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Boer LS, Nierkens S, Weusten BLAM. Applications of cryotherapy in premalignant and malignant esophageal disease: Preventing, treating, palliating disease and enhancing immunogenicity? World J Gastrointest Oncol 2025; 17:103746. [DOI: 10.4251/wjgo.v17.i5.103746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/21/2025] [Accepted: 04/11/2025] [Indexed: 05/15/2025] Open
Abstract
Cryotherapy is a treatment modality that uses extreme cold to destroy unwanted tissue through both immediate and delayed cellular injury. This therapy is increasingly being adopted across various medical specialties due to its minimally invasive nature and technological advancements that have been made. In the esophagus, cryotherapy is particularly utilized for the management of Barrett esophagus. It has been demonstrated to be effective and safe with potential benefits, such as a reduction in pain, over radiofrequency ablation. Additionally, it might offer a valuable alternative for patients unresponsive to radiofrequency ablation. Cryotherapy is applied for other conditions as well, including esophageal squamous cell neoplasia and malignant dysphagia. More research is needed to gain understanding of the utility in these conditions. Interestingly, cryotherapy has shown the ability to enhance the host’s immune response in reaction to antigens left in situ after treatment. While preclinical data have demonstrated promising results, the immune response is often insufficient to induce tumor regression in the clinical setting. Therefore, there is growing interest in the combination of cryotherapy and immunotherapy where ablation creates an antigen depot, and the immune system is subsequently stimulated. This combination holds promise for the future and potentially opens new doors for a breakthrough in cancer treatment.
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Affiliation(s)
- Laura Sophie Boer
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht 3584 CX, Utrecht, Netherlands
- Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein 3435 CM, Utrecht, Netherlands
| | - Stefan Nierkens
- Department of Translational Immunology, University Medical Center Utrecht, Utrecht 3584 CX, Utrecht, Netherlands
| | - Bas L A M Weusten
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht 3584 CX, Utrecht, Netherlands
- Department of Gastroenterology and Hepatology, St. Antonius Hospital, Nieuwegein 3435 CM, Utrecht, Netherlands
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Papaefthymiou A, Norton B, Telese A, Ramai D, Murino A, Gkolfakis P, Vargo J, Haidry RJ. Efficacy and Safety of Cryoablation in Barrett's Esophagus and Comparison with Radiofrequency Ablation: A Meta-Analysis. Cancers (Basel) 2024; 16:2937. [PMID: 39272792 PMCID: PMC11394299 DOI: 10.3390/cancers16172937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/12/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
BACKGROUND The mainstay approach in endoscopic eradication therapy (EET) for dysplastic Barrett's esophagus (BE) includes the endoscopic resection of visible lesions, accompanied by ablation of the residual metaplastic epithelium. Cryoablation therapy is one such emerging ablation technique in this field. This systematic review with a meta-analysis aims to accumulate pooled data on cryoablation performance in the treatment of patients with BE and to compare this technique to the standard of care radiofrequency ablation (RFA). METHODS The MEDLINE, Cochrane, and Scopus databases were searched until June 2024 for studies evaluating BE management using cryoablation for cumulative results. The primary outcome was the complete eradication of dysplasia (CED) and intestinal metaplasia (CEIM) in BE compared to RFA, while secondary outcomes included the respective pooled rates using cryoablation, recurrence, and adverse events, with a separate analysis for strictures. The meta-analyses were based on a random-effects model, and the results were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Subgroup analyses by type of cryoablation were also performed. RESULTS Twenty-three studies (1604 patients) were finally included, four of which were comparative. CED and CEIM did not differ significantly between cryoablation and RFA [OR= 0.95 (95%CI: 0.50-1.81) and OR = 0.57 (95%CI: 0.20-1.63), respectively)]. The pooled rates of CED, CEIM, and recurrence after cryoablation were 84.2% (95%CI: 79.1-89.3), 64.1% (95%CI: 49.2-79.0), and 8.3% (95%CI: 4.7-11.9), accompanied by high rates of heterogeneity. Adverse events were noted in 14.5% (95%CI: 9.9-19.2) of cases, and 6.5% (95%CI: 4.1-9.0) developed strictures. In the subgroup analysis, the cryoballoon achieved a reduction in heterogeneity in CED, adverse events, and stricture formation, whereas spray catheters provided homogenous results in terms of recurrence. CONCLUSIONS Cryoablation provides equal outcomes compared to RFA in the treatment of patients with BE, with the cryoballoon achieving relatively homogenous rates of CED and adverse events.
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Affiliation(s)
| | - Benjamin Norton
- Digestive Diseases and Surgery Institute, Cleveland Clinic, London SW1X 7HY, UK
| | - Andrea Telese
- Digestive Diseases and Surgery Institute, Cleveland Clinic, London SW1X 7HY, UK
| | - Daryl Ramai
- Gastroenterology and Hepatology, University of Utah Health, Salt Lake City, UT 84132, USA
| | - Alberto Murino
- Digestive Diseases and Surgery Institute, Cleveland Clinic, London SW1X 7HY, UK
| | - Paraskevas Gkolfakis
- Department of Gastroenterology, "Konstantopoulio-Patision" General Hospital of Nea Ionia, 142 33 Athens, Greece
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme University Hospital, Université Libre De Bruxelles (ULB), 1070 Brussels, Belgium
| | - John Vargo
- Department of Gastroenterology, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Rehan J Haidry
- Digestive Diseases and Surgery Institute, Cleveland Clinic, London SW1X 7HY, UK
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Chandan S, Bapaye J, Khan SR, Deliwala S, Mohan BP, Ramai D, Dhindsa BS, Goyal H, Kassab LL, Aziz M, Kamal F, Facciorusso A, Adler DG. Safety and efficacy of liquid nitrogen spray cryotherapy in Barrett's neoplasia - a comprehensive review and meta-analysis. Endosc Int Open 2022; 10:E1462-E1473. [PMID: 36397870 PMCID: PMC9666080 DOI: 10.1055/a-1906-4967] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 07/20/2022] [Indexed: 10/17/2022] Open
Abstract
Background and study aims Barrett's esophagus (BE) is a precursor condition to esophageal adenocarcinoma (EAC), resulting in transformation of the squamous epithelium of distal esophagus to columnar-lined epithelium with intestinal metaplasia (IM). Liquid nitrogen spray cryotherapy (LNSC) is a non-contact method of BE eradication and has been used both as primary and salvage therapy. We conducted a systematic review and meta-analysis to assess the safety and efficacy of LNSC. Methods We searched multiple databases from inception through December 2021 to identify studies on use of LNSC for Barrett's neoplasia. Pooled estimates were calculated using random-effects model and results were expressed in terms of pooled proportions with relevant 95 % confidence intervals (CIs) of complete eradication (CE) of dysplasia(D), high grade dysplasia (HGD) and IM. Results Fourteen studies with 707 patients were included in our final analysis. Overall pooled rates of CE-D, CE-HGD and CE-IM were 80.8 % (CI 77.4-83.8; I 2 62), 90.3 % (CI 85.2-93.7; I 2 33) and 55.8 % (CI 51.7-59.8; I 2 73) with follow up ranging from 4.25 months to 69.7 months. In patients with follow up beyond 24 months, the rates of CE-D and CE-IM were 83.6 % (CI 77.6-88.2; I 2 60) and 54.7 % (CI 47.6-61.6; I 2 81). Among LNSC naïve patients with prior history of endoscopic resection, the rates were 79.9 % (CI 73.3-85.2; I 2 50) and 67.1 % (CI 59.5-73.8; I 2 0). Pooled rate of therapeutic failures, defined as lack of response to LNSC therapy, was 23.6 % (CI 19.4-28.3; I 2 73). Post LNSC strictures and perforation pooled rates were 4 % and 0.8 %, respectively, which are similar to those previously reported for RFA. Conclusions Our analysis suggests that liquid nitrogen spray cryotherapy is an acceptable treatment for BE in both ablation naïve and experienced patients.
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Affiliation(s)
- Saurabh Chandan
- Division of Gastroenterology & Hepatology, CHI Creighton University Medical Center, Omaha, Nebraska, United States
| | - Jay Bapaye
- Department of Internal Medicine, Rochester General Hospital, Rochester, New York, New York, United States
| | - Shahab R. Khan
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Smit Deliwala
- Internal Medicine, Hurley Medical Center, Flint, Michigan, United States
| | - Babu P. Mohan
- Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, Utah, United States
| | - Daryl Ramai
- Division of Gastroenterology and Hepatology, University of Utah School of Medicine, Salt Lake City, Utah, United States
| | - Banreet S. Dhindsa
- Division of Gastroenterology and Hepatology, University of Nebraska Medical Center, Omaha, Nebraska, United States
| | - Hemant Goyal
- Department of Gastroenterology, The Wright Center for Graduate Medical Education, Scranton, Pennsylvania, Unites States
| | - Lena L. Kassab
- Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States
| | - Muhammad Aziz
- Division of Gastroenterology and Hepatology, University of Toledo, Toledo, Ohio, United States
| | - Faisal Kamal
- Division of Gastroenterology, University of California-San Francisco, California, United States
| | - Antonio Facciorusso
- Gastroenterology Unit, Department of Surgical and Medical Sciences, University of Foggia, Foggia, Italy
| | - Douglas G. Adler
- Center for Advanced Therapeutic Endoscopy (CATE), Centura Health, Porter Adventist Hospital, Denver, Colorado, United States
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Abstract
Cryotherapy is an ablation modality relying on freeze-thaw cycles to promote cell death through intracellular ice crystal formation, ischemia, and apoptosis. Currently, 2 different cryotherapy systems are available for esophageal use. The first is cryospray ablation, which involves repetitive applications of liquid nitrogen. The second system, cryoballoon ablation, freezes the esophageal mucosa with liquid nitrous oxide using a compliant balloon. To date, studies have shown that cryotherapy is an effective and safe method for eradicating Barrett's esophagus; however, larger prospective series with longer follow-up are warranted to determine the clinical utility of cryotherapy in the treatment of Barrett's esophagus.
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Endoscopic Eradication Therapy for Barrett's Neoplasia: Where Do We Stand a Decade Later? Curr Gastroenterol Rep 2020; 22:61. [PMID: 33277663 DOI: 10.1007/s11894-020-00799-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), a cancer associated with increasing incidence and poor survival. Early identification and effective treatment of BE-related neoplasia prior to the development of invasive adenocarcinoma are essential to limiting the morbidity and mortality associated with this cancer. In this review, we summarized the recent evidence guiding endoscopic eradication therapies (EET) for neoplastic BE. RECENT FINDINGS New sampling technologies and the application of artificial intelligence (AI) systems have potential to revolutionize early neoplasia detection in BE. EET for BE are safe and effective in achieving complete eradication of intestinal metaplasia (CE-IM) and reducing the progression to EAC, a practice endorsed by all GI society guidelines. EET should be considered in patients with high-grade dysplasia (HGD), intramucosal carcinoma (IMC), and select cases with low-grade dysplasia (LGD). The increasing use of endoscopic submucosal dissection (ESD) in the West may allow EET of select cases with submucosal EAC. Post-EET surveillance strategies will continue to evolve as knowledge of specific risk factors and long-term neoplasia recurrence rates improve. In the last decade, major advancements in EET for neoplastic BE have been achieved. These now represent the standard of care in the management of BE-related dysplasia and intramucosal cancer.
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Raphael KL, Trindade AJ. Management of Barrett’s esophagus with dysplasia refractory to radiofrequency ablation. World J Gastroenterol 2020; 26:2030-2039. [PMID: 32536772 PMCID: PMC7267696 DOI: 10.3748/wjg.v26.i17.2030] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 04/08/2020] [Accepted: 04/24/2020] [Indexed: 02/06/2023] Open
Abstract
Radiofrequency ablation (RFA) is very effective for eradication of flat Barrett’s mucosa in dysplastic Barrett’s esophagus after endoscopic resection of raised lesions. However, in a minority of the time, RFA may be ineffective at eradication of the Barrett’s mucosa. Achieving complete eradication of intestinal metaplasia can be challenging in these patients. This review article focuses on the management of patients with dysplastic Barrett’s esophagus refractory to RFA therapy. Management strategies discussed in this review include optimizing the RFA procedure, optimizing acid suppression (with medical, endoscopic, and surgical management), cryotherapy, hybrid argon plasma coagulation, and EndoRotor resection.
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Affiliation(s)
- Kara L Raphael
- Division of Gastroenterology, Long Island Jewish Medical Center, Zucker School of Medicine at Hofstra/Northwell, Northwell Health System, New Hyde Park, NY 11040, United States
| | - Arvind J Trindade
- Division of Gastroenterology, Long Island Jewish Medical Center, Zucker School of Medicine at Hofstra/Northwell, Northwell Health System, New Hyde Park, NY 11040, United States
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