant chemotherapy for btc has not been determined ( 20 ) . kato et al reported that patients with initially unresectable locally advanced btc who underwent neoadjuvant chemotherapy ( gemcitabine ) had a significantly longer survival time compared with those unable to undergo surgery ( 2-year overall survival rate of 45 and 19% , respectively ) ( 21 ) . furthermore , a case of curative resection after gcs chemotherapy for initially unresectable biliary duct cancer and a case of a patient with extrahepatic cholangiocarcinoma after undergoing preoperative gemcitabine - based chemotherapy have been reported ( 22 ) . based on these reports , conversion therapy has recently attracted attention , although there is insufficient evidence regarding the safety and efficacy of performing conversion surgery . to the best of our knowledge , the present case is the first report of a patient diagnosed with unresectable btc who ultimately achieved a pathologically complete response with gcs combination therapy . further studies are required to verify the efficacy of conversion surgery in patients with btc using a prospective study design .