Diseases of the Esophagus (2017) 30, 1–7 DOI: 10.1093/dote/dox087 Original Article Safety and efficacy of endoscopic spray cryotherapy for esophageal cancer F. C. Tsai,1 S. Ghorbani,1 B. D. Greenwald,2 S. Jang,3 J. A. Dumot,3 M. J. McKinley,4 N. J. Shaheen,5 F. Habr,6 H. C. Wolfsen,7 J. A. Abrams,8 C. J. Lightdale,8 N. S. Nishioka,9 M. H. Johnston,10 A. Zfass,11 W. J. Coyle1 1 2 Scripps Clinic, La Jolla, California, University of Maryland School of Medicine and Greenebaum Cancer Center, 3 4 Baltimore, Maryland, Cleveland Clinic, Cleveland, Ohio, North Shore LIJ Health System and ProHEALTHcare 5 Associates, Syosset & Lake Success, New York, University of North Carolina School of Medicine, Chapel Hill, 6 7 North Carolina, Alpert School of Medicine of Brown University, Providence, Rhode Island, Mayo Clinic Jack8 9 sonville, Jacksonville, Florida, Columbia University Medical Center, New York, New York, Massachusetts Gen10 11 eral Hospital, Boston, Massachusetts, Lancaster Gastroenterology, Inc., Lancaster, Pennsylvania, and Virginia Commonwealth University, Richmond, Virginia, USA SUMMARY. Although surgery is traditionally the standard of care for esophageal cancer, esophagectomy carries significant morbidity. Alternative endoscopic therapies are needed for patients who are not candidates for conventional treatment. The objective of this study is to assess the safety, efficacy, and tolerability of spray cryotherapy of esophageal adenocarcinoma. This study includes patients with esophageal adenocarcinoma who had failed or were not candidates for conventional therapy enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Endoscopic spray cryotherapy was performed until biopsy proven local tumor eradication or until treatment was halted due to progression of disease, patient withdrawal or comorbidities. Eighty-eight patients with esophageal adenocarcinoma (median age 76, 80.7% male, mean length 5.1 cm) underwent 359 treatments (mean 4.4 per patient). Tumor stages included 39 with T1a, 25 with T1b, 9 with unspecified T1, and 15 with T2. Eighty-six patients completed treatment with complete response of intraluminal disease in 55.8%, including complete response in 76.3% for T1a, 45.8% for T1b, 66.2% for all T1, and 6.7% for T2. Mean follow-up was 18.4 months. There were no deaths or perforations related to spray cryotherapy. Strictures developed in 12 of 88 patients (13.6%) but were present before spray cryotherapy in 3 of 12. This study suggests that endoscopic spray cryotherapy is a safe, well-tolerated, and effective treatment option for early esophageal adenocarcinoma. KEY WORDS: cryo, cryotherapy, endoscopic therapy, endoscopy, esophageal cancer. Address correspondence to: Franklin Tsai, MD, Department of Gastroenterology, Scripps Clinic, 10666 N Torrey Pines Road, N203, La Jolla, CA, 92037, USA. Email: email@example.com Specific author contributions: Substantial contributions to conception and design of the work: Franklin C. Tsai, Shireen Ghorbani, Bruce D. Greenwald, Walter J. Coyle; Acquisition, analysis and interpretation of data: Franklin C. Tsai, Shireen Ghorbani, Bruce D. Greenwald, Walter J. Coyle; Drafting work and revising it critically for important intellectual content: Franklin C. Tsai, Shireen Ghorbani, Walter J. Coyle. Final approval of version to be published: Franklin C. Tsai, Shireen Ghorbani, Bruce D. Greenwald, Sunguk Jang, John A. Dumot, Matthew J. McKinley, Nicholas J. Shaheen, Fadlallah Habr, Herbert C. Wolfsen, Julian A. Abrams, Charles J. Lightdale, Norman S. Nishioka, Mark H. Johnston, Alvin Zfass, Walter J. Coyle. Agreement to be accountable for all aspects of the work related to accuracy or integrity: Franklin C. Tsai, Shireen Ghorbani, Bruce D. Greenwald, Sunguk Jang, John A. Dumot, Matthew J. McKinley, Nicholas J. Shaheen, Fadlallah Habr, Herbert C. Wolfsen, Julian A. Abrams, Charles J. Lightdale, Norman S. Nishioka, Mark H. Johnston, Alvin Zfass, Walter J. Coyle. Revising work critically for important intellectual content: Bruce D. Greenwald, Sunguk Jang, John A. Dumot, Matthew J. McKinley, Nicholas J. Shaheen, Fadlallah Habr, Herbert C. Wolfsen, Julian A. Abrams, Charles J. Lightdale, Norman S. Nishioka, Mark H. Johnston, Alvin Zfass. Substantial contributions to acquisition, analysis and interpretation of data: Sunguk Jang, John A. Dumot, Matthew J. McKinley, Nicholas J. Shaheen, John A. Dumot, Matthew J. McKinley, Nicholas J. Shaheen, Fadlallah Habr, Herbert C. Wolfsen, Julian A. Abrams, Charles J. Lightdale, Norman S. Nishioka, Mark H. Johnston, Alvin Zfass. Financial disclosure: The authors have no financial disclosures to make. There were no conflicts of interest C The Authors 2017. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org 1 2 Diseases of the Esophagus INTRODUCTION Adenocarcinoma of the esophagus is one of the most rapidly increasing malignancies in the United States.1,2 In 2017 it is estimated that there will be 16,940 new cases diagnosed and 15,690 deaths from esophageal cancer.3 There has been a paradigm shift in the treatment of superficial esophageal cancer. Surgical resection is less commonly performed for superficial malignancy while endoscopic techniques such as endoscopic mucosal resection (EMR) and endoscopic ablation are increasingly performed.4–6 Alternative therapies for esophageal cancer are being developed. Endoscopic spray cryotherapy of esophageal mucosa using low pressure liquid nitrogen was first described in 2007.7 Multiple studies have shown that endoscopic spray cryotherapy of high grade dysplasia is both efficacious and safe.8,9 The efficacy and safety of liquid nitrogen spray cryotherapy for treatment of esophageal cancer were demonstrated in more recent studies.10,11 In a retrospective multicenter cohort of patients with esophageal cancer treated with spray cryotherapy, Greenwald et al. reported complete intraluminal response in 61% of subjects including 75% complete response in those patients with T1a disease who completed therapy.11 No severe adverse events were reported. The aim of this study is to assess the efficacy and safety of spray cryotherapy in patients with adenocarcinoma of the esophagus. MATERIALS AND METHODS Study design This study includes patients enrolled retrospectively and prospectively in an open-label registry and patients in a retrospective cohort from 11 academic and community practices. Patients were enrolled in the registry between October 2008 and December 2011. All patients were treated with the CryoSpray Ablation System (2nd generation, CSA Medical, Baltimore, MD) using low-pressure liquid nitrogen. Participating institutions included Cleveland Clinic, University of Maryland, Mayo Clinic Jacksonville, Virginia Commonwealth University, North Shore LIJ Syosset Hospital, Columbia University, Lancaster Gastroenterology, Massachusetts General Hospital, Rhode Island Hospital, University of North Carolina, and Scripps Clinic, the latter of which served as the data coordination site. The primary outcome was complete eradication of local tumor confirmed by biopsy. Additional outcomes included downgrade of baseline disease and safety outcomes. Subjects Patients at 11 institutions with biopsy proven esophageal adenocarcinoma who were treated with Fig. 1 Liquid nitrogen cryotherapy system. spray cryotherapy with either curative or palliative intent were included. The tumor stages were determined by endoscopic ultrasound, EMR, or surgery. All patients had refused, failed, or were ineligible for conventional therapies including esophagectomy, chemotherapy, or radiotherapy. This study was approved by the institutional review board at each site. Informed consent was obtained for all patients, except for retrospectively enrolled patients if informed consent was waived by the institution’s IRB. Treatment Patients were treated with endoscopic spray cryotherapy, which consists of a console containing a holding tank for medical grade liquid nitrogen (−196◦ C) and uses a spray catheter to deliver low pressure (<5 psi) cryogen with 25 W of energy to the targeted tissue (Fig. 1). Patients were given either moderate sedation with intravenous midazolam combined with meperidine or fentanyl, or monitored anesthesia care (MAC), based on physician discretion. A 16 Fr dual lumen modified decompression tube was introduced through the mouth and passed into the gastric antrum over a guidewire. This tube provided both passive venting and active suction of nitrogen gas to prevent gastric over distention. A freeze-resistant disposable 7 Fr spray catheter was passed through the working channel of a standard Cryotherapy for esophageal cancer 3 Fig. 2 (A) Patient with esophageal adenocarcinoma (T1a by endoscopic ultrasound staging) not a candidate for surgery due to comorbidities or endoscopic mucosal resection due to inability to stop anticoagulation. (B) Spray cryotherapy of nodular lesion. (C) Appearance after 3 months with endoscopic biopsies negative for cancer or dysplasia. endoscope, and liquid nitrogen was delivered to a target site. Each site was typically treated with three cycles of 20-second freezes; however freeze cycles could be interrupted then resumed due to abdominal distention or loss of visibility, and dosimetry could be adjusted based on the endoscopist’s discretion. The timer was initiated after the entire target area was covered with white frost (Fig. 2). The abdomen was continuously monitored for distention by a trained assistant during treatment. Between each cycle, the treated mucosa was allowed to fully thaw, as evidenced by disappearance of the white frost. Cryotherapy sessions were performed at 4 to 6 week intervals until there was complete eradication of local tumor confirmed by biopsies or when treatment was halted due to lack of response, disease progression, patient preference, or comorbid conditions. In some cases, additional spray cryotherapy was performed to eradicate residual intestinal metaplasia. Each site had its own GI pathologists review the biopsy specimens. After completion of treatment, patients underwent surveillance endoscopies at intervals at the discretion of the home institution. Adverse events were recorded at follow-up endoscopy sessions, periodic clinic visits or by follow-up phone calls. Significant adverse events (SAEs) were reported immediately and defined as events associated with complete inability to do work or usual activities, signs and symptoms that were systemic in nature, or need for hospital admission or intensive care. Data analysis For each subject, demographic information, baseline histology, tumor TNM staging, previous or concurrent therapies, adverse events, number of treatment sessions, results of cryotherapy, and final disease type and stage were collected. For the safety analysis, all patients and treatments were analyzed for development of SAEs including severe pain (requiring pain medication), stricture (either asymptomatic or requiring dilation or intervention), and perforation. For the intention to treat efficacy analysis, we included patients who completed treatment based on eradication of local tumor or withdrawal for the abovementioned reasons. Complete response was defined as complete eradication of all luminal cancer confirmed by biopsies. Dropouts and deaths were included in the efficacy analysis as treatment failures. Other concurrent therapies such as endoscopic mucosal resection (EMR), photodynamic therapy (PDT), argon plasma coagulation (APC), and radiofrequency ablation (RFA) were allowed. But patients who underwent esophagectomy, chemotherapy, or radiation after enrollment were considered treatment failures. RESULTS One hundred and four patients were screened among the 11 participating institutions. Sixteen patients were excluded due to missing T stages; therefore, eightyeight patients were enrolled in the study. Thirty patients (34.1%) were enrolled in the open-label registry and 70 patients (79.5%) were enrolled in the retrospective cohort, with 12 of the patients (13.6%) enrolled in both. The median age was 76 years (range: 51–93, IQR 15) and 80.7% of patients were male. Tumor length was reported in 81 patients, with a mean length of 5.09 cm (range: 1–15 cm, SD 3.81). Baseline tumor stages included 39 (44.3%) with T1a, 25 (28.4%) with T1b, 9 (10.2%) with unspecified T1, and 15 (17%) with T2 (Table 1). At baseline, no patients enrolled had known distant metastases (all M0 or MX). Regional lymph node metastasis (N1) was reported in no patients with T1a disease, 1 patient (4%) with T1b disease, and five patients (33.3%) with T2 disease. Patients receiving treatment prior to enrollment included 3 (3.4%) with prior esophagectomy, 14 (15.9%) with prior chemotherapy, 21 (23.9%) with prior radiation therapy, 30 (34.1%) with EMR, 10 (11.4%) with PDT, 4 (4.5%) with APC, 3 (3.4%) with RFA, and 1 (1.1%) with brachytherapy. Of the 14 patients who had previously received chemotherapy, 4 Diseases of the Esophagus Table 1 Demographics and baseline characteristics No. subjects Table 2 Safety analysis Total 88 Completed therapy 86 71 (80.7) 17 (19.3) 76 (51–93, 15) 70 (81.4) 16 (18.6) 76 (51–93, 14) Patients (n = 88) no. (%) Treatments (n = 359) no. (%) 0 (0.0) 17 (19.3) 10 (11.4) 17 (19.3) 12 (13.6) 9 (10.2) 8 (9) 7 (8) 3 (3.4) 3 (3.4) 2 (2.3) 1 (1.1) 1 (1.1) 0 (0.0) 0 (0.0) 0 (0.0) Sex, no. (%) Male Female Age, years, median (range, IQR) Ethnicity, no. (%) White African American Not stated Tumor stage, no. (%) T1a T1b T1 (unspecified) T2 Tumor length, cm, mean (range, SD)† No. treatments, median (range, IQR) 81 (92) 1 (1.1) 6 (6.8) 81 (94.2) 1 (1.2) 4 (4.6) 39 (44.3) 25 (28.4) 9 (10.2) 15 (17) 5.1 (1–15, 3.8) 38 (44.2) 24 (27.9) 9 (10.5) 15 (17.4) 5.1 (1–15, 3.8) 3 (1–25, 3) 3 (1–25, 3) Deaths Treatment related Cancer related Unrelated to treatment/cancer Abdominal Pain Stricture† Dysphagia Sore Throat Chest Pain Nausea Ulcers Odynophagia Heartburn GI bleed‡ Hospitalization Perforation 17 (4.7) 12 (3.3) 16 (4.5) 17 (4.7) 16 (4.5) 4 (1.1) 3 (0.8) 4 (1.1) 2 (0.6) 1 (0.3) 0 (0.0) 0 (0.0) † Three strictures were pre-existing prior to cryotherapy; ‡ Bleeding unrelated to cryotherapy, due to spontaneous bleeding lesion in patient on supratherapeutic warfarin. †7 pts with no reported length. IQR, interquartile range; SD, standard deviation. Table 3 Treatment results (intention to treat analysis) two had stage T1a disease but were not candidates for EMR or surgery due to co-morbidities such as cirrhosis with esophageal varices. Twenty-nine patients (33%) received concurrent therapy including 15 (17%) with EMR, 7 (8%) with APC, 4 (4.5%) with RFA, 3 (3.4%) with radiation, 2 (2.3%) with chemotherapy, 2 (2.3%) with esophageal stent, 1 (1.1%) with brachytherapy, and 6 (6.8%) patients underwent esophagectomy after cryotherapy. Safety analysis A total of 359 cryotherapy treatments were performed in these 88 patients. There were no cryotherapy-related deaths or hospitalizations reported. There were a total of 27 deaths (30.7%) including 17 (19.3%) cancerrelated deaths and 10 (11.4%) deaths from unrelated comorbidities (Table 2). There were 12 (13.6%) patients that had esophageal strictures; however, three of those patients had pre-existing strictures prior to cryotherapy. There was one reported GI hemorrhage due to a spontaneous bleeding lesion in the setting of supratherapeutic warfarin unrelated to cryotherapy. The most commonly reported postprocedure symptoms included abdominal pain (19.3%), dysphagia (10.2%), sore throat (9%), and chest pain (8%). Efficacy analysis Eighty-six patients were included in the efficacy analysis, and the remaining two patients were still receiving cryotherapy treatments at time of analysis. Patients received a median of 3 cryotherapy treatments (range: 1–25, IQR 3). Forty-eight (55.8%) of patients had Total By tumor stage T1 total Mucosal (T1a) Submucosal (T1b) Not stated T2 Complete response no. (%) Persistent tumor no. (%) 48 (55.8) 38 (44.2) 47 (66.2) 29 (76.3) 11 (45.8) 7 (77.8) 1 (6.7) 24 (33.8) 9 (23.7) 13 (54.2) 2 (22.2) 14 (93.3) complete response (eradication of all luminal tumor) and 38 (44.2%) were nonresponders (Table 3). Complete responders underwent a median of 3 treatment sessions (range: 1–13, IQR 2), compared to 4 for nonresponders (range: 1–25, IQR 4). Mean followup was 18.4 months for all patients, and 23.5 months for responders. At time of final follow-up, 44 patients (51.2%) were alive and free of luminal disease, 3 (3.5%) were alive and free of disease postesophagectomy, 11 (13%) were alive with disease, 6 (7%) were dead without disease, 4 (4.7%) were dead with disease, and 18 (20.9%) were dead from disease. Final known luminal histology at time of last follow-up was normal in 29 patients (33.7%), nondysplastic Barrett’s in 10 (11.6%), low grade dysplasia in 4 (4.7%), high grade dysplasia in 6 (7%), and adenocarcinoma in 37 (43%). Response rates by baseline tumor stages are listed in Table 3, including 76.3% response for T1a lesions, 45.8% for T1b lesions, 66.2% for all T1 lesions, and 6.7% for T2 lesions. There was no difference in median age of responders versus nonresponders (75 years versus 75.9 years, P = 0.68). Length of baseline disease was reported in 43/48 responders and 36/38 nonresponders. In those patients, there was no statistically Cryotherapy for esophageal cancer 5 significant difference between mean length of baseline disease between responders versus nonresponders (5 cm vs. 5.2 cm, P = 0.80). In a subgroup analysis of the 29 patients with 2 cm or smaller tumors, the response rates by baseline tumor stages were 62.1% overall, 73.3% for T1a lesions, 42.9% for T1b lesions, 69.2% for all T1 lesions, and 0% for T2 lesions. There were a total of 27 deaths during a mean follow-up period of 18.4 months. For the 17 patients who died of disease, the baseline disease stages were T1a (1), T1b (8), and T2 (8). There were four patients who died with disease from other causes (colon cancer, myocardial infarction, pulmonary embolus, and renal failure) and had baseline disease stages of T1a (1) and T2 (3). There were six patients who died without disease from unrelated causes (cardiac arrest, liver failure, sepsis from leg wound, and three with unreported causes). The baseline disease stages for patients who died without disease were T1a (3) and T1b (3). DISCUSSION The incidence of esophageal adenocarcinoma has increased from 3.6 cases per million in 1973 to 25.6 cases per million in 2006 in the United States.4 Mortality has also increased, suggesting a need for alternative treatment options. Traditionally, esophagectomy had been the standard for treatment of early esophageal adenocarcinoma; however there is a relatively high morbidity rate of 30%–50%.12–14 Advances in surgical technique including minimally invasive esophagectomy and improved perioperative care have decreased operative mortality (3.8%) but is still associated with considerable morbidity of >40% regardless of open versus minimally invasive approach.15 A preference for less invasive modalities has led to the development and evaluation of endoscopic therapy for the treatment of early esophageal carcinoma.16,17 The relatively low incidence of lymph node metastasis in stage T1a esophageal adenocarcinoma makes endoscopic therapy a feasible option.18 In addition, multiple studies have shown no difference in survival and mortality rates between endoscopic and surgical treatment of superficial esophageal adenocarcinoma, and a significantly higher rate of complications with surgery (32% vs. 0%).4,19,20 Endoscopic therapy includes methods that ablate tissue, such as cryotherapy, or those that resect tissue, such as endoscopic mucosal resection.21 Resection therapies have the advantage of also providing histology for staging, with studies showing that EMR changes initial staging in more than 25% of cases.22,23 The use of endoscopic spray cryotherapy to treat early esophageal malignancy was first reported in 2007 for the palliative treatment of recurrent esophageal squamous cell carcinoma, which led to complete remission for 24 months.7 More recently, endoscopic spray cryotherapy has been shown to be a safe and effective alternative to thermal ablative techniques for treatment of early esophageal adenocarcinoma in the appropriate patient population. Spray cryotherapy has the benefit of not requiring tissue apposition in order to be effective, which is useful in a tortuous esophagus or other difficult anatomy, such as a large hiatal hernia.24 In 2009, Dumot et al. reported on a single center, prospective cohort of patients with BE and HGD or T1a esophageal adenocarcinoma who underwent cryotherapy with a median follow-up of 1 year.10 Elimination of cancer and intestinal metaplasia was seen in 80% of patients with T1a esophageal adenocarcinoma. Three of 6 patients with complete response had recurrence of dysplasia or cancer in the gastric cardia. In a 2010 multicenter, retrospective cohort, 79 patients with esophageal adenocarcinoma (94%) or squamous cell carcinoma who were not considered surgical candidates or who refused esophagectomy were treated with spray cryotherapy.11 Of the 49 patients who completed therapy, complete response of intraluminal disease was seen in 72% of all T1 tumors and 75% of all T1a tumors. No serious adverse events were reported and mean follow-up was 10.8 months. For patients who have visible or nodular lesions in the setting of BE, EMR or ESD is preferred as the first step in endoscopic treatment, which will provide pathologic staging.22 In our registry, EMR was not possible in all cases due to inability to stop anticoagulation, scarring from previous treatment, T1b or higher lesion, or inability to visualize the cancer endoscopically, necessitating ablation of the entire segment of BE. When these patients were treated, ESD was not widely available in the United States and widespread adoption continues to be slow. However, studies show that ESD is an effective and safe option and may be considered for patients with superficial esophageal cancer at institutions with expertise in this technique.25,26 In our study, data was pooled from 11 academic and community practices in an open-label registry and retrospective cohort. Eighty-eight subjects with esophageal adenocarcinoma carcinoma who were not surgical candidates or otherwise had failed or refused conventional therapies underwent endoscopic spray cryotherapy using low-pressure liquid nitrogen. Complete eradication of tumor was seen in 76.3% of T1a lesions and 45.8% of T1b lesions with no deaths or severe adverse events directly related to cryotherapy. This suggests that earlier stage appears to predict response of esophageal cancer to spray cryotherapy. There were 12 patients that had strictures, however three of the 12 patients had pre-existing strictures. The strengths of this study include participation of a large number of patients from both academic and community centers, and few exclusion criteria thereby 6 Diseases of the Esophagus better representing those patients encountered in clinical practice. Because most of these patients had failed or were not candidates for conventional therapy, they represent a more challenging cohort of patients to achieve therapeutic success. The main limitation of this study was lack of standardization of treatment across the different centers. We were unable to control for possible variability in technique, dosimetry, and clinical decision making of the investigators at the different sites, issues inherent to all registry studies. This study pooled data from a prospective registry with a retrospective cohort. Additionally, there were 16 patients excluded from the study due to missing T stage. It cannot be determined with certainty if the patients with missing data could have affected the results either positively or negatively. T staging was obtained by pathology in 37.5% of patients but was obtained by EUS for the rest of the patients, including 56% of those with T1a and 44% with T1b disease. Because T1a and T1b disease may be difficult to accurately stage by EUS, it is possible that there was under or over staging. Furthermore, this study was unable to discern intent of treatment as palliative versus curative for each patient, therefore the interpretation of outcomes was conservative, in that a palliative ‘success’ such as alleviation of dysphagia, might still be viewed as a failure in our analysis if there was residual intraluminal disease. It should also be noted that all patients in this study were treated prior to September 2012 using the 2nd generation CryoSpray Ablation System (CSA Medical) which was in clinical use from 2007 to 2013 and has now been replaced by the 3rd generation TruFreeze System (CSA Medical) with several advancements including spray catheter flexibility and more laminar flow of liquid nitrogen. Therefore, the results from this study may not be applicable to the current device in clinical use. Whether the technological advancements of the current generation cryotherapy device will result in improvements in efficacy and safety is an area of ongoing research. This study suggests that endoscopic spray cryotherapy is safe, well tolerated, and efficacious for treatment of early esophageal adenocarcinoma, either as an adjunct or alternative to conventional therapy depending on the clinical situation. Additional studies are needed to evaluate the long-term durability of cryotherapy. ACKNOWLEDGMENTS The administration costs for the registry were partially funded by CSA Medical. Participating investigators include Dr. James S. Barthel, Dr. Amit Bhatt, and Dr. Rohit Makkar for their contributions to the study including collection of data and providing care for study patients. References 1 Hur C, Miller M, Kong C Y et al. Trends in esophageal adenocarcinoma incidence and mortality. Cancer 2013; 119: 1149–58. 2 Pohl H, Sirovich B, Welch H G. 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