Biliary Tract Cancer: Gemcitabine+Cisplatin Called New Standard of Care

205 Background: Gemcitabine (GEM) plus cisplatin (GC) is the standard of care for advanced biliary tract cancer (BTC). However, GC is considered to be toxic because of nausea, vomiting, and appetite loss, and inconvenient due to requiring hydration before and after administration. GEM plus S-1 (GS) was reported to be promising with preferable efficacy and acceptable toxicity profile (UMIN000001685). This phase III study aimed to confirm the non-inferiority of GS to GC in terms of overall survival (OS). Methods: Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable biliary tract adenocarcinoma (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), an ECOG-PS of 0–1, and adequate organ function. In the GC arm, 1 g/m2 of GEM and 25 mg/m2 of cisplatin was infused on days 1 and 8 of a 21-day cycle. In the GS arm, 1 g/m2 of GEM was infused on days 1 and 8, and S-1 60, 80, or 100 mg/day according to body-surface area was administered from days 1 to 14 of a 21-day cycle. The primary endpoint was OS and the secondary endpoints included progression-free survival (PFS), response rate (RR), adverse events (AEs), clinically relevant AEs defined as any of grade 2 or more fatigue, appetite loss, nausea, vomiting, oral mucositis, and diarrhea. The sample size was calculated to be 350 with a one-sided alpha of 5%, a power of 80%, non-inferiority margin of 1.155 in terms of hazard ratio (HR). Results: From May 2013 to March 2016, 354 patients were enrolled. The non-inferiority of GS to GC was demonstrated (median OS: 13.4 months (m) in GC and 15.1 m in GS, HR 0.95; 90% confidence interval (CI), 0.78 to 1.15; P = 0.046 for non-inferiority). Median PFS was 5.8 m in GC and 6.8 m in GS (HR 0.86, 95% CI, 0.70-1.07). RR was 32.4% in GC and 29.8% in GS. Preliminary AEs data demonstrated that both treatments were generally well tolerated, although clinically relevant AEs were observed 34.7% in GC and 31.2 % in GS. Conclusions: GS demonstrated non-inferiority to GC in OS with good tolerability and was considered as new convenient option of standard of care without hydration for advanced BTC. Clinical trial information: UMIN000010667.

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Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study

BMC Cancer ◽

10.1186/s12885-019-6142-y ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 5

Author(s):

L. Perkhofer ◽

A. W. Berger ◽

A. K. Beutel ◽

E. Gallmeier ◽

S. Angermeier ◽

...

Keyword(s):

Quality Of Life ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Phase Ii Study ◽

Locally Advanced ◽

Standard Of Care ◽

Open Label ◽

Tract Cancer ◽

Nanoliposomal Irinotecan

Abstract Background Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. Methods NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. Discussion The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. Trial registration Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.

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Chemotherapy for Biliary Tract Cancer in 2021

Journal of Clinical Medicine ◽

10.3390/jcm10143108 ◽

2021 ◽

Vol 10 (14) ◽

pp. 3108

Author(s):

Takashi Sasaki ◽

Tsuyoshi Takeda ◽

Takeshi Okamoto ◽

Masato Ozaka ◽

Naoki Sasahira

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Growth Factor Receptor ◽

Standard Of Care ◽

Postoperative Recurrence ◽

Genetic Alterations ◽

Cytotoxic Agents ◽

Targeted Agents ◽

Tract Cancer ◽

Molecular Targeted Agents

Biliary tract cancer refers to a group of malignancies including cholangiocarcinoma, gallbladder cancer, and ampullary cancer. While surgical resection is considered the only curative treatment, postoperative recurrence can sometimes occur. Adjuvant chemotherapy is used to prolong prognosis in some cases. Many unresectable cases are also treated with chemotherapy. Therefore, systemic chemotherapy is widely introduced for the treatment of biliary tract cancer. Evidence on chemotherapy for biliary tract cancer is recently on the increase. Combination chemotherapy with gemcitabine and cisplatin is currently the standard of care for first-line chemotherapy in advanced cases. Recently, FOLFOX also demonstrated efficacy as a second-line treatment. In addition, efficacies of isocitrate dehydrogenase inhibitors and fibroblast growth factor receptor inhibitors have been shown. In the adjuvant setting, capecitabine monotherapy has become the standard of care in Western countries. In addition to conventional cytotoxic agents, molecular-targeted agents and immunotherapy have been evaluated in multiple clinical trials. Genetic testing is used to check for genetic alterations and molecular-targeted agents and immunotherapy are introduced based on tumor characteristics. In this article, we review the latest evidence of chemotherapy for biliary tract cancer.

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Cisplatin plus irinotecan versus cisplatin plus gemcitabine in the treatment of advanced or metastatic gallbladder or biliary tract cancer: Results of a randomized phase II trial (NCT01859728)– the Gambit trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.529 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 529-529

Author(s):

Lucas Vieira dos Santos ◽

Gustavo Sanches Faria Pinto ◽

Mauricio Wagner Souto Ferraz ◽

Arinilda Bragagnoli ◽

Florinda Santos ◽

...

Keyword(s):

Adverse Events ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Progression Free Survival ◽

Standard Of Care ◽

Distant Metastases ◽

Complete Response ◽

Current Standard ◽

Tract Cancer ◽

To Receive

529 Background: The combination of gemcitabine-cisplatin (GC) is the current standard of care chemotherapy for metastatic/unresectable biliary tract cancer (BTC). However, the prognosis remains poor. This randomized trial aimed to evaluate the efficacy and safety of irinotecan plus cisplatin (IP) versus GC in advanced or metastatic BTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic BTC, ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent were stratified by ECOG (0 or 1 vs 2) and distant metastases and randomized to receive irinotecan 65 mg/m² IV D1 and D8 plus cisplatin 60 mg/m² D1 repeated every 3 weeks (IP) or gemcitabine 1000 mg/m² IV D1 and D8 plus cisplatin 25 mg/m² IV D1 and D8 repeated every 3 weeks, until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: Between January 2013 and April 2018, 47 pts were randomized (1:1) to receive IP (N = 24) or GC (N = 23). Overall, groups were well balanced according to prognostic factors. The ORR was 35% (complete response 5%, partial response 30%) and 31.8% in IP and GC arms, respectively. Median progression-free survival were 5.3 vs 7.8 months (HR = 1.165, 95%CI 0.628-2.161, p = 0.628) and median overall survival were 11.9 and 9.8 months (HR = 0.859, 95%CI 0.431 – 1.710, p = 0.665) for IP and GC, respectively. Adverse events were not statistically different between arms, and results were consistent with previous experiences with these regimens. No therapy-related death were reported. Conclusions: Irinotecan-cisplatin combination is active in BTC, with similar ORR, PFS and OS when compared to gemcitabine-cisplatin. Irinotecan-cisplatin were well tolerated, and adverse events were manageable. Irinotecan-cisplatin could be considered as an alternative to gemcitabine-cisplatin. Clinical trial information: NCT01859728.

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Towards establishing the standard of care for second-line therapy in advanced biliary tract cancer

The Lancet Oncology ◽

10.1016/s1470-2045(21)00543-x ◽

2021 ◽

Author(s):

Eliza W Beal

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Standard Of Care ◽

Second Line ◽

Second Line Therapy ◽

Tract Cancer ◽

Line Therapy

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O-L06 The use of tumour marker Ca19.9 in the follow up of patients with resected biliary tract cancer: Results from the BILCAP randomised clinical trial

British Journal of Surgery ◽

10.1093/bjs/znab429.029 ◽

2021 ◽

Vol 108 (Supplement_9) ◽

Author(s):

Victoria Morrison-Jones ◽

Fangfei Gao ◽

Peter Fletcher ◽

Juan Valle ◽

O James Garden ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Standard Of Care ◽

Randomised Clinical Trial ◽

Evidence Base ◽

Tumour Marker ◽

Large Trial ◽

Predictive Values ◽

Tract Cancer

Abstract Background Even after resection biliary tract cancer has a poor outlook. Follow-up is commonly utalises and the sialyl-Lewis tetra saccharide antigen Ca19.9, a known tumour marker in pancreatic and biliary malignancy (upper limit of normal (ULN) 37U/ml). However, the evidence base for the utility of Ca19.9 is limited. The UK BILCAP trial examined the use of adjuvant capecitabine chemotherapy in resected biliary tract cancer and establishing a new global standard of care. Ca19.9 was regularly measured as part of the BILCAP protocol, this provides an opportunity to assess the use of this marker in a large trial with complete patient follow-up. Methods Between March 2006 and December 2014 447 patients underwent resectional surgery (R0 or R1) then were randomised to receive capecitabine chemotherapy or observation. CT imaging and Ca19.9 were performed 3 monthly in year 1, 6 monthly in year 2, and annually thereafter up to 5 years. Follow up was continued until all patients had 5 years follow-up. Recurrence was based mainly on imaging criteria combined with the clinical presentation. The cohort was divided into progression and non- progression groups and the Ca19. 9 values recorded were investigated using descriptive analyses with cut-off of 37 (ULN), 100 and 400U/ml. Results Of 447 study patients 440 had at least one Ca19.9 measurement from either post-operative baseline (394) or a follow-up visit (422). Baseline Ca19-9 was elevated above 37U/ml in 96 patients and 82 (85%) went on to develop recurrence. The sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV) of the Ca19.9 on follow up are shown in the table. Conclusions Although high Ca19.9 levels predict recurrence as shown by acceptable positive predictive values at cut-offs of 100 and 400U/ml the negative predictive values are very poor as most patients develop recurrence without elevation of Ca19.9. Ca19.9 measurement is of very limited value in the follow up of patients with resected biliary cancer.

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Cisplatin plus irinotecan in the treatment of gallbladder or biliary tract cancer: A randomized phase II trial (NCT01859728).

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.tps485 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. TPS485-TPS485

Author(s):

Lucas Vieira dos Santos ◽

MauriÂcio Wagner Souto Ferraz ◽

Joao Paulo Lima ◽

Kathia Cristina Abdalla

Keyword(s):

Clinical Trial ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Progression Free Survival ◽

Standard Of Care ◽

Ampulla Of Vater ◽

Metastatic Carcinoma ◽

Tract Cancer ◽

Institutional Review ◽

Platinum Chemotherapy

TPS485 Background: Gallbladder and biliary tract cancer (GBTC) have an aggressive behavior and gemcitabine-platinum chemotherapy emerged as the new standard of care for advanced or metastatic GBTC. Despite optimal management, prognosis is still poor. This randomized trial aims to compare irinotecan plus cisplatin versus gembitabine plus cisplatin in advanced or metastatic GBTC. Methods: Patients with biopsy-proven, chemo-naïve, unresectable or metastatic carcinoma of GBTC (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), ECOG 0-2, measurable disease per RECIST 1.1, adequate organ function and written informed consent are stratified by ECOG (0 or 1 vs 2) and hematogenic metastases (yes vs no) and randomized to receive Irinotecan 65mg/m² D1 and D8 q21 days plus Cisplatin 60mg/m² D1 q 21 days (IP) or Gemcitabine 1000mg/m² D1 and D8 every 21 days plus cisplatin 25mg/m² D1 and D8 every 21 days (GC), until disease progression or unacceptable toxicity, with standard hydration and antiemetics. Computed tomography for response evaluation is undertaken every 6 weeks. The primary end-point is overall response rate (ORR). Assuming p0 = 25%, p1 = 50%, alpha = 5% and beta = 20% in an optimal Simon’s two stage design, 24 patients per arm will be recruited (N1 = 9; R1 = 2; Ntot = 24; Rtot = 9). The sample size for each arm was calculated separately. Secondary end-points are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), quality of life and safety. This clinical trial was activated in January 2013 and the accrual period is expected to end by December 2017. This protocol was approved by institutional review board. Clinical trial information: NCT01859728.

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