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Digital subtraction angiography-guided pancreatic arterial infusion of GEMOX chemotherapy in advanced pancreatic adenocarcinoma: a phase II, open-label, randomized controlled trial comparing with intravenous chemotherapy

BMC Cancer volume 24, Article number: 941 (2024) Cite this article

Abstract

Background

Advanced pancreatic adenocarcinoma lacks effective treatment options, and systemic gemcitabine-based chemotherapy offers only marginal survival benefits at the cost of significant toxicities and adverse events. New therapeutic options with better drug availability are warranted. This study aims to evaluate the safety and efficacy of digital subtraction angiography (DSA)-guided pancreatic arterial infusion (PAI) versus intravenous chemotherapy (IVC) using the gemcitabine and oxaliplatin (GEMOX) regimen in unresectable locally advanced or metastatic pancreatic cancer (PC) patients.

Materials and methods

This study prospectively enrolled 51 eligible treatment-naive patients with unresectable PC to receive GEMOX treatment via PAI or IVC (1:1 ratio randomization) from December 2015 to December 2019. Cycles were repeated monthly, and each process consisted of two treatments administered bi-weekly. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-year survival, 6-month survival, tumor-site subgroup survival, and incidences of adverse events were compared.

Results

The median OS of the PAI and IVC groups were 9.93 months and 10.07 months, respectively (p = 0.3049). The median PFS of the PAI and IVC groups were 5.07 months and 4.23 months (p = 0.1088). No significant differences were found in the ORR (11.54% vs. 4%, p = 0.6312), DCR (53.85% vs. 44%, p = 0.482), and 1-year OS rate (44% vs. 20.92%, p = 0.27) in PAI and IVC groups. The 6-month OS rate was significantly higher in the PAI group (100%) than in the IVC group (83.67%) (p = 0.0173). The median OS of patients in PAI group with pancreatic head and neck tumors were significantly higher than those of body and tail tumors (12.867 months vs. 9 months, p = 0.0214). The incidences of hematologic disorders, liver function disorders, and digestive disorders in the IVC group were higher than in the PAI group (p < 0.05).

Conclusion

GEMOX PAI therapy presented a higher 6-month OS rate and fewer adverse events than IVC in advanced pancreatic adenocarcinoma patients. Those with pancreatic head and neck tumors may yield a superior treatment outcome from PAI treatment.

Trial registration number

NCT02635971.

Date of registration

21/12/2015.

Peer Review reports

Introduction

Digital subtraction angiography (DSA)-guided catheterized interventional treatment has been successfully evaluated in various solid tumors, particularly in liver neoplasms [1, 2]. In addition to its substantial improvement of image quality and spatial resolution assiting diagnosis, this route of chemotherapy infusion deliver remarkably higher concentration of anti-cancer agents to act directly on tumor than systemic infusion as well as limiting adverse events (AEs) [3,4,5,6]. As early as in the 1980s, DSA with selective angiography-guided arterial infusion of chemotherapy has been attemped across clinical observational studies as an loco-regional therapeutic approach aiming to deliver higher concentrations of antineoplastic agents to the tumor site [7,8,9]. This therapeutic approach has already been successfully evaluated for the treatment of several types of tumors, specifically in primary and metastatic liver tumours, demonstrating higher regional concentrations of drugs and limited systemic toxicities [10, 11]. Eversince, its clinical application is emerging in interventional oncology.

Pancreatic cancer (PC), a notorious ischemic cancer with dismal prognosis and limited treatment options, warrants new therapeutic options [12, 13]. Its highly chemoresistant biological feature at least in part contribute to the low response rate, unsatisfactory progression-free survival and overall survival [14]. Since the approval of gemcitabine as a treatment for PC in the 1990s following a trial showing survival benefits over 5-FU infusion [15], gemcitabine-based regiments, such as gemcitabine combined with oxaliplatin (GEMOX), showed to increase the overall survival in two phases III trials [16, 17]. For advanced pancreatic cancer, its current most effective regimen, the FOLFIRINOX schedule (5-fluorouracil, folic acid, irinotecan, oxaliplatin) is accompanied with several grade 3–4 adverse events, thereby, limiting its clinical applications [18]. Aside from the mechanical barrier formed by densely fibrotic envelope surrounding the pancreatic tumors, the poor vascularity of tumor and the pancreas itself hampers the delivery of chemotherapy drugs to the tumor site through systemic infucion. Therefore, new therapeutic options with better drug availability are warranted.

In PC, DSA with selective angio-graphy applied to celiac, superior mesenteric, hepatic and gastroduodenal arteriographies has allowed the visualization of arterial, capillary and venous phases of the tumors infiltration under contrast agents, assiting in the lcocalization of tumor as well as vascularity and micrometastatic lesions [19,20,21]. Pancreatic arterial infusion (PAI) of chemotherapeutics under selective-DSA has been suggested to raises the accuracy and safety of chemotherapeutic agent delivery, yields higher local concentrations of drugs and, at the same time, of limiting systemic toxicity across clinical observations [22]. As for advanced PC, only a few clinical trials have investigated PAI’ safety and efficacy with promising results, especially high response rates compared to systemic chemotherapy [23]. However, clear evidence assessing its efficacy by well-design controlled trials are yet to be established.

The present study aims to prospectively evaluate the safety and efficacy of DSA-guided PAI therapy compared to IVC using GEMOX regimen in unresectable locally advanced or liver metastatic PC, in aims to provide more valuable evidence-based medical observation for the application and optimization of PAI in interventional oncology.

Materials and methods

Patient eligibility and study design

A single-center, prospective, randomized, parallel-controlled, open-label, phase II trial (NCT02635971) of GEMOX PAI for the treatment of unresectable pancreatic adenocarcinoma was performed. The study protocol was approved by the Institutional Ethics Committee (Ethic approval No. 1509152-3-1711 A). Written informed consent was obtained from all participants included in this study. The study design is shown in Fig. 1, and the detailed inclusion and exclusion criteria are shown in Supplemenrary Table S1. Eligible participants were randomized at a 1:1 ratio using the Interactive Web Response System (IWRS, Zhejiang Taimei Medical Technology Co., Ltd) into the PAI treatment group or the IVC control group. All patients registered in the protocol were analyzed using the intention-to-treat analysis. This study was performed according to the Declaration of Helsinki and its later amendments.

Fig. 1
figure 1

Patient inclusion chart and treatment plan

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Treatment procedures

All patients received gemcitabine and oxaliplatin-based chemotherapy (GEMOX) with Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 once every two weeks and four weeks (28 days) as one cycle. In the IVC control group, gemcitabine, dissolved in normal saline, was administered intravenously in a 1000 mg/m2 infusion for 30 min, followed by oxaliplatin, diluted with 5% glucose, in a 2-hour infusion.

In the PAI group, GEMOX infusion was performed under DSA. Once every two-week, using the Seldinger method, catheterization was performed through alternating punctures of the bilateral femoral arteries to prolong the interval of vascular puncture and avoid femoral artery injury and thrombosis [24]. Angiographies were performed at the celiac artery and the superior mesenteric artery-opening to identify the tumor-feeding artery for infusion. For the pancreatic head and neck tumors, chemotherapy drugs were infused through the gastroduodenal artery or superior mesenteric artery, where appropriate. As for the pancreatic body and tail, tumors were infused through the splenic artery or superior mesenteric artery, where applicable. For patients with liver metastases, half of the drugs were infused into the proper hepatic artery or other feeding arteries of liver metastases. Representative images of DSA and computed tomography (CT) are shown in Fig. 2. Gemcitabine was administered trans-arterially in 1000 mg/m2, dissolved in normal saline, and infusion for 20 min, followed by oxaliplatin, diluted with 5% glucose, in a 20 min infusion. The catheter placement during drug infusion was monitored under DSA. The catheter was removed at the end of the infusion, and hemostasis was achieved by manual compression.

Fig. 2
figure 2

Representative images of DSA and CT in PAI-treated patients with different tumor-sites. (A) Anatomical diagram of blood supply of pancreatic tumors. (B-C) Pancreatic head and neck tumors, chemotherapy drugs were infused through the gastroduodenal artery or superior mesenteric artery; (D-E) Pancreatic body and tail tumors, chemotherapy drugs were infused through the splenic artery or superior mesenteric artery. Yellow arrows indicate tumor lesions

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Baseline assessments and outcome evaluations

Prior to enrollment, the medical history, physical examination, laboratory tests, and tumor assessment through imaging examinations (CT or MRI) are collected as the baseline. Before each cycle of treatment, biochemical profiles and performance status were assessed. Blood routine examination was done weekly. Tumor response evaluation during treatment was performed at the end of each two cycles (per 8 weeks) and in the follow-up periods by imaging examinations and assessed in accordance with the Response Evaluation Criteria in Solid Tumors (RECISIT) version 1.1 [25]. Adverse events were rated according to National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0.3). Survival follow-up was performed every eight weeks until the patient died or was lost to follow-up.

The treatment was discontinued under the following circumstances: (1) disease progression; (2) intolerable adverse reactions after dose adjustment; (3) patients need to receive antineoplastic therapy other than the study regimen (such as radiotherapy, etc.); (4) patient voluntarily requests to withdraw from the study.

Statistical considerations and analysis

The primary endpoint was overall survival (OS), defined as the time from randomization to death. The secondary endpoints were progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), 1-year survival, and 6-month survival. PFS is defined as the time from randomization to the first onset of progressive disease (PD) or death of any cause, whichever came first or was censored at the last follow-up. Subjects who have never progressed and survived will be censored on the date of the last tumor evaluation; subjects who have not been evaluated and survived in the study will be censored on a randomized day. ORR is defined as the proportion of subjects with complete response (CR) or partial response (PR) in each treatment group. DCR is defined as the proportion of subjects with CR, PR, or stable disease (SD) in each treatment group.

The survival analysis was carried out using the Kaplan–Meier method with a log-rank test comparison between the two groups. Statistical analyses were conducted using the GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA) and SPSS 25.0 (SPSS Inc., Chicago, IL, USA) software on the intention-to-treat (ITT) populations. Continuous variables were expressed by mean, standard deviation, or median. The categorical variables were compared with the chi-square test or Fisher’s exact test. A two-sided p-value < 0.05 was considered significant.

Results

Patient characteristics

Fifty-one patients were included between December 2015 and December 2019. Among the included patients, 26 patients received GEMOX pancreatic arterial infusion treatment, and 25 patients received GEMOX intravenous chemotherapy, referred to as the PAI group (13 males and 13 females, median age 65 years) and the IVC group (15 males and 10 females, median age 65 years) respectively. 13 patients had liver metastasis (25.49%). Overall, 26 patients had tumors located in the head and neck of the pancreas (PAI vs. IVC: 13 vs. 13), and 25 in the body and tail of the pancreas (PAI vs. IVC: 13 vs. 12). There was no significant difference between the two groups in baseline characteristics. The flowchart of patients throughout the study is shown in Fig. 1, and the baseline characteristics of participants are shown in Table 1. The median numbers of treatment cycles in the PAI and IVC groups were 3.5 (range, 2–10) and 3 (range, 2–8), respectively (p = 0.7284).

Table 1 Baseline characteristics
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Survival

The median follow-up of the PAI and IVC groups was 9.73 months and 9.97 months, respectively. The Kaplan–Meier curves of OS and PFS among the included participants were presented in Fig. 3. The median OS was 9.93 months in the PAI group compared with 10.07 months in the IVC group (p = 0.3049). The median PFS of the PAI group and the IVC group was 5.07 months and 4.23 months (p = 0.1088). The two groups had no statistical significance in median OS and median PFS. The 1-year survival rate of the PAI group was 44.0%, and that of the IVC group was 20.92% (p = 0.27). The 6-month OS rate of the PAI group (100%) was significantly higher than that of the IVC group (83.67%) (p = 0.0173). Interestingly, we found that the median OS of patients with tumors in head and neck of pancreas (11 months) was slightly higher than those of pancreatic body and tail tumors (9.1 months, p = 0.0768) in the whole cohort (Fig. 4A), and no significant difference in PFS (Fig. 4B). Therefore, we subdivided the two different treatment groups into different tumor-site subgroups, and then compared their survival differences. In the PAI group, the median OS of patients with pancreatic head and neck tumors was significantly higher than that of body and tail tumors (12.867 months vs. 9 months, p = 0.0214), but there was no significant difference in IVC group (Fig. 4C-D). Comparison of OS and PFS of four subgroups of PAI or IVC for pancreatic head and neck tumors or body and tail tumors were showed in Supplementary Figure S1 with no significant difference.

Fig. 3
figure 3

Summary of the primary and secondary endpoints. Kaplan-Meier analysis of (A) Overall survival, (B) Progression-free survival, (C) 1-year survival, and (D) 6-month survival in the ITT population. Objective response rate (E) and disease control rate (F) in PAI and IVC group, respectively

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Fig. 4
figure 4

Kaplan-Meier survival curves of tumor-site subgroups. (A) Overall survival and (B) Progression-free survival comparison between tumor-site subgroups of pancreatic head and neck tumor lesions and pancreatic body and tail lesions in the whole cohort. Overall survival of pancreatic head and neck tumors and body and tail tumors in PAI group (C) and IVC group (D)

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Response

The overall objective response rate (ORR) was 11.54% in the PAI group compared to 4% in the IVC group (p = 0.6312), while the disease control rate (DCR) was 53.85% and 44.0% in the PAI group and the IVC group, respectively (p = 0.482) (Fig. 3G-H). Specifically, three and one patients in the PAI and the IVC group showed partial response (PR), respectively (Table 2). In addition, 11 patients (42.31%) in the PAI group had stable disease (SD), and 10 patients (40%) were in the IVC group (p = 0.8671). PD occurred in 12 patients (46.15%) in the PAI group and 14 patients (56%) in the IVC group (p = 0.482). Treatment responses of tumor-site subgroups of pancreatic head and neck tumor lesions and pancreatic body and tail lesions were presented in Supplementary Figure S1 and Table 3. The ORR was 23.08% in the PAI group with pancreatic head and neck tumors compared with 0% in PAI patients with pancreatic body and tail tumors (p = 0.22). However, there was no significant difference in ORR and DCR among the four subgroups (PAI-Head & neck vs. PAI-Body & tail vs. IVC-Head & neck vs. IVC-Body & tail) as a whole. Serum tumor marker analysis showed that 80.77% of the patients in the PAI group showed a decrease or stable status in serum Ca19-9 level after treatment. In comparison, 76% of the patients in the IVC group showed a decrease or stable status in serum Ca19-9. Moreover, the serum Ca242 was suppressed in 80.77% and 72% of patients in the PAI and IVC groups, respectively (Fig. 5).

Table 2 Treatment responses and survival outcomes
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Table 3 Treatment responses and survival outcomes of tumor-site subgroups of pancreatic head and neck tumor lesions and pancreatic body and tail lesions
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Fig. 5
figure 5

Changes of blood indexes before and after treatment. (A) Serum tumor markers and blood biochemistry; (B) Blood routine and biochemistry. Ca19-9 carbohydrate antigen199, Ca242 carbohydrate antigen242, TBIL total bilirubin, ALP alkaline phosphatase, ALT amino alanine transferase, AST aspartate amino transferase, LDH lactate dehydrogenase, CRE creatinine, TP total protein, WBC white blood cell, GRAN neutrophils, RBC red blood cell, HGB hemoglobin, PLT platelet

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Adverse events

The PAI treatment was well tolerated with no major complications or mortality, and the incidences of treatment-related adverse events were summarized in Table 4. In the statistics of all levels of adverse events, the results showed that the incidences of hematologic disorders, liver function disorders, and digestive disorders in the IVC group were higher than in the PAI group. The most significant grade 3–4 event was liver function disorders in the IVC group, where six patients (24%) showed elevated transaminases (ALT or AST) or elevated total bilirubin (TBIL). The most common adverse event was hematologic disorders, including anemia, thrombocytopenia, and neutropenia.

Table 4 Adverse events
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Statistically, significantly more hematologic disorders occurred in the IVC group (22 patients, 88%) compared to that of the PAI group (16 patients, 61.54%) (p = 0.0302). The changes in hematological indicators of biochemical profiles (hepatic and renal function) and complete blood count before and after treatment are shown in Fig. 5A and B, respectively. As shown in Figs. 5A and 40% of patients in the IVC group presented with elevated TBIL after treatment, while only 34.62% of patients in the PAI group showed an increase in TBIL. It is worth noting that more than 50% of the patients in the PAI group had an improvement in TBIL levels towards the normal level following the maximal number of courses received. In addition, the proportion of elevated AST, ALT, and LDH in the IVC group was higher than in the PAI group, suggesting that patients in the IVC group are more prone to liver dysfunction. No statistically significant difference was found in serum creatinine between the two groups. As shown in Fig. 5B, the complete blood count of patients showed a decrease in white blood cell (WBC) count among 56% of patients in the IVC group, while 23.08% of the patients in the PAI group presented with a reduction of WBC count. Additionally, patients in the IVC group showed a higher rate of granulocyte (GRAN) count decreases (36%) than that in the PAI group (15.38%). Notably, hemoglobulin (HGB) and platelet (PLT) levels were reduced in both groups (HGB: 73.08% in the PAI group and 84% in the IVC group; PLT: 57.69% in the PAI group and 72% in the IVC group); while the red blood cell (RBC) count remained relatively stable before and after treatment.

Digestive disorders, including loss of appetite, abdominal distension, nausea/vomiting, diarrhea, and constipation, were observed in 14 patients (56%) in the IVC group and seven patients (26.92%) in the PAI group (p = 0.0349). Both the IVC and PAI groups had one case of grade 3–4 nausea and vomiting (p = 0.9774). Dermal disorders were not reported in the PAI group and occurred in 2 patients in the IVC group, with one report of itching (4%) and one report of rashes (4%) (p = 0.1412).

Five patients (19.23%) in the PAI group reported pain in the abdomen, back, or lower back during oxaliplatin infusion. The pain lasted less than 24 h for all cases without needing post-interventional analgesics. And most of the pain that occurred during the PAI process was relieved immediately after treatment. Other adverse events, including peripheral neuropathy, respiratory disorders, ascites, hematemesis, and insomnia, were slatternly reported without statistically significant differences between the PAI and the IVC groups.

Discussion

Locally advanced or liver metastatic PC lacks effective treatment option, and systemic gemcitabine chemotherapy offers only marginal survival benefits at the cost of significant toxicities and adverse events. Therefore, there is a need for better palliative treatment options for PC patients with unresectable diseases. In this study, we evaluated the efficacy and tolerability of GEMOX PAI therapy and IVC in patients with locally advanced or liver metastatic PC.

The GEMOX regimen, which is known for its moderate activity and good tolerability compared to mFOLFIRINOX or AG combination, was used in patients with superior physical performance status [26,27,28]. Our results suggest that although no statistically significant difference in overall efficacy was found between the two groups, our outcome on median OS of 10.07 months is comparable to that reported by Chen et al. [29]. Consistently to previous reports by Louvet C et al. (2002), Alberts SR et al. (2003), and Baize N et al. (2005), our results of the intravenous infusion group are comparable. On the other hand, PAI has been reported to prolong survival [30], obtain complete tumor response [31], and improve clinical outcomes [32] in In LAPC and metastatic PC. However, most of the studies on PAI in PC were case studies or retrospective analyses. A meta-analysis of 6 randomized controlled trials with a total of 298 patients comparing regional trans-arterial versus systemic chemotherapy for LAPC reported a longer median overall of 5–21 months of the PAI compared to that of systematic chemotherapy (2.7–14 months) and the 1-year survival rate of PAI (28.6–41.2%) was also higher than that of systematic chemotherapy (0–12.9%) [33,34,35,36,37]. To our knowledge, this is the first study investigating the infusion of GEMOX through trans-arterial or intra-venous in a prospective clinical trial setting.

Our results suggest that although there was no statistically significant difference in overall efficacy between the two groups, PAI therapy is better in short-term efficacy, especially in the first six months of the research (6-month OS rate PAI vs. IVC: 100% vs. 83.67%, p = 0.0173). Meanwhile, the PFS tended to be slightly longer in PAI group than the IVC group (5.07 months vs. 4.23 months, p = 0.1088), indicating potential survival benefits. There was no treatment-related death in the PAI group, and the 1-year survival rate was higher in the PAI group than in the IVC group (44% and 20.92%, respectively, p = 0.27). It should be noted that the most extended treatment for patients in PAI group was over 2 years, which was a patient with stage III head and neck pancreatic cancer. Due to the patient’s strong adaptability and confidence in the treatment process of PAI chemotherapy, after 11 months of GEMOX arterial infusion chemotherapy, PD developed, and we attempted an alteration of GEMOX regimen to AG regimen to maintain arterial infusion therapy after consultation with the patient. Fortunately, the patient’s overall condition was relatively stable after regimen change with good tolerance, and arterial perfusion of AG regimen was maintained for one year until treatment was terminated. This case enlighted us on the possibility of convenience and adaptable long-term maintenance of PAI chemotherapy and also inspired us to use AG regimen of PAI to further determine the efficacy of arterial infusion in the future. Our subgroup analysis of the pancreatic head and neck lesions using PAI treatment, compared to pancreatic body and tail lesions demonstrated a better median OS. A possible explanation for the varying efficacy of percutaneous arterial infusion treatment for pancreatic tumors are the anatomical vascularization of the lesions. Tumors located in the pancreatic head are predominantly supplied by the gastroduodenal artery or by the celiac trunk-common hepatic artery-proper hepatic artery. These vessels can be superselected using the current microcatheter (with an outer diameter of 0.93 mm) to administer drugs directly to the tumor. However, tumors located in the pancreatic body and tail are mainly supplied by small blood vessels separated from the spleen, such as the dorsal pancreatic artery or the branch of pancreatica magna artery. Unfortunately, the existing microcatheter cannot accurately select these vessels, resulting in poor drug efficacy as most drugs flow to the spleen instead of the tumor. Thus, it is essential to identify tumor locations and evaluate which patients are suitable for PAI treatment.

Although the PAI group did not demonstrate better outcomes in terms of tumor response rate and survival time compared to the IVC group, which was consistent with a study by Meyer et al. [38], the PAI treatment group had a shorter infusion time in our study. This could be due to the drug infusion being completed in the operating room to ensure aseptic operation. The shorter infusion time may be one of the reasons why PAI did not achieve a better effect than IVC. Nevertheless, no catheter-related infections were observed in our study. The total duration of hospital stay for enrolled patients were two days only, including follow-up visits, serological tests, and imaging for treatment response evaluations. The entire treatment process can be completed in 24 h, the same for both groups, avoiding depriving patients of valuable time at home with their families. In future studies, it may be beneficial to explore the effectiveness of employing the successful hepatic arterial infusion chemotherapy (HAIC) treatment of hepatocellular carcinoma [39] in PC treatment. This approach involves covering and protecting the wound at the intubation site and allowing patients to continue the infusion after returning to the ward, extending the time of drug infusion to 2–4 h or longer, potentially achieving better efficacy. However, other studies have suggested that a fixed-dose rate infusion of gemcitabine at 10mg/m2/min may yield superior clinical outcomes [28, 40]. Moreover, artery infusion pump chemotherapy has been reported to have better overall response rates in intrahepatic lesions of pancreatic cancer with synchronous liver metastasis [41, 42]. Therefore, it would be interesting to compare the efficacy of these treatments in a phase III trial for patients with advanced PC.

In this study, we also investigated the safety of PAI in comparison to IVC of GEMOX regimen in advanced PC. The results showed that the PAI group had a lower incidence of grade 3–4 toxicity (3.85%) compared to the IVC group (24%) with liver function disorders being the most common adverse effect. The hematological disorders were also less frequent in the PAI group (61.54%) than in the IVC group (88%). Pain assessment revealed that the PAI group had a higher rate of treatment-related pain (19.23%) than the IVC group (4%), which was likely due to gemcitabine-related vascular irritation during infusion. However, the pain was transient and relieved immediately after PAI for most cases. The lower toxicity observed in the PAI group could be attributed to the reduced dose of drug to systemic circulation after passing through the tumor. Moreover, PAI was found to be easier for patients to tolerate, with stable curative effects and fewer adverse reactions. The study used the same dose as IVC once every two weeks for arterial infusion, but in our practical clinical application, similar response was also observed under the condition of 1/2 dose once a month. However, this administration regimen needs further clinical trials to verify its efficacy.

This current study had certain limitations. Primarily, the study did not achieve the intended number of patient recruitments due to the removal of the GEMOX regimen from first-line chemotherapy for advanced PC and the subsequent discontinuation of reimbursement by the Chinese national medical insurance during this implementation research [43]. Furthermore, the AG regimen and mFOLFIRINOX regimen have become more commonly used, leading to enrollment difficulties and reduced confidence of patients and attending physicians to prescribe the GEMOX regimen. Consequently, the study recruitment was discontinued in 2020. Despite the small sample size, PAI still demonstrated better short-term efficacy and safety. Secondly, adverse events that occurred after discharge were actively reported by patients during their subsequent treatment admission, which may have led to underreporting of some adverse events. Therefore, further studies with appropriate up-to-date chemotherapy regimens, such as the AG regimen [44, 45], and a more reasonably designed drug arterial perfusion duration are needed to evaluate the efficacy and tolerability of PAI in advanced PC patients.

Conclusion

In conclusion, our study demonstrates that PAI therapy using GEMOX is a safe and effective short-term treatment option for patients with advanced PC, particularly those with tumors located in the pancreatic head and neck regions. Therefore, PAI should be considered as a potential therapeutic option for managing both locally advanced and liver metastatic PC, but larger, well-designed trials are necessary to determine its optimal role.

Data availability

The datasets analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

PAI:

Pancreatic arterial infusion

IVC:

Intravenous chemotherapy

DSA:

Digital subtraction angiography

CT:

Computed tomography

Ca19-9:

Carbohydrate antigen199

Ca242:

Carbohydrate antigen242

ITT:

Intention-to-treat

TBIL:

Total bilirubin

ALP:

Alkaline phosphatase

ALT:

Amino alanine transferase

AST:

Aspartate amino transferase

LDH:

Lactate dehydrogenase

CRE:

Creatinine

TP:

Total protein

WBC:

White blood cell

GRAN:

Neutrophils

RBC:

Red blood cell

HGB:

Hemoglobin

PLT:

Platelet

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Acknowledgements

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Funding

This study was supported by clinical research funding of Fudan University Shanghai Cancer Center (Grant No. YJLC201504) and funding of the National Natural Science Foundation of China (Grant No. 82074204).

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Author notes

  1. Changjing Huang and Chien-shan Cheng contributed equally to this work.

Authors and Affiliations

  1. Minimally Invasive Therapy Center, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Changjing Huang, Chien-shan Cheng, Yehua Shen, Hao Chen, Junhua Lin, Yongqiang Hua, Lanyun Feng, Caijun Wu, Peng Wang, Zhen Chen & Zhiqiang Meng

  2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Changjing Huang, Chien-shan Cheng, Yehua Shen, Hao Chen, Junhua Lin, Yongqiang Hua, Lanyun Feng, Caijun Wu, Peng Wang, Zhen Chen & Zhiqiang Meng

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Contributions

MZQ, SYH: Conceptualization, Methodology, Supervision, Writing - Review & Editing. HCJ: Investigation, Formal analysis, Visualization, Writing - Original Draft. CJS: Investigation, Visualization, Data Curation, Writing - Review & Editing. CH, LJH, HYQ, FLY, WCJ, WP, CZ: Resources, Investigation, Writing - Review & Editing.

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Correspondence to Yehua Shen or Zhiqiang Meng.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Ethics Committee of Fudan University Shanghai Cancer Center, Shanghai, China (Ethic approval No. 1509152-3-1711 A). Informed consent was obtained from all individual participants included in the study.

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Supplementary figure S1

: Kaplan-Meier survival curves and treatment responses in different tumor sites. Comparison of OS (A) and PFS (B) of four subgroups of arterial infusion chemotherapy or intravenous chemotherapy for pancreatic head and neck tumors or body and tail tumors in the whole cohort. PFS of pancreatic head and neck tumors and body and tail tumors in PAI group (C) and IVC group (D). Bar plots of ORR (E-G) and DCR (H-J) in different tumor-site subgroups

Supplementary Material 2

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Huang, C., Cheng, Cs., Shen, Y. et al. Digital subtraction angiography-guided pancreatic arterial infusion of GEMOX chemotherapy in advanced pancreatic adenocarcinoma: a phase II, open-label, randomized controlled trial comparing with intravenous chemotherapy. BMC Cancer 24, 941 (2024). https://doi.org/10.1186/s12885-024-12695-8

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Keywords

BMC Cancer

ISSN: 1471-2407

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