What is the evidence for intra-arterial use of gemcitabine for locally advanced pancreatic cancer? Including any dosing, preparation, and administration information available?

Comment by InpharmD Researcher

Evidence for intra-arterial gemcitabine in locally advanced pancreatic cancer includes an interim analysis of the ongoing phase 3 TiGeR-PaC trial showing median overall survival of 16 months versus 10 months for intravenous gemcitabine/nab-paclitaxel (p= 0.08), with fewer adverse events and higher treatment completion (61% vs 23%). Pharmacokinetic sub-studies indicate that intra-arterial gemcitabine at 1000 mg/m² over 20 minutes via the RenovoCath dual-balloon catheter produces lower systemic gemcitabine exposure but higher levels of the inactive metabolite dFdU, which correlates with CA19-9 reduction, suggesting localized drug delivery and metabolism. A 2024 scoping review reports gemcitabine-based intra-arterial chemotherapy yields median overall survival of approximately 7–15 months, with dose-limiting myelotoxicity above 1000 mg/m² and gastrointestinal toxicities mainly at higher infusion doses; administration may be every other week or continuous 24-hour infusion, and perioperative antibiotics are recommended for patients with prior biliary drainage/stents.
Background

As of August 2026, TiGeR-PaC is currently an ongoing multi-center, open-label, randomized, active-controlled clinical trial evaluating treatment options for adults with locally advanced, unresectable pancreatic adenocarcinoma. All participants first receive about four months of induction therapy consisting of intravenous gemcitabine plus nab-paclitaxel along with stereotactic body radiation therapy. Those who remain eligible and are not candidates for surgery are then randomized into one of two groups: one receiving targeted intra-arterial gemcitabine delivered through the RenovoCath device every other week (1000 mg/m2), and the other continuing standard intravenous gemcitabine plus nab-paclitaxel. Randomized treatment continues for up to 16 weeks or until disease progression, after which participants may continue systemic chemotherapy at the investigator's discretion and are followed for survival over five years. The study's primary goal is to compare overall survival between the two groups, with eligibility limited to individuals aged 18 or older who have confirmed disease and good performance status. [1]

A 2024 pharmacokinetic and pharmacodynamic sub-study within the TIGeR-PaC phase 3 clinical trial evaluated intra-arterial gemcitabine (IAG) versus intravenous gemcitabine (IVG) in 16 patients with locally advanced pancreatic cancer across six study sites. Eleven patients received IAG administered at 1000 mg/m² over 20 minutes using the RenovoCath dual balloon catheter, while five patients received IVG at the same dose over 30 minutes. Blood samples were collected at multiple time points from infusion onset to 90 minutes post-infusion to quantify plasma concentrations of gemcitabine and its inactive metabolite difluorodeoxyuridine (dFdU). Pharmacokinetic parameters including maximum plasma concentration (C_max) and area under the concentration-time curve (AUC_0-t) were compared between groups. Tumor marker CA 19-9 levels were measured before treatment and two weeks thereafter, with correlation analysis performed between AUC_0-t and percent change in CA 19-9, excluding three patients with normal baseline values. The analysis demonstrated that IAG resulted in significantly lower systemic gemcitabine exposure, with mean AUC_0-t reduced compared to IVG (4.9 vs 8.8 hr·mcg/mL; p=0.018), although C_max differences were not statistically significant. Conversely, dFdU plasma levels were elevated following IAG administration, with higher mean C_max (48.3 vs 30.6 mcg/mL; p= 0.012) and a trend toward increased AUC_0-t (46.3 vs 37.1 hr·mcg/mL; p=0.097), indicating more rapid conversion of gemcitabine to its inactive metabolite in targeted tissue. Importantly, a positive correlation (Pearson’s r= 0.75; p= 0.034) was observed between increased dFdU exposure and reduction in CA 19-9 after IAG, suggesting that local gemcitabine metabolism may serve as a surrogate marker for therapeutic response. [2]

Another 2026 pharmacokinetic and pharmacodynamic sub-study nested within the TIGeR-PaC phase 3 clinical trial evaluated IAG delivered via a dual balloon catheter against standard IVG in patients with locally advanced pancreatic cancer. Sixteen participants across multiple sites were enrolled, with 11 receiving IAG at 1000 mg/m² over 20 minutes and 5 receiving IVG at the same dose over 30 minutes. Serial blood samples were collected at multiple time points from five minutes before infusion to 90 minutes after onset, and plasma concentrations of gemcitabine and its inactive metabolite, difluorodeoxyuridine (dFdU), were measured. Key pharmacokinetic parameters including C_max and AUC were compared between the two groups. Additionally, CA19-9 tumor marker levels were assessed before treatment and two weeks post-procedure to explore correlations with systemic drug levels. The findings demonstrated that IAG resulted in lower systemic gemcitabine exposure, reflected by reduced C_max and AUC values compared to IVG, consistent with localized drug delivery minimizing systemic circulation levels. Conversely, the metabolite dFdU showed higher C_max and AUC following IAG, indicating a more rapid conversion of gemcitabine to its inactive form at the tissue level. A moderate positive correlation (r= 0.66) was observed between increased systemic dFdU levels and decreased CA19-9 levels within the IAG group, suggesting that dFdU may serve as a surrogate pharmacodynamic marker for tumor response. [3]

The first interim analysis of the TiGeR-PaC trial was performed after the 26th event in the trial, at which point 45 patients had been randomized, 23 to intra-arterial gemcitabine and 22 to intravenous gemcitabine plus nab-paclitaxel, with the survival status of all subjects included. Each arm had an equal number of primary events, 13. Median overall survival was 16 months in the intra-arterial arm versus 10 months in the intravenous arm, with a p-value of 0.08 based on Wilcoxon's non-proportional hazard ratio. Progression-free survival was 15 months with intra-arterial therapy compared with 7 months in the intravenous arm (HR 0.55; CI: 0.21–1.47). Adverse events were roughly three times higher in the intravenous arm than the intra-arterial arm (245 versus 85), with most of the difference driven by hematological toxicities such as neutropenia and thrombocytopenia; 15% of patients in the intravenous arm received colony-stimulating factor compared with none in the intra-arterial arm. In terms of tolerability, 61% of patients in the intra-arterial arm completed all four cycles of active treatment without modification versus 23% in the intravenous arm. Quality of life assessments are still pending. [4]

A 2024 scoping review evaluated IAC as a targeted treatment modality for patients with locally advanced or metastatic pancreatic adenocarcinoma. The review included eight studies, focusing on publications from 2014 to early 2024. Exclusion criteria removed studies involving resectable or borderline resectable pancreatic cancer, radiation therapy adjuncts, or non-English articles. The included studies predominantly involved small, heterogeneous patient cohorts treated with either the FLEC regimen (5-fluorouracil, leucovorin, epirubicin, carboplatin) or gemcitabine-based IAC, with some incorporating combination therapies like nab-paclitaxel and oxaliplatin. Results consistently demonstrated that regional intra-arterial delivery enhanced local drug concentrations while minimizing systemic exposure and toxicity compared to conventional systemic chemotherapy. The FLEC regimen administered via the celiac axis yielded a median overall survival (OS) of 10.5 months in locally advanced disease and 6.6 months in metastatic cases, with manageable hematologic toxicities and no severe angiographic complications reported. Gemcitabine-based IAC, including innovative delivery devices such as the Renovocath dual-balloon catheter and continuous 24-hour infusion protocols, showed median OS ranging from approximately 7 to 15 months, depending on treatment compliance and disease extent. Toxicity profiles for gemcitabine IAC were favorable overall, though dose-limiting myelotoxicity occurred at doses above 1000 mg/m², and gastrointestinal adverse events such as duodenal ischemia and bleeding were observed primarily at higher infusion doses. Combination regimens like gemcitabine, nab-paclitaxel, oxaliplatin, and itraconazole (GnPO-ITC) also showed promising efficacy with median OS around 14.4 months and acceptable peripheral neuropathy rates. [5]

Background References: [1] ClinicalTrials.gov. Intra-arterial Gemcitabine vs. IV Gemcitabine and Nab-Paclitaxel Following Radiotherapy for LAPC (TIGeR-PaC). Updated August 24, 2026. Accessed August 25, 2026. https://clinicaltrials.gov/study/NCT03257033
[2] Nazemzadeh R, Kasi PM, Novelli PM, et al. The TIGeR-PaC phase 3 clinical trial examining intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic and pharmacodynamic sub-study. J Clin Oncol. 2026;44(16_suppl). doi:10.1200/JCO.2026.44.16_suppl.e16463
[3] Novelli PM, Zureikat AH, Pishvaian MJ, et al. Intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic and pharmacodynamic sub-study of the TIGeR-PaC phase 3 clinical trial. J Clin Oncol. 2026;44(2_suppl):732-732. doi:10.1200/JCO.2026.44.2_suppl.732
[4] Pishvaian M, Lopez C, Zervos E, et al. LBA-1 The Phase III Study: Targeted intra-arterial gemcitabine vs. continuation of IV gemcitabine plus nab-paclitaxel following induction with sequential IV gemcitabine plus nab-paclitaxel and radiotherapy for locally advanced pancreatic cancer (TIGeR-PaC). Annals of Oncology. 2023;34:S178. doi:10.1016/j.annonc.2023.04.011
[5] Basra M, Patel H, Biglione A. Intra-arterial Chemotherapy in Patients With Metastatic or Locally Aggressive Pancreatic Adenocarcinoma: A Scoping Review. Cureus. 2024;16(5):e60696. Published 2024 May 20. doi:10.7759/cureus.60696
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the evidence for intra-arterial use of gemcitabine for locally advanced pancreatic cancer? Including any dosing, preparation, and administration information available?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

Gemcitabine-Based Regional Intra-Arterial Infusion Chemotherapy in Patients With Advanced Pancreatic Adenocarcinoma
Design

Observational study

N= 354
Objective To investigate the prognostic factors in patients who received intra-arterial infusion for advanced pancreatic cancer and to describe the detailed procedure of intra-arterial infusion chemotherapy
Study Groups

Patients who received 1 cycle of intra-arterial infusion (n= 274)

Patients who received 2 or more cycles (n= 80)
Inclusion Criteria Patients >18 years of age with advanced pancreatic adenocarcinoma who received intra-arterial infusion at Zhongshan Hospital and did not undergo any previous treatment for pancreatic cancer
Exclusion Criteria Patients who received ERBD or PTCD without infusion chemotherapy
Methods

Gemcitabine-based RIAC was administered under local anesthesia. Right femoral artery puncture and intubation were performed with a 5-Fr arterial sheath. Celiac artery and superior mesenteric artery angiography was carried out with a 4-or 5-Fr catheter. Gemcitabine was given at a dose of 1000 mg/m2, followed by oxaliplatin 100 mg/m2. The infusion was tailored based on tumor location, with supportive care provided post-infusion.
Duration January 2012 to April 2015
Outcome Measures

Primary: Overall survival (OS)

Secondary: 6, 12, 18 month survival rate
Baseline Characteristics   Patients Received 1 Cycle Treatment (n= 274) Patients Received 2 or More Cycles Treatment (n= 80)  
Gender - Male 176 (64.9%) 54 (67.5%)  
Gender - Female 98 (35.1%) 26 (32.5%)  
Age, y (Median, Q1–Q3) 62 (55, 71) 63 (55, 67)  
Tumor location - Head 132 (41.5%) 40 (50%)  
Tumor location - Body or tail 158 (58.5%) 40 (50%)  
Diabetes 107 (40.3%) 31 (38.8%)  
Stage - Locally advanced 187 48  
Stage - Metastasis 87 32  
Baseline CA19-9 level (median, Q1–Q3) U/mL 781.4 (31.5, 4398.0) 878.35 (250.7, 3157.0)  
Results   All patients (N= 354) Patients Received 1 Cycle Treatment (n= 274) Patients Received 2 or More Cycles Treatment (n= 80)
6-month survival rate 0.48  -- --
12-month survival rate 0.28  -- --
18-month survival rate 0.18  -- --
Median OS, months (95% CI) -- 6.0 (5.0, 8.0) 7.0 (6.0, 9.0)
Adverse Events Not discussed
Study Author Conclusions

The gemcitabine-based RIAC presented a potential treatment method for advanced pancreatic adenocarcinoma. Young age, pretreatment CA19-9 value <1000 U/mL, and tumor located at the head of pancreas indicated better response to the regional intra-arterial chemotherapy and better overall survival.
Critique

The study provides a comprehensive analysis of prognostic factors and detailed procedural insights into RIAC for advanced pancreatic adenocarcinoma. However, the retrospective nature and lack of a control group for comparison with systemic chemotherapy limit the ability to draw definitive conclusions about the superiority of RIAC. Additionally, the influence of traditional Chinese medicine as an adjunct therapy was not fully explored, which could affect the interpretation of results.

 

Table 1 References:
[6] Liu X, Yang X, Zhou G, Chen Y, Li C, Wang X. Gemcitabine-Based Regional Intra-Arterial Infusion Chemotherapy in Patients With Advanced Pancreatic Adenocarcinoma. Medicine (Baltimore). 2016;95(11):e3098. doi:10.1097/MD.0000000000003098
Safety Study of Targeted and Localized Intra-Arterial Delivery of Gemcitabine in Patients with Locally Advanced Pancreatic Adenocarcinoma
Design

First-in-man safety study

N= 20
Objective To evaluate the safety and feasibility of targeted intra-arterial delivery of gemcitabine in patients with locally advanced pancreatic cancer using the RenovoCath catheter
Study Groups All patients (n= 20)
Inclusion Criteria Patients with stage 3 locally advanced unresectable pancreatic cancer, Karnofsky score of 70 or greater, able to undergo catheterization procedure
Exclusion Criteria Prior pancreatic resection surgery
Methods

Patients received intra-arterial gemcitabine via the RenovoCath catheter in a four-stage dose escalation up to 1000 mg/m2. Treatment was delivered in a 28-day cycle with two doses per cycle. Periprocedural antibiotics were administered to patients with prior biliary stent/drain to prevent sepsis.
Duration May 2015 to July 2016
Outcome Measures

Primary: Maximum tolerated dose of gemcitabine, safety and tolerability of intra-arterial delivery

Secondary: Tumor response (RECIST criteria), tumor marker reduction, overall survival
Baseline Characteristics   All patients (n= 20)
Age, median years 70 (range: 51-84)
Sex - Male 9 (45%)
Sex - Female 11 (55%)
Prior treatment - Yes 11 (55%)
Prior treatment - No 9 (45%)
Prior chemotherapy only - Yes 5 (25%)
Prior chemoradiation - Yes 6 (30%)
Prior surgery - No 20 (100%)
Results   All patients (n= 15)
Stable disease 11 (73%)
Progression 3 (20%)
Partial response 1 (7%)
CA 19-9 reduction 9 (60%)
>20% CA 19-9 reduction 5 (33%)
Adverse Events Sepsis (n= 3), grade 3 neutropenia (n= 3), guide-mediated vascular dissection (n= 3), pulmonary toxicity (n= 1). No elevated liver or pancreatic enzymes observed
Study Author Conclusions

Localized and selective intra-arterial delivery of gemcitabine using the RenovoCath catheter is feasible and safe, with perioperative antibiotics required for patients with prior biliary drainage/stent. Preliminary efficacy results suggest a survival benefit compared to historical controls.
Critique

The study provides promising safety and feasibility data for localized intra-arterial delivery of gemcitabine. However, the small sample size and potential bias due to industry sponsorship may limit the generalizability of the findings. Further studies with larger cohorts are needed to confirm efficacy and safety.

 

Table 2 References:
[7] Rosemurgy AS, Ross SB, Vitulli PL, Malek R, Li J, Agah R. Safety Study of Targeted and Localized Intra-Arterial Delivery of Gemcitabine in Patients with Locally Advanced Pancreatic Adenocarcinoma. J Pancreat Cancer. 2017;3(1):58-65. Published 2017 Aug 1. doi:10.1089/pancan.2017.0011

 

Intra-arterial Chemoinfusion prior to Chemoradiotherapy with Full-dose Systemic Gemcitabine for Management of Locally Advanced Pancreatic Cancer

Design

 Case reports

Case presentation 1

A 62-year-old man with an unresectable 4.5 cm pancreatic body adenocarcinoma invading the superior mesenteric, common hepatic, and splenic arteries and an elevated CA-19-9 of 302 U/ml underwent coil embolization of peri-pancreatic arteries arising from the superior mesenteric artery and placement of an indwelling catheter in the celiac artery connected to a port; contrast-enhanced CT via the port showed that most of the tumor was supplied by this route, but the portion invading the superior mesenteric artery was not enhanced.

The patient then received six cycles of neoadjuvant intra-arterial 5-FU (1,000 mg/m² over 5 hours) combined with intravenous gemcitabine (1,000 mg/m²) on days 1, 8, and 15 of each 28-day cycle, resulting in tumor shrinkage to 2.5 cm but growth of the poorly perfused superior mesenteric artery portion and a CA-19-9 reduction to 68 U/ml. This was followed by stereotactic body radiotherapy delivering 54 Gy in 18 fractions over 3.6 weeks with concurrent systemic gemcitabine, after which tumor size remained stable and CA-19-9 normalized to 34 U/ml without adverse events. The patient received maintenance gemcitabine, switched to paclitaxel after 24 months due to a slight CA-19-9 increase, and survived for 42 months after presentation.

Case presentation 2

A 60-year-old woman with a 5.0 cm pancreatic body adenocarcinoma invading the superior mesenteric artery and a serum CA19-9 of 178 U/ml underwent the same pancreatic arterial flow alteration and catheter-port placement; contrast-enhanced CT via the port showed that most of the tumor was supplied by this route but the portion invading the superior mesenteric artery was poorly perfused.

She then received five cycles of intra-arterial 5-FU combined with systemic gemcitabine, complicated by grade 2 neutropenia and depression but completed on an outpatient basis, after which the tumor decreased to 3.2 cm although the superior mesenteric artery portion enlarged and CA19-9 fell to 47 U/ml. For the residual tumor, intensity-modulated radiotherapy using the Novalis system with five co-planar beams delivered 50 Gy in 25 fractions over 5 weeks with concurrent full-dose gemcitabine; grade 2 neutropenia occurred but treatment was continued without postponement, and CA19-9 normalized to 25 U/ml. She received maintenance gemcitabine, had tumor progression at 26 months and was switched to S1, and survived for 38 months after presentation.

Study Author Conclusions

 Intra-arterial chemoinfusion followed by chemoradiation with full-dose systemic gemcitabine has a theoretical advantage, and this strategy might prove to be a promising therapeutic approach for locally advanced pancreatic cancer. Large prospective Phase II trials of this combination regimen are warranted.

 

Table 3 References:
[8] Tanaka T, Nishiofuku H, Tamamoto T, et al. Intra-arterial chemoinfusion prior to chemoradiotherapy with full-dose systemic gemcitabine for management of locally advanced pancreatic cancer. Anticancer Res. 2011;31(11):3909-3912.