Dysphagia is a common presenting symptom in esophageal cancer. Poor nutrition and
diminished quality of life are often the result. Traditional options to manage dysphagia
– esophageal stents, radiation, chemotherapy, and dilation – all have limitations.
Liquid nitrogen spray cryotherapy (truFreeze, CSA Medical, Inc., Lexington, Massachusetts,
United States) has been used successfully to treat inoperable early-stage esophageal
cancer and to palliate dysphagia in locally advanced tumors [1]. This non-contact method uses liquid nitrogen at –196° to effectively freeze and
destroy esophageal tumors with excellent tolerability and safety profile.
In a recent multicenter retrospective study, endoscopic liquid nitrogen spray cryotherapy
was used to palliate dysphagia in 49 patients with inoperable (mostly stage IV) esophageal
cancer [2]. A significant improvement in dysphagia score was reported in the majority of patients.
Prior to cryotherapy, median dysphagia score was 2.6 (1 = dysphagia to solids, 2 = dysphagia
to semi-solids, 3 = dysphagia to liquids), while after treatment, this score significantly
improved to 1.7. Forty-one percent of those treated had a dysphagia score ≤ 1 after
their last treatment. Cryotherapy may also induce tumor necrosis through immunologic
mechanisms [3]. Cryotherapy-induced cancer cell lysis releases intact intracellular contents, which
may induce a specific antitumor immune response. While this response has not been
studied specifically in esophageal cancer, it may serve as an additional mechanism
of antitumor therapy in these patients.
Concurrent systemic chemotherapy and external beam radiotherapy (chemoradiation) with
or without esophagectomy is the primary therapy offered for non-metastatic advanced
stage esophageal cancer. However, complete response to therapy is seen in fewer than
50 % of patients in multiple studies. Attempts to improve response with increased
radiation dose or alternative chemotherapy regimens have not been successful. Dysphagia
palliation does occur with chemoradiation, but it typically takes several weeks before
relief of dysphagia is reported. In those with severe dysphagia, chemoradiation may
be delayed due to malnutrition and poor performance status. Options to improve dysphagia
and nutrition in this setting include self-expanding metal stents or enteral feeding
tubes (gastrostomy or jejunostomy). Feeding tubes provide no relief of dysphagia but
can improve nutritional status. Esophageal stents, while often providing rapid dysphagia
relief, are associated with pain, gastroesophageal reflux (for distal tumors), stent
migration, and perhaps worse outcomes [4].
In this issue, Shah et al evaluate the safety and efficacy of a single treatment with
endoscopic liquid nitrogen spray cryotherapy for improvement in dysphagia in 25 patients
with treatment-naïve esophageal cancer [5]. In some cases, treatment was performed at the time of staging by endoscopic ultrasound
(EUS), while in others it was administered in a separate session. Spray cryotherapy
was used as primary treatment for dysphagia or as a “bridge” treatment to improve
swallowing until systemic therapy was given. As expected, the treatment was safe,
with no cryotherapy-related serious adverse events. Improvement in dysphagia was seen
in 71 % at 1 week and 50 % in 2 weeks, with improvement at 4 weeks persisting in nearly
half of the patients. Chemoradiation was administered in nine patients at a median
time of 27 days after cryotherapy. None of these patients required a stent, but two
required a jejunostomy tube at 4 weeks due to return of dysphagia prior to chemoradiation.
Following chemoradiation, the authors note that 67 % of patients had a complete local
response (no tumor cells on biopsy) and 50 % had a clinical response (no tumor cells
on biopsy and no evidence of nodal or metastatic disease), as assessed by endoscopy
with biopsy and positron emission tomography (PET) scan, and they postulate that an
immune mechanism may have contributed to these high response rates. These results
must be interpreted with caution due to small numbers of patients, low negative predictive
value of endoscopy and PET to predict residual persistent tumor, and absence of esophagectomy
data to confirm pathologic response.
Based on these data, liquid nitrogen spray cryotherapy appears to be a reasonable
alternative to esophageal stenting for patients with treatment-naïve esophageal cancer
who require palliation of dysphagia, including prior to initiation of systemic therapy.
The treatment is safe and can be administered at the time of staging EUS. Persistent
improvement in swallowing was seen in many patients, providing relief until the effects
of systemic therapy can occur. Earlier studies have shown that intermittent cryotherapy
can provide prolonged relief of dysphagia in those not suitable for systemic therapy.
Compared to stenting, pain and reflux are less common, although the degree of dysphagia
relief may not be as great. At the current time, spray cryotherapy is only available
in the United States, so widespread use is limited. Larger studies will be helpful
to confirm the beneficial effect of cryotherapy as primary therapy for dysphagia and
as an adjuvant to systemic therapy. Further investigation into potential immune-mediated
cell death are warranted as well, especially now that checkpoint inhibitors and other
immunotherapies are becoming widely available.
