Early Tumor Shrinkage and Depth of Response as Predictors of Survival for Advanced Biliary Tract Cancer: An Exploratory Analysis of JCOG1113.

BACKGROUND: Recent studies suggest that early tumor shrinkage (ETS) and depth of response (DpR) reflect outcomes of chemotherapy in various cancers. This study evaluated the association of ETS and DpR with clinical outcomes using data from JCOG1113, which demonstrated the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) for chemotherapy-naïve advanced biliary tract cancer. MATERIAL AND METHODS: In total, 354 (289 with measurable target lesions) patients enrolled in JCOG1113 were divided into ETS-unachieved and ETS-achieved groups (≥20% tumor reduction at week 6) and DpR-low and DpR-high groups (≥40% maximum shrinkage) until 12 weeks after enrollment. The impact of ETS and DpR on survival outcome was evaluated using the multivariable Cox proportional hazard model. RESULTS: The proportions of patients in the ETS-achieved and DpR-high groups were similar between the 2 treatment arms. The hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for the ETS-achieved group were 0.70 (95% confidence interval (CI), 0.52-0.93) and 0.60 (95%CI, 0.44-0.81), respectively. The HRs of PFS and OS for the DpR-high group were 0.67 (95%CI, 0.48-0.94) and 0.64 (95%CI, 0.46-0.90), respectively. In the subpopulation treatment effect pattern plot analysis, most patients in the ETS-achieved group in the GC arm did not experience disease progression after 12 weeks from the landmark. CONCLUSION: As on-treatment markers, ETS and DpR were effective tools. ETS was clinically useful, because it can be used to evaluate the outcomes of treatment early at a specific time.

Real-world treatment outcomes of metastatic biliary tract cancer patients in Japan: the Tokushukai REAl-world data project 04 (TREAD 04).

OBJECTIVES: To investigate temporal trends in treatment patterns and prognostic factors for overall survival in patients with metastatic biliary tract cancer. METHODS: From the Tokushukai REAl-world Data project, we identified 945 patients with metastatic biliary tract cancer treated with gemcitabine, tegafur/gimeracil/oteracil, gemcitabine plus cisplatin, gemcitabine plus tegafur/gimeracil/oteracil or gemcitabine plus cisplatin and tegafur/gimeracil/oteracil between April 2010 and March 2022. Stratified/conventional Cox regression analyses were conducted to examine the association between overall survival and patient- and tumour-related factors, study period, hospital volume, hospital type and first-line chemotherapy regimen. Using inverse probability of treatment weighting with propensity scores, overall survival was also compared between monotherapy and combination therapy groups. RESULTS: We enrolled 366 patients (199 men; median age, 72 years). Over a median follow-up of 5.2 months, the median overall survival was 7.0 months (95% confidence interval 6.2-9.0), and the median time to treatment failure was 3.5 months (95% confidence interval 3.1-4.5). Median overall survival and time to treatment failure for gemcitabine/tegafur-gimeracil-oteracil/gemcitabine plus cisplatin/gemcitabine plus tegafur-gimeracil-oteracil/gemcitabine plus cisplatin and tegafur-gimeracil-oteracil regimen were 6.2/6.6/7.9/16.2/15.1 and 2.8/3.4/4.1/15.3/7.4 months, respectively. Primary disease site, previous surgery, previous endoscopic procedures and hospital type were identified as significant prognostic factors. Inverse probability of treatment weighting analysis demonstrated that combination therapy had a significantly better prognosis than monotherapy (hazard ratio 0.61, 95% confidence interval 0.43-0.88, P = 0.006). CONCLUSIONS: Our real-world data analysis showed that standard care for metastatic biliary tract cancer is widely used in hospitals throughout Japan and verified the survival benefits of combination therapy over monotherapy observed in prior clinical trials. CLINICAL TRIAL NUMBER: UMIN000050590 (http://www.umin.ac.jp/ctr/index.htm).

[GEM plus CDDP Combination Therapy for Unresectable Biliary Tract Cancer-A Single Institution Experience].

BACKGROUND: Since a randomized phase Ⅲ trial conducted in the UK in 2009 showed the superiority of gemcitabine (GEM)plus cisplatin(CDDP)combination therapy over GEM monotherapy, GEM plus CDDP combination therapy has been first-line chemotherapy for unresectable biliary tract cancer. METHODS: GEM plus CDDP combination therapy was administered to 29 patients with unresectable biliary tract cancer from 2016 to 2021. RESULTS: The mean age was 71.9 years, male/ female 19/10. The target of chemotherapy was below, local progression was 3 cases, first distant metastasis 7 cases, metastatic recurrence 19 cases. The type of cancer was below, intrahepatic bile duct carcinoma was 8 cases, hepatic hilar bile duct carcinoma 6 cases, gallbladder carcinoma 5 cases, cystic duct carcinoma 1 case, distal bile duct carcinoma 6 cases, and papilla Vater's cancer 3 cases. The dosing period was 23.1 weeks(range 2-52 weeks). The relative dose intensities of GEM and CDDP were 73.7% and 75.1%. The adverse events were below, the hematological toxicities of Grade 3 or higher were neutropenia(65.5%), leukopenia(3.4%), and thrombocytopenia(10.3%). Non-hematological toxicities of Grade 2 or higher were fatigue(13.7%)and skin rash(6.9%). There was no interstitial pneumonia. The disease control rate was 66.7 %(complete response, n=0; partial response, n=6; stable disease, n=10; progressive disease, n=8). CONCLUSION: GEM plus CDDP combination therapy was safe to perform and was an effective treatment for unresectable biliary tract cancer.

Suboptimal outcome for patients with biliary rhabdomyosarcoma treated on low-risk clinical trials: A report from the Children's Oncology Group.

BACKGROUND: Biliary rhabdomyosarcoma (RMS) is the most common biliary tumor in children. The biliary tract is classified as a favorable primary site. Therefore, patients with localized biliary RMS were included in two consecutive low-risk studies, D9602 and ARST0331, by the Children's Oncology Group (COG). The outcome for these patients treated with low-risk therapy has not been reported. PROCEDURE: Patients with biliary RMS enrolled on COG low-risk trials D9602 or ARST0331 were analyzed. All patients received systemic chemotherapy and those with Group II (microscopic residual) or Group III (macroscopic residual) disease received 36-50.4 Gy adjuvant radiotherapy (RT). Delayed primary excision (DPE) was allowed on both studies. RESULTS: Seventeen patients with biliary RMS were treated on D9602 (n = 7) or ARST0331 (n = 10). Median age was 3.5 years (range 1.7-10.3). Ten (59%) patients had tumors >5 cm and 14 (82%) had Group III disease. Fifteen (88%) patients received RT. The 5-year event-free survival (EFS) and overall survival (OS) were 70.6% (95% confidence interval [CI]: 46.9-94.3%) and 76.5% (95% CI: 54.6-98.4%), respectively. The majority of patients (80%) who received RT did not have disease recurrence while both patients who did not receive RT had local relapse. Five (36%) of 14 patients with Group III disease underwent DPE; two experienced a local relapse. In the nine patients without DPE, two developed local relapse. CONCLUSIONS: Patients with localized biliary RMS treated on low-risk studies had suboptimal outcomes. These patients may benefit from therapy on intermediate-risk studies.

A randomised phase II study of second-line XELIRI regimen versus irinotecan monotherapy in advanced biliary tract cancer patients progressed on gemcitabine and cisplatin.

BACKGROUND: The majority of advanced biliary tract cancer (ABTC) patients will progress after gemcitabine and cisplatin (GP) doublet therapy, while the standard second-line regimen has not been established. We conducted this study to assess the efficacy and safety of second-line irinotecan and capecitabine (XELIRI) regimen vs. irinotecan monotherapy in ABTC patients progressed on GP. METHODS: Sixty-four GP refractory ABTC patients were randomised to either irinotecan 180 mg/m2 on day 1 plus capecitabine 1000 mg/m2 twice daily on days 1-10 of a 14-day cycle (XELIRI-arm) or single-agent irinotecan 180 mg/m2 on day 1 of a 14-day cycle (IRI-arm). Treatments were repeated until disease progression or unacceptable toxicity occurred. RESULTS: A total of 60 patients were included in the analysis. For XELIRI and IRI-arms, respectively, the median PFS was 3.7 vs. 2.4 months, 9-month survival rate 60.9% vs. 32.0%, median OS 10.1 vs. 7.3 months, and disease control rate 63.3% vs. 50.0%. The most common grade 3 or 4 toxicities were leucopaenia and neutropaenia. CONCLUSIONS: This randomised, phase II study of irinotecan-containing regimens in good PS second-line ABTC patients showed a clear benefit of XELIRI regimen over irinotecan monotherapy in prolonging PFS, with acceptable toxicity.

[Treatment Outcomes of Gemcitabine and Cisplatin Combination Therapy for Unresectable and Recurrent Biliary Tract Cancer].

Gemcitabine and cisplatin combination therapy(GC therapy)is now considered a highly effective regimen for patients with unresectable and metastatic biliary tract cancer. We performed GC therapy for 18 patients between January 2014 and April 2018. The median age of the patients was 67.5 years, and 13 patients were men. Fifteen patients had a performance status (PS)score of 0, and 3 patients had a PS score of 1. Nine patients had distal cholangiocarcinoma, 3 had intrahepatic cholangiocarcinoma, 3 had duodenum papilla cancer, and 3 had gallbladder cancer. Fourteen patients showed recurrence after the radical resection, and 9 had liver metastasis. Sixteen patients had over Grade 3 hematological or non-hematological toxicities. The most-common adverse event was neutropenia. None of the patients had Grade 5 adverse events. The response rate was 11.1%, and the disease-control ratio was 66.7%. GC therapy was effective for patients with unresectable and recurrent biliary tract cancer. However, it is necessary to examine the eligibility of patients before treatment.

Quality of life, long-term survivors and long-term outcome from the ABC-02 study.

BACKGROUND: The ABC-02 (Advanced Biliary Tract Cancer) study established cisplatin and gemcitabine (CisGem) as the standard first-line chemotherapy for patients with locally advanced or metastatic biliary tract cancer (BTC). We examine quality of life (QoL), describe the long-term survivors and provide a long-term outcome. METHODS: A total of 410 BTC patients were randomised to receive either CisGem or gemcitabine alone (Gem); 324 patients consented to complete EORTC QLQ-C30 and EORTC QLQ-PAN26 QoL questionnaires; 268 (83%) patients returned at least one QoL questionnaire (134 in each arm). Long-term survivors were defined as those surviving over 2 years and we performed a final analysis of the primary outcome; overall survival (OS). RESULTS: Most QoL scales showed a trend favouring the combined CisGem arm, including functional and symptomatic scales, although the differences were not statistically significant. Forty-five (11%)) patients survived at least 2 years (34 received CisGem and 11 Gem) and 21 (5%) 3 years or more (14 received CisGem and 7 Gem). After a median follow-up of 9.2 months and 398 deaths, the median OS was 11.7 months for CisGem and 8.1 months for Gem (hazard ratio (HR)=0.65, 95% CI: 0.53-0.79, P<0.001). CONCLUSIONS: The survival advantage of CisGem compared to Gem was not associated with an improvement or deterioration of QoL. Long-term survivors were more likely to have received CisGem and the long-term OS is identical to that previously described.

Effect of NF-κB inhibition on chemoresistance in biliary-pancreatic cancer.

Biliary cancer and pancreatic cancer are considered to be difficult diseases to cure. Although complete resection provides the only means of curing these cancers, the rate of resectability is not high. Therefore, chemotherapy is often selected in patients with advanced unresectable biliary-pancreatic cancer. Many combination chemotherapy regimens have been applied in clinical trials. However, the survival time is not satisfactory. On the other hand, most chemotherapeutic agents induce anti-apoptotic transcriptional factor nuclear factor kappa b (NF-κB) activation, and agent-induced NF-κB activation is deeply involved in the onset of chemoresistance. Recently, novel approaches to potentiating chemosensitivity in cases of biliary-pancreatic cancer using NF-κB inhibitors with cytotoxic agents have been reported, most of which comprise translational research, although some clinical trials have also been conducted. Nevertheless, to date, there is no breakthrough chemotherapy regimen for these diseases. As some reports show promising data, combination chemotherapy consisting of a NF-κB inhibitor with chemotherapeutic agents seems to improve chemosensitivity and prolong the survival time of biliary-pancreatic cancer patients.

A single-center analysis of the survival benefits of adjuvant gemcitabine chemotherapy for biliary tract cancer.

BACKGROUND: Surgical resection is the only curative treatment of biliary tract cancer (BTC). However, the prognosis of BTC remains unsatisfactory. The aim of this study is to evaluate the benefits of adjuvant gemcitabine chemotherapy for BTC. METHODS: We performed a historical cohort study that involved 198 patients who underwent R0 surgical resection. Patients who underwent major hepatectomy were administered biweekly intravenous gemcitabine at a dose of 800 mg/m(2). Otherwise, patients were administered intravenous gemcitabine at a dose of 1,000 mg/m(2) in 3 weekly infusions, which were followed by a 1-week pause. The primary outcome was overall survival. The hazard ratio (HR) of adjuvant chemotherapy was estimated by propensity score-stratified Cox regression that was adjusted for confounders. RESULTS: Forty patients received adjuvant chemotherapy. The HR of adjuvant chemotherapy was 0.47 [95 % confidence interval (CI) 0.28-0.95; P = 0.03]. Subgroup analysis showed that the survival benefits were possibly modified by lymph node positivity (HR 0.19; 95 % CI 0.07-0.58; interaction, P = 0.22), stage III (HR 0.11; 95 % CI 0.02-0.50; interaction, P < 0.01), intrahepatic cholangiocarcinoma (ICC) (HR 0.09; 95 % CI 0.01-0.67; interaction, P = 0.05), and poorly differentiated tumor (HR 0.16; 95 % CI 0.03-0.85; interaction, P = 0.13). CONCLUSIONS: Adjuvant gemcitabine chemotherapy for BTC may be effective, particularly for patients with stage III and ICC.

Clinical outcomes of immune checkpoint inhibitor combined with other targeted or immunological therapy regimens for the treatment of advanced bile tract cancer: a systematic review and meta-analysis.

Background and aims: A single immune checkpoint inhibitor (ICI) regimen has limited value in treating advanced bile tract cancer (BTC); therefore, ICI combination therapy is often applied. This meta-analysis aimed to evaluate the effectiveness and safety of ICI combination therapy for advanced BTC. Methods: The study protocol was registered on PROSPERO (CRD42023452422). Data on the median progression-free survival (PFS), median overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade ≥3 adverse events (AEs) reported in relevant studies were pooled and analyzed to determine the efficacy and safety of ICI combination therapy. Results: In total, 15 studies with 665 patients were included in this meta-analysis. The overall ORR and DCR were 34.6% and 77.6%, respectively. The overall median PFS and OS were 6.06 months [95% confidence interval (CI): 4.91-7.21] and 12.11 months (95% CI: 10.66-13.55), respectively. Patients receiving ICI combination therapy in addition to other therapies had a considerably prolonged median PFS and OS (z=9.69, p<0.001 and z=16.17, p<0.001). Patients treated as first-line treatment had a substantially longer median PFS and OS compared to patients treated as non-first-line treatment (z=11.19, p<0.001 and z=49.17, p<0.001). The overall pooled grade ≥3 AEs rate was 38.2% (95% CI: 0.268-0.497) and was not influenced by whether ICI therapy was combined with other treatments or not or the treatment line. Conclusion: Advanced BTC patients may benefit from ICI combination treatment without additional AEs. However, concurrent chemotherapy or radiotherapy is still needed to achieve better outcomes. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023452422.

A phase I study of sorafenib, oxaliplatin and 2 days of high dose capecitabine in advanced pancreatic and biliary tract cancer: a Wisconsin oncology network study.

Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2,250 mg/m2 PO every 8 h x 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID.

Durvalumab: A Review in Advanced Biliary Tract Cancer.

Durvalumab (Imfinzi®), a therapeutic human monoclonal antibody which binds to and blocks the activity of the immunosuppressive programmed death-ligand 1 (PD-L1) protein, is approved in the USA, EU, Japan and other countries in combination with gemcitabine and cisplatin for adults with advanced biliary tract cancer. In the pivotal phase 3 TOPAZ-1 trial, durvalumab plus gemcitabine and cisplatin significantly prolonged overall survival and progression-free survival compared with placebo plus gemcitabine and cisplatin in adults with advanced biliary tract cancer. Benefit from durvalumab was seen irrespective of primary tumour location, disease status at diagnosis (unresectable or recurrent), or initial levels of PD-L1 expression. The tolerability of durvalumab plus gemcitabine and cisplatin was manageable. Overall, the addition of durvalumab to gemcitabine and cisplatin is a valuable new treatment option for adults with advanced biliary tract cancer.

Biliary tract cancers are a diverse group of cancers that develop in the bile ducts or the gallbladder. Patients with these cancers typically have poor survival. Chemotherapy (gemcitabine plus cisplatin) has been the first-line treatment for biliary tract cancer for over a decade, with no new treatments further improving on its overall survival benefit until recently. Durvalumab (Imfinzi^®) belongs to a class of drugs known as checkpoint inhibitors; these drugs activate the immune system to help fight cancer. In the phase 3 TOPAZ-1 trial, the addition of durvalumab to first-line chemotherapy prolonged the overall survival compared with placebo plus chemotherapy in adults with advanced biliary tract cancer. The tolerability of durvalumab in combination with chemotherapy was manageable. Thus, durvalumab plus gemcitabine and cisplatin is a valuable new treatment option for adults with advanced biliary tract cancer.

Randomized phase III study of gemcitabine, cisplatin plus S-1 versus gemcitabine, cisplatin for advanced biliary tract cancer (KHBO1401- MITSUBA).

BACKGROUND: Gemcitabine/cisplatin (GC) combination therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). No randomized clinical trials have been able to demonstrate the survival benefit over GC during the past decade. In our previous phase II trial, adding S-1 to GC (GCS) showed promising efficacy and we aimed to determine whether GCS could improve overall survival compared with GC for patients with advanced BTC. METHODS: We performed a mulitcenter, randomized phase III trial across 39 centers. Enrolled patients were randomly allocated (1:1) to either the GCS or GC arm. The GCS regimen comprised gemcitabine (1000 mg/m2 ) and cisplatin (25 mg/m2 ) infusion on day 1 and 80 mg/m2 of S-1 on days 1-7 every 2 weeks. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response rate (RR), and adverse events (AEs). This study is registered with Clinical trial identification: NCT02182778. RESULTS: Between July 2014 and February 2016, 246 patients were enrolled. The median OS and 1-year OS rate were 13.5 months and 59.4% in the GCS arm and 12.6 months and 53.7% in the GC arm, respectively (hazard ratio [HR] 0.79, 90% confidence interval [CI]: 0.628-0.996; P = .046 [stratified log-rank test]). Median PFS was 7.4 months in the GCS arm and 5.5 months in the GC arm (HR 0.75, 95% CI: 0.577-0.970; P = .015). RR was 41.5% in the GCS arm and 15.0% in the GC arm. Grade 3 or worse AEs did not show significant differences between the two arms. CONCLUSIONS: GCS is the first regimen which demonstrated survival benefits as well as higher RR over GC in a randomized phase III trial and could be the new first-line standard chemotherapy for advanced BTC. To exploit the advantage of its high RR, GCS is now tested in the neoadjuvant setting in a randomized phase III trial for potentially resectable BTC.

The clinical outcomes of combination chemotherapy in elderly patients with advanced biliary tract cancer: an exploratory analysis of JCOG1113.

In the FUGA-BT trial (JCOG1113), gemcitabine plus S-1 (GS) showed non-inferiority to gemcitabine plus cisplatin (GC) in overall survival (OS) with good tolerance for patients with advanced biliary tract cancer (BTC). We performed a subgroup analysis focused on the elderly cohort of this trial. All 354 enrolled patients in JCOG1113 were classify into two groups; < 75 (non-elderly) and ≥ 75 years (elderly) group. We investigated the influence of age on the safety analysis, including the incidence of chemotherapeutic adverse events and the efficacy analysis, including OS. There were no remarkable differences in OS between the elderly (n = 60) and the non-elderly groups (n = 294). In the elderly group, median OS was 12.7 and 17.7 months for those who received GC (n = 20) and GS (n = 40), respectively. The prevalence of all-grade adverse events was similar between the elderly and the non-elderly groups. However, among the elderly group, Grade ≥ 3 hematological adverse events were more frequently observed in the GC arm than in the GS arm. The clinical outcomes of combination chemotherapy in elderly patients with advanced BTC were comparable to non-elderly patients. GS may be the more favorable treatment for elderly patients with advanced BTC.

Chemotherapy for advanced gallbladder cancer (GBC): A systematic review and meta-analysis.

BACKGROUND: The benefit from chemotherapy, specifically for patients with gallbladder cancer (GBC), has been poorly explored since GBC is mostly studied jointly with other biliary tract cancers (BTC). METHODS: Eligible studies reporting outcome of palliative systemic chemotherapy for advanced GBC were identified through MEDLINE, cross-referencing and conferences (PROSPERO-CRD42019155745). Meta-analysis of proportions and calculation of pooled weighted means were performed. RESULTS: 58 eligible studies (n = 1,986 patients); cisplatin/gemcitabine (33 % of patients), gemcitabine/oxaliplatin (14 %) or gemcitabine monotherapy (9%). Estimated pooled overall radiological response rate(ORR), and pooled weighted mean progression-free (PFS) and overall survivals (OS) were 23.2 % (95 %-CI 20.0-26.5) (I2: 52.5 % (p < 0.001)), 4.8 months (95 %-CI 4.3-5.2) and 8.3 months (95 %CI 7.6-8.9), respectively. Patients with non-GBC BTCs achieved a lower ORR than GBC [odds ratio 0.65 (95 % CI, 0.50-0.84)]. CONCLUSIONS: GBC benefit from chemotherapy differs from other BTCs, with shorter PFS/OS despite higher ORR; new treatment options are urgently required for management of advanced GBC.

Gemcitabine alone or in combination with cisplatin in patients with biliary tract cancer: a comparative multicentre study in Japan.

BACKGROUND: A British randomised study of gemcitabine plus cisplatin (GC) combination showed promising results in biliary tract cancer (BTC) patients. In our study, we evaluated the efficacy and safety of this combination compared with gemcitabine alone (G) in Japanese BTC patients. METHODS: Overall, 84 advanced BTC patients were randomised to either cisplatin 25 mg m(-2) plus gemcitabine 1000 mg m(-2) on days 1, 8 of a 21-day cycle (GC-arm), or single-agent gemcitabine 1000 mg m(-2) on days 1, 8 and 15 of a 28-day cycle (G-arm). Treatments were repeated for at least 12 weeks until disease progression or unacceptable toxicity occurred, up to a maximum of 48 weeks. RESULTS: A total of 83 patients were included in the analysis. For the GC and G-arms, respectively, the 1-year survival rate was 39.0 vs 31.0%, median survival time 11.2 vs 7.7 months, median progression-free survival time 5.8 vs 3.7 months and overall response rate 19.5 vs 11.9%. The most common grade 3 or 4 toxicities (GC-arm/G-arm) were neutropenia (56.1%/38.1%), thrombocytopenia (39.0%/7.1%), leukopenia (29.3%/19.0%), haemoglobin decrease (36.6%/16.7%) and gamma-GTP increase (29.3%/35.7%). CONCLUSIONS: Gemcitabine plus cisplatin combination therapy was found to be effective and well tolerated, suggesting that it could also be a standard regimen for Japanese patients.

Gemcitabine, irinotecan and celecoxib in patients with biliary cancer.

The incidence of hepatobiliary cancers is increasing and no standard therapy currently exists. Gemcitabine is an active drug in this disease. Previous studies suggest that the combination of gemcitabine and irinotecan is active with reasonable toxicity profiles in pancreatic and hepatobiliary cancers. COX-2 induction and overexpression have been documented in biliary dysplasia and biliary malignancies. We report on a case series of the efficacy and toxicity of gemcitabine plus irinotecan plus celecoxib in patients with advanced biliary cancer. The treatment consisted of gemcitabine 1000 mg/m given intravenously on days 1 and 8, irinotecan 100 mg/m given intravenously on days 1 and 8, and celecoxib 400 mg orally twice daily every 21 days. Six patients were enrolled, one was ineligible, therefore data were examined on the five remaining patients. One patient had a complete response, one had a partial response, two had stable disease, and one received one cycle of treatment and decided on surgery hence could not be assessed. The treatment was well tolerated with one grade 4 adverse event of thrombocytopenia. In conclusion, the combination of gemcitabine, irinotecan, and celecoxib appears to be well tolerated with some activity against biliary cancer. Further studies using this combination are warranted.

[Chemoradiotherapy for locally recurrence after primary resection of biliary-pancreatic cancer].

Chemoradiotherapy for the unresectable pancreatic cancer and biliary cancer has been used for improving survival. In this study, we examined its safety and efficacy in cases with the local recurrence of pancreatic or biliary cancer after primary resection. Seven consecutive patients with recurrence of carcinoma of pancreas (n=3) and biliary system (n =4) were treated chemoradiotherapy. Local recurrence occurred around the portal vein in 6 patients and remnant pancreas in one patient respectively. Disease free survival after primary surgery was 22 months (range: 5-84). All patients received 50 Gy of conformal three-dimensional radiotherapy with concurrent 5-FU, Gemcitabine or S-1. Grade 3 of anorexia and elevation of transaminase level occurred in one patient respectively. Local tumor response was observed in two patients of pancreatic and biliary cancer respectively. Median survival calculated from the start of the chemoradiotherapy was 14.5 months (range: 6.4-23.9) in pancreatic cancer and 13.5 months (range: 10.8-19.8)in biliary cancer. Our data suggest that chemoradiotherapy is feasible and effective treatment option in patients who present local recurrence after primary surgery in pancreatic or biliary cancer.

Combination versus mono-therapy as salvage treatment for advanced biliary tract cancer: A comprehensive meta-analysis of published data.

AIM: Gemcitabine-based chemotherapy regimens remain the standard first-line treatment for advanced biliary tract cancers (BTCs) patients with no second-line treatments established yet. The preset meta-analysis aims to comprehensively evaluate the role of second-line treatment for advanced BTCs in terms of response, overall survival and toxicities. MATERIALS AND METHODS: Eligible studies were identified using Medline, Pubmed, and meeting abstracts. Searches were last updated on April 30, 2018. Eligible studies reported survival and/or response data for refractory BTCs patients receiving second-line therapy. Primary outcomes of interest were objective response rate (ORR), disease controlled rate (DCR), 1-year overall survival (OS), and progression free survival (PFS). RESULTS: A total of 38 cohorts from 32 studies were eligible for analysis: 23 prospective phase II trials and 9 retrospective studies. In total, data from 1391 patients were reported with median number of patients included in each cohort of 28.5 (range: 9-255). The weighted median PFS and OS for refractory BTCs received second-line therapy were 2.6 months and 6.5 months, respectively. Fluoropyrimidine-based, gemcitabine-based, or Taxanes-based chemotherapy was not superior to single targeted/toxic agent in terms of ORR. In addition, the pooled disease control rate (DCR) and 1-year overall survival (OS) of fluoropyrimidine-based chemotherapy was inferior to single targeted/toxic agent (DCR: 47% versus 60%, RR 0.78, 95%CI: 0.61-1.00, p = 0.03; 1-year OS: 15% versus 29.6%, RR 0.90, 95%CI: 0.29-0.87, p = 0.006), but not for GEM-based or taxanes-based chemotherapy. In addition, correlation analysis indicates that the best correlations were between median OS and median PFS for all cohorts (r=0.57; P = 0.003). CONCLUSION: Combined second-line treatment is not superior to single targeted/toxic agent as salvage treatment for advanced BTCs in terms of ORR, DCR and 1-year OS, and fluoropyrimidine-based chemotherapy seems to be inferior to other second-line regimens. With available evidence from published data, we could not clearly recommend a preferred second-line regimen for advanced BTCs. Further prospective randomized studies are needed to confirm our findings and investigate more efficient second-line therapy in this setting.