In early July 2019, the network of European HTA agencies, EUnetHTA, published the report titled “Irreversible electroporation for the treatment of liver and pancreatic cancer”.
The project was executed by the Scientific Advice Unit (Avalia-t) of the Galician Agency for Health Knowledge Management (ACIS), Spain and the Ludwig Boltzmann Institute for Health Technology Assessment (LBI-HTA), Austria, as co-authors. The dedicated reviewers come from the State Health Care Accreditation Agency Under the Ministry of Health of the Republic of Lithuania (VASPVT), National Institute of Pharmacy and Nutrition (NIPN) in Hungary and the Swiss Network for Health Technology Assessment (SNHTA).
Irreversible electroporation (IRE) is a nonthermal ablative method involving the application of short high-voltage and low-frequency electric fields to create nanoscale pores in tissue, resulting in permeabilization of cell membranes. This permeabilization can become irreversible when the magnitude, duration, and a number of the electrical fields applied are above a certain threshold. Because of the mostly nonthermal effect, it is alleged that IRE leads to less damage to adjacent structures in comparison to other thermal ablative approaches (radiofrequency ablation [RFA], microwave ablation [MWA] and cryoablation). This allows ablation of pancreatic and liver tumors that are localized close to major blood vessels or other sensitive structures such as nerves and the bile duct without causing them damage. IRE can be performed percutaneously, laparoscopically, or as part of open surgery.
The only commercialized IRE device is the NanoKnife System® (AngioDynamics®). This system has the Conformité Européenne (CE) mark for cell membrane electroporation and US Food and Drug Administration (FDA) approval for soft tissue ablation. It has not received clearance for therapy or treatment of any specific disease or condition.
The intended population for IRE is patients diagnosed with unresectable locally advanced pancreatic tumors. The standard-of-care therapy for these patients is chemotherapy (CHEMO), with or without radiation therapy (chemoradiotherapy [CRT]). Radiotherapy (RT) is also typically offered as a palliative option as it reduces pain. Regarding liver cancer, the intended population for IRE consists of patients with unresectable primary or secondary liver cancer who have a contraindication to thermal ablation. The most common treatment options include transarterial chemoembolization (TACE), multikinase inhibitors such as sorafenib and levatinib, and palliative and symptomatic therapy.
A systematic literature search was carried out on 26 September 2018 (and updated in January 2019) using the Centre for Research and Dissemination (CRD), Cochrane Library (Wiley), Embase (OVID), Medline (PubMed), Web of Science (Web of Knowledge) and Scopus. A manual search of the reference list of relevant studies was also undertaken to recover published studies that might have been missed by the search. Guideline repositories were used to identify relevant guidelines for the current use of the technology (CUR) domain.
The authoring team independently screened the titles and abstracts according to the predefined inclusion criteria. Data were extracted independently by two authors and double-checked regarding consistency and accuracy by the co-author. Discrepancies between authors about data were resolved through discussion and consultation with the co-author until an agreement was reached. The risk of bias at the study level was assessed using the Institute of Health Economics (IHE) 20-Criteria Checklist for single-arm studies (case series) and Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) for nonrandomized controlled trials (non-RCTs). The quality of the body of evidence was assessed and synthesized according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system.
Two individual patients were also involved in the assessment.
Results – Available evidence:
The systematic literature search identified 15 observational studies that met the eligibility criteria, eight for pancreatic cancer, and seven for liver cancer. No RCTs were found. For pancreatic cancer, there was one non-RCT, including 21 patients in the intervention arm and 32 in the control arm and seven prospective single-arm observational studies that enrolled 226 patients treated with IRE. Six of these had a median follow-up of ≤12 months. The longest follow-up was 28.1 months. For liver cancer, seven prospective single-arm trials were included involving 151 patients with 220 IRE-treated lesions. The mean follow-up was ≤18 months in five of these studies and the maximum recorded was 24 months.
For pancreatic cancer, articles included in the SAF domain do not differ from those for the EFF domain. For liver cancer, one study was not included as safety outcomes were not reported.
Results – Clinical effectiveness:
- Pancreatic cancer: According to the only comparative study, the median overall survival (OS) for patients after IRE did not differ significantly between the treatment and control group (10.03 vs 9.3 months; p = 0.053). The median survival after IRE based on Kaplan-Meier estimations ranged from 4.3 to 12 months in four of the single-arm trials. Only three studies provided data to calculate the OS from the time of diagnosis. The median OS in these studies varied from 12.5 months to 17.5 months. The three studies that reported on progression-free survival (PFS) after IRE showed median OS between 3.2 months and 15.4 months. One study reported time to progression (TTP), which was 3.3 months (95% CI 2.30, 6.38). The median time to local recurrence varied from 6.8 months to 12 months
- Liver cancer: The mean OS after IRE was only available from one study, which was 37.9 months (95% CI 30.28, 45.57). OS from the time of diagnosis or PFS was not reported in the liver cancer studies. Median TTP was only available in one study, which was 15.6 months
Results – Safety:
- Pancreatic cancer: None of the studies reported intervention-specific deaths (during the intervention). In total, 19.5% of treated patients experienced major adverse events (AEs). The overall procedure-related mortality (grade V AE) was 1.6% among all studies. The causes of death were hemorrhage, duodenal and bile duct necrosis and portal vein thrombosis. The frequency of grade III or IV IRE procedure-related complications in the studies that provided relevant data was 10.6% (range 0–44%). For patients who underwent IRE for primary control, the frequency was 5.6% for open surgery (>90% of cases) and 20.3% for the percutaneous approach. The frequency of minor (grade I–II) complications in the studies that provided relevant data were 32.7%. Most of the minor AEs were gastrointestinal problems, infection, and others such as bleeding and thrombosis.
- Liver cancer: None of the studies reported intervention-specific deaths. The overall frequency of major AEs was 8.7%. None reported procedure-related mortality. Major AEs included hemothorax, hemoperitoneum, bleeding, and stricture of the portal vein or bile duct. The most common minor AEs were pain, hematomas, and cholestasis.
Results – upcoming evidence
A search for ongoing studies identified 22 trials in the pancreatic cancer setting, most of which are single-arm trials that are still recruiting patients. One of the studies is a patient registry. For liver cancer, 16 trials were found, of which at least eight are still recruiting. Most of these are single-arm trials, and some are finished, but no publication was found.
Conclusions – pancreatic cancer:
- There is insufficient evidence to establish whether IRE is more effective than, or at least as effective as, the conventional standard of care (CHEMO, CRT or palliative therapy) for the treatment of unresectable locally advanced pancreatic cancer (LAPC)
- There is insufficient evidence to establish whether IRE is safer than, or at least as safe as, the conventional standard of care for the treatment of unresectable LAPC
- The existing evidence raises doubts regarding the efficacy of IRE for achieving complete ablation of unresectable LAPC. The existing evidence raises doubts regarding the efficacy of IRE as a sole primary local treatment for LAPC. Currently, it is unclear whether IRE needs to be combined with CHEMO and, if so, which regimens are optimal
- There are uncertainties regarding the occurrence of severe AEs when IRE is used for the treatment of unresectable LAPC
Conclusions - liver cancer:
- There is a lack of data to establish whether IRE is more effective than, or at least as effective as, the conventional standard of care (TACE, sorafenib or palliative therapy) for the treatment of patients with primary or secondary unresectable liver cancer that is not suitable for thermal ablation
- There is a lack of evidence to establish whether IRE is safer than, or at least as safe as, the conventional standard of care for the treatment of patients with primary or secondary unresectable liver cancer that is not suitable for thermal ablation
- The existing evidence raises doubts regarding the efficacy of IRE for achieving complete ablation of primary or secondary unresectable liver tumors that are not suitable for thermal ablation
- The existing evidence raises doubts regarding the efficacy of IRE as a sole primary local treatment for primary or secondary liver tumors that are not suitable for thermal ablation
- There are uncertainties regarding the occurrence of severe AEs when IRE is used for the treatment of liver tumors that are not suitable for thermal ablation
See the report in English here.
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