Shan-Shuo Liu a , b , Hai-Yu Wang a , b , Ying Sun a , b , Ya-Wen Zou a , b , Zhi-Gang Ren a , b ,Xin-Hua Chen c , Zu-Jiang Yu a , b , *

a Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

b Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

c Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou 310 0 03, China

Pancreatic cancer is a major health problem worldwide, with a high incidence and mortality rate. It is estimated that it has become the sixth leading cause of cancer-related death in China and the fourth leading cause of cancer-related death globally [1] .For patients with locally advanced pancreatic cancer (LAPC), there are no standard treatment options. National Comprehensive Cancer Network (NCCN) guidelines define LAPC as that affecting the superior mesenteric artery (SMA) or the celiac axis (CA) more than 180 ° or nonrepairable infiltration of the superior mesenteric vein(SMV) or portal vein (PV). Although chemotherapy is a treatment option for these patients, the response rates are extremely low and survival benefits are limited [2] . As an emerging local tumor ablation technique, irreversible electroporation (IRE) works by inducing permanent cell membrane porosity through high voltage and microsecond pulses. Because of its lack of thermal effect, it can cause permanent cell death without damaging the surrounding tissues,which is a good option for tumors with large blood vessels, nerves and important tissue structures around the tumors. Additionally,the survival time of patients with LAPC is limited by radiotherapy or chemotherapy alone, and an adjuvant or consolidated local treatment is needed clinically to provide longer local control to relieve pain and possibly improve the survival of LAPC patients. More importantly, IRE allows larger blood vessels to remain intact, and activated antigen-presenting cells can infiltrate lesions and deliver infiltrating tumor fragments to the lymph nodes in place which activates adaptive immune system [ 3 , 4 ].

Fig. 1. The selection process of the included studies. IRE: irreversible electroporation.

To evaluate the efficacy and safety of IRE therapy, we performed a meta-analysis. The terms for literature retrieval were as follows: “IRE”, “irreversible electroporation”, “nano knife”, “pancreatic cancer”, “l(fā)ocally advanced pancreatic cancer” and their various combinations. The flow chart of the included studies is shown in Fig. 1 . After a detailed and sufficient evaluation, 5 studies [ 5 -9 ]meeting our inclusion criteria were retrieved for further analysis.The characteristics of the 383 patients involved in the five studies are summarized in Table 1 . The patients treated with standard chemotherapy (control group) and chemotherapy plus IRE (experimental group) were compared. In these five studies, there were no significant differences in the baseline clinical characteristics or other characteristics between the two groups.

Fig. 2. Forest plot showing outcomes of patients with LAPC undergoing standard chemotherapy and chemotherapy plus IRE. A : 1-year survival rate; B : the tumor progression;C : vomiting; D : leucopenia; E : diarrhea.

In these five studies, we examined the dose and duration of chemotherapy. All chemotherapy regimens chose the recognized standard drug, but the specific dosage and course of treatment were different. Cheng et al. [6] and Huang et al. [7] both chose gemcitabine as chemotherapy drug (IRE + gemcitabine versus single gemcitabine), while Huang et al. additionally applied radiotherapy in the control group. Cheng et al. [6] started chemotherapy at week 4 after IRE, and administrated gemcitabine intravenously at a dose of 10 0 0 mg/m2on day 1, 8, and 15, respectively, 28 days/cycle, for a total of 6 cycles, while Huang et al. [7] started chemotherapy on day 4 after the IRE and 21 days/cycle. In the study by van Veldhuisen et al. [8] , after at least three cycles of FOLFIRINOX (including 85 mg/m2of oxaliplatin and 400 mg/m2of folinic acid intravenously within 2 h, 30 min later, 180 mg/m2intravenously for 90 min, and 400 mg/m2intravenously for fluorouracil, followed by 2400 mg/m2intravenously for 46 h, 15 days/cycle), the experimental group received IRE. In the study by He et al. [5] , induction chemotherapy was performed with gemcitabine (3 cycles) or FOLFIRINOX (4-6 cycles) followed by IRE, while the control group received chemotherapy (gemc-itabine or FOLFIRINOX) only. Their treatment was asynchronous,with chemotherapy followed by IRE. Martin et al. [9] treated 54 patients with IRE. Among them, 49 (91%) had pre-IRE chemotherapy alone or chemoradiation therapy; 40 (74%) underwent post-IRE chemotherapy or chemoradiation.

Table 1 Characteristics of studies included in the meta-analysis.

The main outcome was overall survival (OS), and the secondary outcomes were the assessment of tumor progression and adverse reactions, including vomiting, leukopenia, and diarrhea. The oneyear OS rate in Cheng’s study [6] was 54.2% in the IRE group and 15% in the control group; these rates in Huang’s study [7] were 63.4% and 40.1%; and in He’s study [5] were 89.8% and 18.1%. According to the forest plot, the 1-year OS in the IRE group was better than that of the control group (OR = 4.11, 95% CI: 1.68-10.05,P= 0.002,I2= 42%; Fig. 2 A). According to the Solid Tumor Effi-cacy Evaluation Criteria, tumor progression was defined as tumor volume enlargement of 20% or more, or the emergence of new lesions. The tumor progression rates in the IRE and control groups were 16.7% and 65% (Cheng et al. [6] ), 13.8% and 22.2% (Huang et al. [7] ), 61.1% and 61.1% (He et al. [5] ), and 10% and 21% (van Veldhuisen et al. [8] ), respectively. As seen in the forest plot, IRE did not significantly block tumor progression (OR = 0.40, 95% CI:0.15-1.13,P= 0.08,I2= 62%; Fig. 2 B). According to the forest plot, the incidence of vomiting in the IRE group was significantly lower than that in the control group (OR = 0.27, 95% CI: 0.11-0.69,P= 0.006,I2= 45%; Fig. 2 C). However, IRE did not affect leukopenia (OR = 0.44, 95% CI: 0.20-1.01,P= 0.05,I2= 40%; Fig. 2 D) and diarrhea (OR = 0.65, 95% CI: 0.11-3.86,P= 0.63,I2= 76%; Fig. 2 E).

IRE is widely used because it has no thermal effect and has been shown to be effective in the treatment of prostate cancer and symptomatic atrial fibrillation caused by localized tissue necrosis. The combination of IRE and immunotherapy can improve the safety and effectiveness of treatment [10] . Our meta-analysis showed that IRE has significant advantages in prolonging patient’s survival time and improving the prognosis of patients with pancreatic cancer, which are the two aspects most concerned by doctors and patients. For patients with advanced pancreatic cancer who have lost the optimal timing of surgery and who are not sensitive to the few chemotherapy regimens clinically, combined treatment with nanosecond knife ablation has become the key to control the disease. However, the residual tumor after ablation will aggravate the local recurrence of the lesion area, with faster growth rate,higher aggressiveness, and the possibility of drug resistance. Therefore, the complete destruction of the lesion area and the elimination of residual are crucial to ensure the efficacy of ablation.

However, there are some limitations to draw this conclusion.First, our combined results are based on five studies and a relatively small sample size. Second, not all these studies were highquality randomized controlled trials. Therefore, more studies are still needed to prove the safety and effectiveness of IRE.In conclusion, the combination of IRE and standard chemotherapy has more advantages in the treatment and prognosis of LAPC.Compared with chemotherapy alone, this regimen significantly improved the overall survival time and quality of life of patients,and reduced complications, which can provide a safe and effective method for clinical treatment of LAPC. In particular, IRE has unique advantages for LAPC with a specific anatomical site. We hope that with the development of endoscopic technology and accumulation of surgical experience, this technique will be applicable to more patients.

Acknowledgments

None.

CRediT authorship contribution statement

Shan-Shuo Liu : Data curation, Methodology, Writing - original draft. Hai-Yu Wang : Data curation, Methodology, Writing - original draft. Ying Sun : Formal analysis, Investigation. Ya-Wen Zou :Formal analysis, Investigation. Zhi-Gang Ren : Project administration, Funding acquisition. Xin-Hua Chen : Supervision, Resources.Zu-Jiang Yu : Conceptualization, Writing - review & editing.

Funding

This study was supported by grants from the National Science and Technology Major Project of China ( 2018ZX10301201 ),China Postdoctoral Science Foundation ( 2020T130609 and 2020T130109ZX ), Henan Province Science and Technology Project( 202 102 310 055 ), and Key Scientific Research Projects of Higher Education Institutions in Henan Province ( 20A320056 ).

Ethical approval

Not needed.

Competing interestNo benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.