This retrospective observational study evaluated 68 patients who underwent cryoablation for metastatic lung cancers between 2013 and 2019. The study was designed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines  and complied with the principles of the Declaration of Helsinki. The study was approved by the institutional ethics committee in January 2013 (approval number, 12-047).
Patients were considered eligible if they fulfilled the following criteria: (1) ≤6 new or growing pulmonary nodules with a history of malignancy; (2) surgery was not appropriate because the tumor was located deeply in lung parenchyma; and/or (3) the patient had refused surgery. The exclusion criteria were as follows: (1) a Karnofsky performance scale score of <60; (2) incurable primary or other metastatic tumors; and (3) tumors with a diameter of ≥5 cm, because it would exceed a “-20°C cytotoxic zone” even when using two cryoprobes. Treatment indication was decided at the in-hospital conference of the chest group, including departments of respiratory medicine, thoracic surgery, medical oncology, and radiology. All patients provided written informed consent after fully discussing the risks and benefits of cryoablation. A written consent for publication was obtained from all patients for every individual person’s data included in the study.
The treatment was usually performed with a single 10-G cryoprobe (3.4 mm in diameter) using liquid nitrogen (IceSense 3; IceCure Medical Ltd., Caesarea, Israel) under computed tomography (CT) (Brilliance iCT SP; Philips Co., Amsterdam, Netherlands). However, two cryoprobes were used for tumors ≥3 cm employing two machines of IceSense3, because one machine was available for one cryoprobe. To penetrate the tumor with cryoprobe under spontaneous breathing, a guide needle kit (Daimon coaxial system; Silux Co., Kawaguchi, Japan) consisting of a 21-G guide needle and an 8-G stainless-steel coaxial system was used (Fig. 1).
After administration of pethidine hydrochloride (35 mg) and/or midazolam (2–3 mg), the patient was placed on a table of CT in supine or prone position according to the tumor location. For multiple tumors on one side lung, the cryoablation was conducted in one procedure, whereas for multiple tumors on both sides, the treatment was conducted separately. After local anesthesia, the guide needle was penetrated through the tumor under real-time CT imaging (Fig.2). The inner and outer sheaths were advanced over the guide needle. After the outer sheath penetrated the tumor, the guide needle and inner sheath were withdrawn and the cryoprobe was inserted into the outer sheath. Cryoablation was generally performed with 3 cycles using the following sequence: 5-min freeze, 8-min passive thaw, 8-min freeze, 10-min passive thaw, 8-min freeze, and finally 4-min active thaw, i.e., 43 min in total. Technical success was defined as a consolidated area or a zone of ground-glass appearance encompassing the tumor at least 5mm of circumferential ablative margin (Fig.2d). After the cryoprobe was removed from the outer sheath, a fibrin glue or a 33% of n-butyl-2-cyanoacrylate (B. Braun Aesculap Co., Tokyo, Japan) mixed with lipiodol was injected through the outer sheath to plug the needle tract for preventing pneumothorax.
Adverse events that happened within 30 days of the treatment were graded with the Common Terminology for Adverse Criteria for Adverse Events (CTCAE version 4.03) . Pneumothorax was defined as the adverse event when the thoracic drainage or puncture was required, because a transient free air space was sometimes seen around the insertion site of cryoprobe.
Follow-up was conducted by CT, which was performed every 3 to 4 months for the first 3 years after treatment; thereafter at least every 6 months. Local progression was defined as recurrence at the treated site. When the local recurrence was suspected on CT, needle aspiration biopsy was conducted for diagnosis. Local control period was evaluated based on the date of CT imaging. Medical records were searched in January 2021.
Evaluation of factors that predicted local control
Local control was evaluated based on tumor size, histology, location, and chemotherapy after cryoablation. Tumor histology was classified as carcinoma or sarcoma. Tumor location was classified as peripheral (<2 cm from pleura), intermediate (≥2 cm from pleura), or hilar (<1 cm from lobar artery or vein) on CT.
Evaluation of preserved pulmonary function
Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured using a dry rolling-seal spirometer (CHEST AC-8800; CHEST Ltd., Tokyo, Japan) before treatment and 6 months after treatment. The percentage of preserved pulmonary function (%PPF) was calculated using the following formula: [FEV1 after treatment/FEV1 before treatment] × 100 (%). For patients who underwent cryoablations more than two times, the %PPF was evaluated at 6 months after the final treatment.
Evaluation of factors that predicted pneumothorax
The incidence of pneumothorax was evaluated based on age, sex, FEV1/FVC, number of treated tumors, tumor location, and number of needles used for each tumor ablation.
Primary outcome was the local control and incidence of pneumothorax. Secondary outcome was whether preserved pulmonary function 6 months after cryoablation varied according to number of treated tumors.
Comorbidities were evaluated using the Charlson comorbidity index . The optimal cut-off value for tumor size to predict local recurrence was determined using a receiver-operating characteristic curve and the Youden’s index. The Kaplan-Meier method was used to evaluate local control and overall survival period . Variables that were significantly associated with local control in the univariate analyses were entered into a multivariate Cox regression model. The differences in %PPF for treatments for one tumor, 2 tumors, and ≥3 tumors were analyzed using an analysis of variance. Differences were considered statistically significant at p-values <0.05. All statistical analyses were performed using Microsoft Excel (version 10; Redmond, WA).