Cryotherapy for the prevention and treatment of esophageal cancer: when does efficacy equal success?
Article Outline
Abbreviation: RFA, radiofrequency ablation
In contrast to the good news of the decreasing number of colon cancer–related deaths attributed to screening efforts, the outlook is not quite the same for esophageal cancer. Deaths from esophageal cancer have actually increased slightly in recent years, with an estimated 14,530 patients who died in the United States last year.1 Recently, the Institute of Medicine placed the use of upper endoscopy in GERD as it relates to esophageal cancer at the highest priority in the Initial National Priorities for Comparative Effectiveness Research. Esophageal cancer remains a dismal disease with a 5-year survival rate of only 17%. Esophagectomy, which has been the de facto criterion standard for treating patients with Barrett's and high-grade dysplasia and early esophageal cancer arising from Barrett's esophagus, is far from ideal, with a curative resection rate of 20% to 70%2 and a perioperative mortality rate of 4% to 12%.3
Several strategies using endoscopy have emerged in recent years and are in a current state of evolution. EMR, which can be both potentially curative and diagnostic, because deeper layers of Barrett's tissue can be staged, has not been widely adopted in the United States, although there are ongoing trials in this field. Among them are studies combining EMR with endoscopic ablative therapy. Two forms of endoscopic ablation have received attention: radiofrequency ablation (RFA) and spray cryotherapy. Photodynamic therapy, although shown to be effective, has fallen out of favor because of a higher complication rate compared with that of RFA. In a recent randomized, sham-controlled trial,4 RFA completely eradicated intestinal metaplasia in 74% of patients with high-grade dysplasia at 12 months. Spray cryotherapy is the newcomer in this arena, having obtained U.S. Food and Drug Administration approval in December 2007.
There are 2 interesting multicenter, retrospective cohort studies on spray cryotherapy reported in the current issue of the GIE. Greenwald et al5 looked into the efficacy and safety of spray cryotherapy for esophageal cancer. The main outcomes measured were complete eradication of cancer and adverse events. Patients were included if conventional therapy failed or if they refused or became ineligible. There were 79 enrolled subjects, of whom 49 completed treatment and were included in the efficacy analysis. The remaining 30 patients, who were still receiving spray cryotherapy treatments, were excluded from the efficacy analysis. Of the 49 patients, 30 (61.2%) had complete response with a mean follow-up of 10.6 months.
Shaheen et al6 studied the safety and efficacy of spray cryotherapy for Barrett's esophagus with high-grade dysplasia. Of 98 patients with high-grade dysplasia, 14 (14%) had some form of previous unsuccessful ablative treatment. Sixty of the 98 subjects had finished all planned spray cryotherapy treatments and were included in the efficacy analysis, whereas 38 were still undergoing planned therapy and were excluded from the efficacy analysis. All 60 who completed all planned spray cryotherapy were followed for a mean of 10.5 months, and 58 (97%) were found to have complete eradication of high-grade dysplasia, whereas 34 (57%) had complete eradication of intestinal metaplasia. There were 2 cases of subsquamous intestinal metaplasia post-ablation. A statistical comparison of responders and nonresponders is not available.
The authors of both studies5, 6 are to be commended for expanding the groundwork of an area of technology that could be potentially game-changing in our fight against esophageal cancer. Indeed, it is quite an effort to synthesize data from multiple institutions in a real-world setting. However, there are 2 points to consider before accepting the conclusion that cryotherapy is effective, even in the short term. As the authors of both studies pointed out, short-term follow-up is clearly one of the major limitations here. Some patients were followed for only a few months, as in the study of Greenwald et al,5 which is not a very meaningful duration for them to be labeled complete responders. More importantly, the success criterion was based on repeating the upper endoscopy with histologic confirmation, but there was no predetermined time period for doing so. Defining the outcome a priori that includes a set period of at least 12 months for performing confirmatory upper endoscopy is essential to minimize bias. Thus, subjects with inadequate follow-up (eg, less than 12 months) will be excluded from the numerator of the efficacy analysis. Long-term durability is critical to define and assess the true efficacy as well as determine appropriate endoscopic surveillance intervals.7
The second issue involves deciding when the spray cryotherapy treatment is deemed complete, which was done in a similar fashion in these 2 studies.5, 6 Inherent not just in these 2 studies but in most retrospective, multicenter studies, deciding on the stopping criterion for treatment can be inadvertently nebulous, affecting the measured outcomes, and ultimately the studies' frame of reference. For example, the Shaheen et al6 study allowed the “clinician and/or patient … to halt treatment for clinical reasons, including worsening comorbidities, disease progression, and patient preference.” If this is the stopping criterion, what does it mean to fail to complete “all planned treatments”? Is it possible that some of those excluded in the efficacy analysis had treatment failure from spray cryotherapy? From the data provided, we can infer that the 38 subjects still undergoing treatment have completed an average of 2.5 cryotherapy treatments (93 treatments/38 subjects). Thus, half of the 38 have had more than 3 cryotherapy treatments but were still requiring further treatments and were excluded from the efficacy analysis. Is it fair to say that these 19 subjects had treatment failure? If one agrees that this is so, adding 19 to the denominator will change the efficacy of cryotherapy from 97% to 73% for eradicating high-grade dysplasia or from 57% to 43% for eradicating intestinal metaplasia.
In terms of preventing and treating esophageal cancer and reducing cancer-related deaths, how does this affect how we look at cryotherapy or endoscopic ablative therapy in general? Clearly, these findings are preliminary. However, we can surmise at this early stage that endoscopic ablative therapy is a viable alternative to esophagectomy. Comparing the efficacy rate and procedure-related mortality of a hypothetical endoscopic ablative therapy with that of esophagectomy, it seems that more lives will be saved with ablation. Assuming that the annual rate of progression from high-grade dysplasia to cancer is 0.07, more lives (on the order of hundreds) per year could be saved with ablation than with esophagectomy, even if we use the least optimistic efficacy rate for ablation and the most optimistic efficacy rate for esophagectomy. Ablative therapies such as cryotherapy and RFA have the theoretical upper hand because of their low procedure mortality rate compared with that of esophagectomy.
In fact, many readers can see past the face value of an efficacy rate and can decide for themselves which salient features should be included in the numerator and denominator. What is more relevant is showing that the elimination of cancer or high-grade dysplasia is durable. This unfortunately has not been elucidated in the literature. It is not clear whether spray cryotherapy at current doses is capable of ablating deep into the submucosal layer that may harbor neoplastic cells. We await studies on the optimal dose of spray cryotherapy that can achieve this task with the fewest adverse effects on patients. Failure to eradicate intestinal metaplasia, either superficial or beneath the neosquamous epithelium (“buried glands”), is an issue with ablative therapies4, 8 in varying degrees, and, as seen here, spray cryotherapy is no exception. The strongest predictor of recurrent neoplasia after ablation seems to be residual intestinal metaplasia (hazard ratio 2.8; P = .012).8 Data from patients who underwent photodynamic therapy revealed persistent genetic abnormalities in residual nonburied Barrett's tissue, which raises concern for malignant potential.9, 10
If we define success in terms of reducing esophageal cancer–related deaths, we need to follow patients who underwent ablation over several years and determine the net change in risk of cancer progression. Only then can we answer the question of whether efficacy equals success.
Disclosure
The following author disclosed a financial relationship relevant to this publication: G. M. Eisen: Research support from Barrx Medical. L. Hernandez disclosed no financial relationships relevant to this publication.
References
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- Effect of operative volume on morbidity, mortality, and hospital use after esophagectomy for cancer. J Thorac Cardiovasc Surg. 2000;119:1126–1132
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- Endoscopic spray cryotherapy for esophageal cancer: safety and efficacy. Gastrointest Endosc. 2010;71:686–693
- Safety and efficacy of endoscopic spray cryotherapy for Barrett's esophagus with high-grade dysplasia. Gastrointest Endosc. 2010;71:680–685
- A cost-utility analysis of ablative therapy for Barrett's esophagus. Gastroenterology. 2009;136:2101–2114
- Prevalence and predictors of recurrent neoplasia after ablation of Barrett's esophagus. Gastrointest Endosc. 2010;71:697–703
- Genomic analysis of Barrett's esophagus after ablative therapy: persistence of genetic alterations at tumor suppressor loci. Int J Cancer. 2006;118:155–160
- . Histopathology of Barrett's esophagus after ablation and endoscopic mucosal resection therapy. Endoscopy. 2008;40:1008–1015
PII: S0016-5107(10)00198-7
doi:10.1016/j.gie.2010.02.026
© 2010 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.
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Endoscopic spray cryotherapy for esophageal cancer: safety and efficacy
