Jinwoo Lee

Seok-Chul Yang

Young Sik Park

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EDITORIALEDITORIAL
DOI: 10.3904/kjim.2011.26.2.132
The Endoscopic Cryotherapy of Lung and Bronchial Tumors: 
A Systematic Review 
-Can We Expect a New Era of Cryotherapy in Lung Cancer?
Jinwoo Lee1, Young Sik Park1, and Seok-Chul Yang1,2
1Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Lung Institute of Medical Research 
Center, Seoul National University College of Medicine; 2Seoul National University Cancer Hospital Bronchoscopy Center, Seoul, 
Korea
Since the introduction of the flexible bronchoscope by 
Ikeda et al. [1], it has become one of the most important 
tools for diagnosing and treating pulmonary diseases. 
Its applications range from airway evaluations to 
interventional therapy for airway lesions. Interventional 
bronchoscopy using rigid and flexible bronchoscopes has 
progressed with the introduction of new techniques to 
relieve airway obstructions and bleeding control, which 
can be life-threatening complications of advanced lung 
cancer. Malignancy in the central airway may cause diverse 
clinical signs and symptoms depending on the location, 
growth rate of the obstructive lesion, diagnosis time, and 
involvement of surrounding structures [2,3]. The efficacy 
of interventional bronchoscopy for palliation of central 
airway obstructions has been well established, and its 
curative potential for early lung cancer has evolved along 
with current treatment modalities. The main indication 
for therapeutic bronchoscopy is the presence of an airway 
disorder resulting in a central airway obstruction to relief 
blockage [4]. Interventional bronchoscopy, particularly 
therapeutic bronchoscopy, includes many diverse 
modalities, such as the Nd:YAG laser, electrocautery, 
argon plasma coagulation, photodynamic therapy, airway 
stenting, brachytherapy, and cryotherapy, which all have 
advantages and disadvantages.
Endobronchial cryotherapy, which is intended to ablate 
endobronchial tumors and carcinomas in situ using an 
ice freezing effect, was initially reported in the 1970s 
[5]. Although it was largely abandoned in favor of other 
modalities, such as laser treatment, particularly in the 
United States, interest in cryotherapy has continued in 
Europe. Endobronchial cryotherapy has been used to 
destroy endobronchial tumors by its cytotoxic effects of 
freezing tissue, thus, causing tissue death. Its clinical 
uses are primarily in treating patients with inoperable 
obstructive central lung cancers. The mechanism 
of local tissue destruction is applying extremely low 
temperatures (below -20 to -40°C). The first successful 
use of low temperature for treating a tumor was reported 
by James Arnott [6] to treat an advanced uterine 
carcinoma more than 150 years ago. Rigid and semi-rigid 
cryoprobes are used with a rigid bronchoscope, whereas 
a flexible cryoprobe can be used with both instruments. 
Cryotherapy has also been used to treat carcinoma in situ 
as well as benign endobronchial tumors. The advantage of 
endobronchial cryotherapy is that it has proven effective 
with minimal complications. It is also relatively easy to 
use and economical compared with other therapeutic 
modalities. Cryotherapy is safe, with no danger of 
bronchial wall perforation, no radiation danger, no risk 
of electrical accidents or fires, and does not require 
much special training. Patients tolerate the procedure 
well and show a significant improvement in symptoms. 
Disadvantages include delayed results and the requirement 
Correspondence to Seok-Chul Yang, M.D.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, 
Jongno-gu, Seoul 110-744, Korea
Tel: 82-2-2072-0354, Fax: 82-2-762-9662, E-mail: scyang@snu.ac.kr
See Article on Page 137-144
Lee JW, et al. Cryotherapy of lung cancer    133
for multiple bronchoscopies to remove debris or to retreat, 
which is a serious issue for cryotherapy in a patient with 
impending respiratory failure due to an obstructive 
airway lesion. The success of freeze injury, which is the 
main mechanism of cryotherapy for malignancy, may 
be influenced by many factors; the survival of cells is 
dependent on the cooling rate [7,8], the thawing rate [9], 
the lowest temperature achieved [10], and repeated freeze-
thaw cycles [11]. Applying a low-temperature probe to a 
tissue first induces immediate adherence between the 
probe and tissue and then the appearance of intra- and 
extracellular ice crystals [12]. These crystals damage 
intracellular organelles, particularly mitochondria. 
The formation of pure extracellular ice crystals causes 
additional ion and water movement, resulting in cellular 
dehydration. A maximum effect is achieved by rapid 
cooling of the tissue followed by slow thawing [13].
As evidence for additional cryotherapy applications for 
endobronchial tumors increase for patients with advanced 
lung cancer who suffer from obstructive lesions, Lee and 
colleagues provide a systematic innovative literature 
review of cryotherapy in this issue of KJIM (see page 137-
144). This group systematically analyzed and evaluated 
the endoscopic cryotherapy literature and present 
reference materials useful for treating endobronchial 
airway obstruction by tumors. Sixteen key studies 
were used to determine the safety and effectiveness of 
cryotherapy. Based on this study, the overall success rate 
for effective recanalization of tumor obstruction was 
about 80%, and the complication rate of the cryotherapy 
procedure was 0-11.1% of the cases, most of which were 
minor and manageable with conservative methods. 
Some studies evaluated for this systemic review revealed 
much improvement in respiratory symptoms, pulmonary 
function tests, and performance status even with the 
limitations of the study data. This review also showed 
a 0-7.1% mortality rate within 30 days of the procedure 
in five of 16 studies. The case study by Hetzel et al. [14] 
had a 61% complete response rate and a 22% partial 
response rate, which is as effective as other interventional 
modalities. This study also shows that most of the cases 
resulted in airway reopening and endobronchial tumor 
shrinkage, suggesting that cryotherapy can still be used 
almost exclusively for palliation and not for curative 
intent in advanced lung cancers with the advantage of 
ease of use and minimal complications. Even after a 
systemic literature review, there are some limitations 
to this study; the clinical efficacy and complications of 
cryotherapy cannot be readily compared considering the 
diverse clinical situations, many differing indications, and 
different methods for successful evaluation. Furthermore, 
the use of other co-modalities, such as combined laser or 
electrocautery treatment, must be considered.
Advanced stage lung cancer poses a serious threat 
to quality of life due to local tumor growth and distant 
metastases. Most patients suffer from end-stage tumor 
recurrences and failed treatments, including surgery 
or chemoradiotherapy. Imminent suffocation and poor 
physical condition may provide little space for a timely and 
safe intervention. Interventional bronchoscopy, including 
cryotherapy, is warranted and should be considered for 
palliation of obstructive lesions.
Although cryotherapy is a unique destructive method 
based on the cytotoxic effects of cold on living tissue, the 
role of cryotherapy is still limited compared with other 
endobronchial treatments. It is safe, less expensive, and 
easy to use, but less versatile than electrocautery and has 
a delayed effect. Therapeutic bronchoscopy, including 
cryotherapy, may be of benefit for patients requiring 
chemotherapy, including recent target agents for epidermal 
growth factor mutation, echinoderm microtubule-
associated protein-like 4, and anaplastic lymphoma kinase 
or irradiation therapy. Further investigations in this 
area may lead to an additional new therapeutic modality 
for advanced lung cancer. Can we expect a new era of 
cryotherapy for lung cancer soon? (Korean J Intern Med 
2011;26:132-134)
Conflict of interest
No potential conflict of interest relevant to this article 
was reported.
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The Endoscopic Cryotherapy of Lung and Bronchial Tumors: A Systematic Review -Can We Expect a New Era of Cryotherapy in Lung Cancer?

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The Endoscopic Cryotherapy of Lung and Bronchial Tumors: A Systematic Review -Can We Expect a New Era of Cryotherapy in Lung Cancer?

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