Cryotherapy has emerged as a promising treatment option for various stages of esophageal cancer, offering a minimally invasive approach to managing early-stage and advanced disease. At the 2024 annual meeting of the American Foregut Society, Tilak Shah, MD, MHS, the medical director of the Pancreas Center at Cleveland Clinic Weston Hospital, in Florida, provided an in-depth look at the practical applications of cryotherapy, particularly for patients who may not be suitable candidates for traditional interventions.
“Spray cryotherapy offers a promising alternative for patients with complex presentations of esophageal cancer, especially when surgical intervention or other standard treatments are not feasible,” Dr. Shah said. “Our findings suggest that cryotherapy can effectively manage symptoms and potentially improve outcomes in challenging cases.”
Esophageal cancer remains a significant health concern, with adenocarcinoma being a prevalent subtype. As Dr. Shah explained, esophageal cancer often is diagnosed in its later stages, limiting treatment options. Although surgery, radiation and chemotherapy remain the mainstays of treatment, many patients are not suited for these interventions due to underlying health conditions.
Cryotherapy, a minimally invasive technique that uses extreme cold to destroy abnormal tissue, is increasingly being explored for its effectiveness in managing esophageal cancer, especially in high-risk patients (see box).
According to Dr. Shah, cryotherapy offers potential benefits over radiofrequency ablation (RFA) and photodynamic therapy (PDT) by providing deeper tissue penetration with fewer side effects. RFA often is used to treat Barrett’s esophagus (BE) but is limited by its shallow depth of penetration, Dr. Shah said, making it less effective for bulky or deeply invasive tumors. Although PDT is effective in some cases, it can result in significant side effects, he said, particularly photosensitivity, which is problematic for patients in sunnier climates.
Alternatively, cryotherapy offers greater depth of tissue penetration without many of the complications associated with other therapies. “In patients with high-risk comorbidities, cryotherapy offers a safer, less invasive option,” Dr. Shah noted, referencing studies that show approximately 60% complete response rates in patients with T1b esophageal cancer treated with cryotherapy.
Neoadjuvant Applications And Advanced Cancer
Cryotherapy also has proven to be valuable when used in conjunction with neoadjuvant chemoradiation for patients with more advanced esophageal cancer. Dr. Shah shared findings from two small trials involving 14 patients each, in which cryotherapy was combined with neoadjuvant chemoradiation (Endosc Int Open 2019;7[11]:E1522-E1527). These patients underwent one to three sessions of spray cryotherapy, which resulted in a complete clinical response rate of more than 50%. According to Dr. Shah, this rate is nearly double the expected 25% to 30% complete response rate for chemoradiation alone.
“What’s particularly promising is that we observed no grade 2 or 3 toxicities, and patients reported significant improvements in dysphagia and overall quality of life,” Dr. Shah added. “These early results suggest that cryotherapy could play a critical role in improving outcomes for patients undergoing multimodal therapy.”
Palliative Role of Cryotherapy
For patients with inoperable esophageal cancer, cryotherapy has shown significant benefits in improving quality of life by reducing symptoms such as dysphagia. Dr. Shah shared a case involving a 77-year-old patient with T3N0 esophageal adenocarcinoma. The patient, who was not a surgical candidate, experienced notable relief after undergoing cryotherapy, which improved his ability to eat and manage daily activities.
Another case involved a patient with a 2-cm adenocarcinoma within a long segment of BE, staged as T1bSM2/3. The patient was not a candidate for surgery due to poor health and anticoagulation therapy. Traditional options such as endoscopic resection posed a higher risk for complications, said Dr. Shah, who noted that radiation therapy alone was insufficient for treating both the adenocarcinoma and Barrett’s segment. Cryotherapy was used as a palliative treatment to manage the adenocarcinoma and BE.
Dr. Shah also referenced recent findings from a prospective multicenter study involving 55 patients, which found that 80% of those treated with cryotherapy experienced improvements in their dysphagia (Endoscopy 2023;55[10]:889-897). He noted that these benefits were particularly evident in patients who received two cryotherapy sessions within three weeks—a more intensive treatment regimen that appeared to yield better outcomes without increasing the risk for complications.
“While not curative in every case, cryotherapy can effectively reduce tumor size and alleviate symptoms such as dysphagia,” Dr. Shah concluded. “Although initial results are promising, further research is needed to validate the efficacy of cryotherapy in this context and expand its potential applications for patients with esophageal cancer.”
In a recent study presented at ACG 2024 (abstract P0473), Cary Cotton, MD, MPH, an assistant professor of medicine at the University of North Carolina School of Medicine, in Chapel Hill, and his co-investigators assessed liquid nitrogen spray cryotherapy (LNSCT) for dysphagia palliation in patients with esophageal cancer who were not eligible for further cancer therapy.
The prospective multicenter study included patients 18 to 89 years old with luminal esophageal cancer who were naÏve to LNSCT and who did not have esophageal stents at baseline. Patient symptoms were assessed at baseline and 14 days after each treatment using the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire (QLQ-C30), esophageal symptoms module (QLQ-OES18) and an ordinal dysphagia score.
Among 54 enrolled patients, 49 received treatment and 48 had complete symptom indices and were included in analyses. Patients received an average of 5.4 cryotherapy treatments. Fourteen days after a spray cryotherapy treatment, the average improvement in the QLQ-C30 and QLQ-OES18 were 1.7 (95% CI, 0.1-3.3) and 1.8 (95% CI, 0.4-3.3), respectively, and the odds of improving a category in the ordinal score were 1.09 (95% CI, 0.71-1.68).
The investigators reported that the “magnitude improvement for each repeated treatment at 14 days was essentially stable” (mean difference in QLQ-C30, 0.1; 95% CI, –0.3 to 0.4; mean difference in QLQ-OES18, –0.2; 95% CI, –0.5 to 0.2; odds of improving a category in the ordinal score, 1.03; 95% CI, 0.95-1.12).
For each subsequent round of treatment, the mean difference in the baseline QLQ-C30 was –0.3 (95% CI, -0.9-0.3), the mean difference in the baseline QLQ-OES18 was –0.3 (95% CI, –0.7 to 0.2), and the odds of a category improvement in the ordinal score was 0.91 (95% CI, 0.67-0.98).
The investigators acknowledged that “the observational design of this study is susceptible to bias due to the placebo effect and differential loss to follow-up,” but Dr. Cotton noted that the long-term follow-up of patients, as well as the comparison with patients in SEER data are strengths. He said the results add “to the literature to show at least a subgroup of … patients found long-term palliation with repeated treatments, with mortality rates similar or better than propensity-matched SEER participants.”
Looking Ahead
“Endoscopic cryotherapy has made significant advancements since its introduction nearly two decades ago,” said Vivek Kaul, MD, a professor of medicine at University of Rochester Medical Center, in New York, who was a co-investigator with Dr. Cotton. “Today, it plays a well-established role in managing not only dysplastic Barrett’s but also esophageal neoplasia,” he added.
Speaking about the evolving role of cryotherapy, Dr. Kaul said he expects wider application “in Barrett’s treatment, particularly for refractory and complex cases” and a growing role of “palliative cryotherapy … particularly in combination with traditional neoadjuvant therapies” in patients with esophageal neoplasia.
To “ensure proper integration of cryotherapy into the endoscopic treatment armamentarium,” Dr. Kaul cited the need for large-scale data in the cancer realm and added that it is also “crucial to raise awareness in the GI and oncology community.” He said he believes that “further investigation, including larger, well-funded trials” are needed, but is excited by the “prospect of being able to provide a safe, effective and well-tolerated treatment alternative for malignant dysphagia, with fewer complications and reduced morbidity.”
Dr. Cotton echoed these sentiments, noting that “there is room for larger observational studies to answer questions about subgroups with particular benefit or risk, about the learning curve for new providers and about any observational signal for an effect on cancer progression over time.”
—Chase Doyle and Natasha Albaneze, MPH
Dr. Cotton reported a financial relationship with Pentax. Dr. Kaul reported a financial relationship with Steris. He is a member of Gastroenterology & Endoscopy News editorial board. Dr. Shah reported no relevant financial disclosures.