460 J Formos Med Assoc | 2011 • Vol 110 • No 7

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Journal of the Formosan Medical Association

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J Formos Med Assoc 2011;110(7):460–466

Journal of the Formosan Medical Association

ISSN 0929 6646

Formosan Medical AssociationTaipei, Taiwan

Volume 110 Number 7 July 2011

Enterovirus 71 vaccine: When will it be available?GRP78 in embryonic development and neurological disordersDirectly observed therapy for Tuberculosis patients in TaiwanHIV infection among incarcerated female drug users

Original Article

Percutaneous Computed Tomography-guidedCryotherapy of Thoracic Masses in NonsurgicalCandidates: Experience in 19 PatientsSiu-Cheung Chan,1,5* Hui-Ping Liu,2 Winnie Chiu-Wing Chu,3 Tzu-Ping Chen4,5

Background/Purpose: Percutaneous cryotherapy has become a minimally invasive treatment option forunresectable lung malignancies. We report the experience and outcomes with percutaneous computed tomography (CT)-guided cryotherapy of primary lung malignancies, as well as recurrence and metastases,in patients ineligible for surgery.Methods: The procedure was performed after administration of local anesthesia on 23 tumors in 19 patients(10 male and 9 female patients; mean age, 58.7 years). None of the patients were surgical candidates and un-derwent CT-guided percutaneous cryotherapy for treatment of the malignant mass in the lung. Visualizationof low-attenuation ice ball formation was performed using CT scanning after each cycle of freezing and thaw-ing therapy. Subsequent CT scans were scheduled at 3-month intervals post-procedure to assess tumor control.Results: No lethal complication, major bleeding or bronchial damage was observed in any of the 23-cryotherapy sessions performed. Three patients developed pneumothorax and one patient required chest tubeinsertion. Thirteen tumors (56.5%) regressed, including two complete responses, five tumors (21.7%) werestationary and the remaining five tumors (21.7%) were found to be progressing at the 3-month follow-ups.No recurrence was found in the 11 regressed tumors for 6 months, and there was also no recurrence in thetwo tumors that completely responded up to 12 months later with a satisfactory procedure.Conclusion: Percutaneous cryotherapy for primary lung cancer, recurrence and metastatic lung tumors isfeasible and safe for local control.

Key Words: computed tomography, cryotherapy, pulmonary nodules

Percutaneous cryotherapy is recommended for

a range of anatomic and tumor treatment options

because of its low pain, good ice visualization,

and preservation of collagenous tissue architecture.

Cryotherapy has been performed in the liver, pros-

tate, kidney, and breast with good outcomes.1–4

In patients in whom the lung tumor is inaccessible

through the tracheobronchial tree, and surgical

©2011 Elsevier & Formosan Medical Association. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1Department of Diagnostic Radiology, Chang Gung Memorial Hospital at Keelung and Linkou Medical Center, Keelung,Taiwan; 2Division of Thoracic Surgery, BenQ Medical Center, Nanjing, China; 3Department of Diagnostic Radiology and OrganImaging, The Chinese University of Hong Kong, Hong Kong SAR, China; 4Division of Thoracic Surgery, Chang Gung MemorialHospital at Keelung and Linkou Medical Center, Keelung, and 5College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Received: November 27, 2009Revised: May 16, 2010Accepted: May 24, 2010

*Correspondence to: Dr Siu-Cheung Chan, Department of Diagnostic Radiology, ChangGung Memorial Hospital at Keelung, 222 Mei Chin Road, Keelung, Taiwan.E-mail: chan3015@gmail.com

Percutaneous CT-guided cryotherapy of thoracic masses

J Formos Med Assoc | 2011 • Vol 110 • No 7 461

resection is not indicated, oncological treatment

of large tumors is often of limited benefit. There-

fore, treatment options are severely restricted.1

Computed tomography (CT)-guided percutaneous

cryotherapy of lung malignancy is considered for

patients ineligible for surgery, and a metastatic

tumor is associated with low procedural morbid-

ity.5 Cryotherapy causes coagulation necrosis con-

fined to the tissues within the region of probe

application, and ice-ball formation occurs as a

result of the dehydration caused by the intracellu-

lar ice crystals that form at very low temperatures.

This leads to protein denaturation and solute tox-

icity within the cells.6,7 The extent and degree of

tissue destruction correlate with the size of the

ice ball and the temperature within it. The latest

generation of cryotherapy machines use the Joule-

Thomson effect, in which different gases undergo

unique temperature changes when depressurized,

according to unique gas coefficients. The proper-

ties of argon make it useful for cooling to below

−180ºC, whereas helium is ideal for thawing andre-warming. The use of gas allows for rapid tran-

sition from freezing to defrosting, which facili-

tates tighter control, as well as expedition of the

procedure.8 Based on the biological effect of ex-

treme cold, a lethal temperature of approximately

−100ºC at the tumor level is required to achievetotal destruction of tumors 2 cm or larger in di-

ameter.9 We performed percutaneous cryotherapy

under CT guidance with local anesthesia as a lo-

cally curative treatment for unresectable lung tu-

mors. Twenty-three cryotherapy procedures were

performed successfully in 19 patients, with tissue

proof of unresected primary lung malignancy,

recurrent lung malignancy and lung metastasis.

Materials and Methods

PatientsThe institutional review board of our hospital

approved this retrospective study and informed

consent was waived due to the retrospective and

anonymous nature of the analysis. A total of 23

pulmonary masses in 19 patients (10 male and

9 female patients; mean age, 58.7 years; age range,

19–77 years) were treated with cryotherapy be-

tween October 2007 and September 2009. Five pa-

tients had unresectable non-small cell lung cancer,

six had non-small cell lung cancer after lobectomy

with recurrence, and the remaining eight patients

had lung metastasis. The patients were considered

ineligible for surgery or had undergone other lung

cancer therapies that were unsuccessful. All of the

patients met at least one of the following inclu-

sion criteria: (1) single or multiple peripheral lung

masses larger than 1 cm but less than 5 cm in di-

ameter, with previous therapies (radiation ther-

apy, chemotherapy, and/or surgery) having failed;

(2) a nonresectable central lung cancer (as deter-

mined by means of surgical consultation, accord-

ing to size, stage or health status); (3) fewer than

five metastatic tumors; and (4) a mass or adenopa-

thy involving the mediastinum and/or the peri-

cardium without distant metastasis. The latter was

considered as an inclusion criterion only when it

was associated with a distant measurable primary

lung tumor.

Cryotherapy techniqueThe location and size of tumors were noted at

preoperative evaluation. A tumor was considered

a central mass if it abutted any of the mediastinal

or hilar structures. Tumor measurements were ob-

tained in two dimensions on CT images, at the

level of the tumor’s most prominent appearance in

the transverse plane. Patients were placed feet first

into the CT gantry for better cryoprobe access.

Cryotherapy was performed after administra-

tion of local anesthesia by one thoracic surgeon

and one radiologist. For sedation, the patients re-

ceived 50 mg pethidine (Demoral; Roche, Basel,

Switzerland) and 5 mg midazolam (Dormicum;

Roche, Basel, Switzerland).

A 21-gauge 15-cm needle was inserted into the

center of each mass under CT-guidance (Light

speed VCT, GE Medical System, Milwaukee, WI,

USA), and used as a guide for subsequent insertion

of cryoprobes. The cryoprobe used was a PERC24

(Endocare, Irvine, CA, USA), it was 2.4 mm in

diameter and it was inserted directly into the

S.C. Chan, et al

462 J Formos Med Assoc | 2011 • Vol 110 • No 7

patient. The cryosurgical unit, the Cryocare Surgical

System (Endocare), offers a “stick” function for

fixating a probe’s position once it is inserted into

the tumor. This maximized accuracy when multi-

ple cryoprobes were placed.

Cryoablation is achieved using high-pressure

argon and helium gas for freezing and thawing,

respectively, based on the Joule-Thompson prin-

ciple. Rapid freezing of tissue with a cryoprobe

is based on the rapid expansion of argon gas in

a sealed probe with a distal uninsulated portion.

This process results in rapid cooling to −100ºCwithin a few seconds. Active thawing of the ice

ball is achieved by introducing helium gas into

the probes instead of argon gas. The cryoablation

procedure we used consisted of two cycles of

10 minutes of freezing and a 5-minute active thaw

between the cycles. During freezing, ice ball growth

and tumor coverage were monitored at 5-minute

intervals by CT scan. For a mass within the lung

tissue, a 2.4-mm cryoprobe can generate an ice

ball up to 3.7 cm in diameter and up to 5.7 cm

along the probe shaft. For this reason, a single

cryoprobe was placed for tumors 2 cm or less in

diameter. An additional cryoprobe was used for

larger tumors to ensure that an adequate freezing

margin of 5–10 mm was achieved. After comple-

tion of the final freeze in the cryotherapy proce-

dure, the cryoprobes were warmed by helium gas

until the temperature was higher than 20ºC. The

cryoprobes were then withdrawn.

Post-procedural evaluationImmediately after the cryoprobes were removed,

the patient was placed back into the CT gantry for

scanning and measurement of the low-attenuation

ice ball formation. All CT scans obtained after the

percutaneous cryoablation were acquired within

2–3 minutes of termination of freezing; the visible

size of the ice ball remains relatively unchanged

during this time.2,10,11 A repeat CT scan was per-

formed 24 hours after the procedure to evaluate

the type and frequency of complications.

Follow-up helical CT scans of patients were

performed at 3 months post-procedure. Changes

in tumors following cryotherapy were measured

using the Response Evaluation Criteria in Solid

Tumors (RECIST) protocol,12,13 which is based on

objective measurements of lesion size before and

after treatment. “Complete response” (CR) indica-

tes disappearance of the lesion, “partial response”

(PR) is a decrease of at least 30% in the sum of the

longest diameter of target lesions, “progressive

disease“ (PD) is an increase of at least 20% in the

sum of the longest diameter of target lesions, and

“stable disease” (SD) is neither sufficient shrink-

age to qualify for partial response nor a sufficient

increase to qualify for progressive disease.

Results

A total of 23 pulmonary masses in 19 patients

were treated with cryotherapy. In all cases, cryo-

therapy was performed percutaneously under CT

guidance with local anesthesia without major

complications. Complications are listed in Table 1.

The mean hospital stay after treatment was 2.8 days

(range, 2–9 days). There were no treatment-related

deaths or conversions to surgical intervention.

The responses to cryotherapy, measured using

the RECIST protocol, are listed in Table 2. We

observed a CR in two (8.7%) tumors, PR in 11

(47.8%) tumors, SD in five (21.7%) tumors and

PD in five (21.7%) tumors, giving a response rate

of 56.5% (Figures 1 and 2).

Discussion

Percutaneous cryotherapy of lung masses is tech-

nically feasible and may provide an important

Table 1. Complications after cryoablation

Complications n (%)

Pneumothorax 4 (17.4)Chest tube 1 (4.3)Observation 3 (13)

Hemoptysis (without additional treatment) 4 (17.4)

Pleural effusion (without additional 3 (13)treatment)

Percutaneous CT-guided cryotherapy of thoracic masses

J Formos Med Assoc | 2011 • Vol 110 • No 7 463

treatment alternative when other treatments do

not yield sufficient local tumor control.14 The

ability to visualize a low-attenuating ice ball as it

thoroughly covers a soft tissue tumor mass during

the freeze cycles is a potential benefit that is not

available with heat-based treatment.

Cryotherapy kills cells and ablates tissue by

direct cell injury resulting from ice crystal forma-

tion and related deleterious effects, as well as vas-

cular stasis caused by microcirculatory failure. As

temperatures fall, direct cellular injury occurs as

a result of cellular metabolism failure. When the

temperature reaches −20ºC, water in the extra-cellular environment crystallizes into ice, and with-

drawal of the water from the system results in a

hyperosmotic extracellular environment. Conse-

quently, denaturation and electrolyte imbalances

occur.15,16 During thawing, ice crystals fuse to

form larger crystals, which eventually disrupt the

cell membrane, which is another pathway for

causing cell injury. Gage and Baust recommend a

minimum freezing temperature of −40ºC for atleast 3 minutes for complete eradication of the tu-

mor and a minimum of two freeze-thaw cycles.15,16

This leads to modification of cryotherapy tech-

niques, in turn leading to improved biochemical

and histological outcomes.17

In our series, the response of the lung masses

was evaluated using the RECIST protocol. In the

11 (47.8%) of 23 tumors diagnosed as PR, local

Table 2. Radiographic response and clinical result

Patient Nodules Each tumor’s

Clinical outcome (prognosis after Primary tumor treated with response after

no.cryotherapya 3 mob

initial cryotherapy)

1 Alveolar soft part sarcoma 2 CRof the thigh PR Stationary (24 POM)

2 Recurrent NSCLC 1 PR Stationary (18 POM)3 Recurrent NSCLC 1 PD Progression (3 POM, 9 POM dead)4 Recurrent NSCLC 1 SD Liver metastasis (19 POM alive)5 Recurrent NSCLC 1 PR New pulmonary nodule (16 POM alive)6 Liposarcoma of the chest wall 2 SD, SD Stationary (17 POM)7 Esophageal cancer 2 PR, PR New pulmonary nodule (7 POM,

15 POM dead)8 Rectal cancer 1 PR Liver metastasis (7 POM alive under

chemotherapy)9 NSCLC 1 PR New pulmonary nodule and multiple

metastasis (10 POM, alive)10 NSCLC 1 PR Stationary (16 POM)11 NSCLC 1 PR Focal regression

New pulmonary nodule (6 POM alive)12 NSCLC 1 PD Died at 4 POM13 Recurrent NSCLC 1 CR Disease-free at 14 POM14 Osteogenic sarcoma 2 PD, PD Progression (3 POM alive)15 NSCLC 1 SD Stationary (6 POM)16 Recurrent NSCLC 1 PD Progression and new pulmonary

nodule (3 POM alive)17 Colon cancer 1 PR Regression (6 POM)18 High-grade sarcoma of the thigh 1 PR Regression (6 POM)19 Renal cell carcinoma 1 SD Stationary (6 POM)

aTotal pulmonary nodules (n = 23); bCR (n = 2, 8.7%), PR (n = 11, 47.8%), SD (n = 5, 21.7%), and PD (n = 5, 21.7%). CR = complete regression; PR = partial response; SD = stable disease; PD = progressive disease; POM = post operative months; NSCLC = non-small celllung cancer.

S.C. Chan, et al

464 J Formos Med Assoc | 2011 • Vol 110 • No 7

recurrence did not occur during more than

6 months of follow-up. In the two (8.7%) of 23

tumors diagnosed as CR, there was no recurrence

during 12 months of follow-up; therefore, our

series had a response rate of 56.5%.

Cryotherapy offers the opportunity to have ex-

cellent healing and resistance to infection. The

cryogenic lesion is an anesthetic lesion that ini-

tially shows minimal surrounding edema or in-

flammation.15,16 Because of this localized effect,

cryotherapy is a well-tolerated procedure. These

lesions, which have been found to be relatively

resistant to infection, show excellent healing, with

minimal scar formation and preservation of tissue

planes.15,16

We achieved our major treatment goals of

using local sedation during the procedures and

preserving underlying tissue architecture with

minimal complications. Because metastatic lung

tumors may associate with other latent metastatic

lesions in the lung, pulmonary reserve after treat-

ment can be important. Greater pulmonary reserve

is expected after cryotherapy, when applied to cen-

trally located tumors than after surgical procedures

such as lobectomy, which is usually required for

resection of such tumors.

In conclusion, percutaneous CT-guided cryo-

therapy offers a viable alternative for a nonsur-

gical lung mass, because it is minimally invasive

and uses local anesthesia, with satisfactory local

control. It preserves respiratory function and

is well tolerated by the patient. The procedure

demands careful patient selection and technical

expertise to achieve satisfactory cancer control,

patient satisfaction, and acceptable quality of

life.

A B

C D

Figure 1. (A) A 1.5-cm lung nodule in the Right lower lobe (RLL) caused by lung metastasis due to recurrent alveolar softpart sarcoma. (B) The RLL nodule is being treated from the lateral approach. One cryoprobe is seen bracketing the nod-ule. Ten minutes after the beginning of second freezing, an ice ball with hazy consolidation can be seen surrounding theRLL nodule. (C) Complete resolution of the RLL nodule with linear scarring was observed 3 months after the procedure.(D) At the 12-month follow-up, complete resolution of the RLL and no recurrence or residual tumor were observed.

Percutaneous CT-guided cryotherapy of thoracic masses

J Formos Med Assoc | 2011 • Vol 110 • No 7 465

Acknowledgments

We thank William Chan for secretarial assistance.

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A B

C D

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