Study design
This retrospective study evaluated 68 patients who underwent cryoablation for metastatic lung cancers between 2013 and 2019 in Kameda Medical Center, which is an educational and cancer designated hospital. The study was designed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology guidelines [14] 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).
Eligibility
Patients were considered eligible if they fulfilled the following criteria: (1) ≤ 3 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. Treatment 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 informed consent after fully discussing the risks and benefits of cryoablation.
Cryoablation procedure
Cryoablation was conducted by a radiologist (I.K.) who had 25 years of experience with interventional radiology. The treatment was usually performed with a single 13-G cryoprobe using liquid nitrogen (IceSense 3; IceCure Medical Ltd., Caesarea, Israel) under CT (Brilliance iCT SP; Philips Co., Amsterdam, Netherlands); however, two cryoprobes were used for tumors ≥3 cm with using 2 machines of IceSense3, because one cryoprobe was available for one IceSense 3. To penetrate the tumor with the 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. After local anesthesia, the guide needle was inserted in the tumor under real-time CT imaging. The inner and outer sheaths were advanced over the guide needle to reach the tumor. After the outer sheath penetrated the tumor, the guide needle and inner sheath were withdrawn and the cryoprobe was inserted into the outer sheath (Fig.S1). Cryoablation was generally performed with 3 cycles as 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. 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.
Follow-up
Follow-up was conducted by CT with a slice thickness of 2 mm, 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, the PET-CT or needle aspiration biopsy was conducted for the diagnosis. The local control period was evaluated based on the date of CT imaging. Medical records were searched in December 2020.
Outcomes
Outcomes were local control, preserved pulmonary function after treatment, and treatment complications.
Evaluation of factors that predicted local control
Local control was evaluated based on tumor size, histology, location, the distance from a vessel with a diameter of ≥3 mm, and chemotherapy after cryoablation. Tumor histology was classified as carcinoma or sarcoma. Tumor location was classified as peripheral (<2 cm from pleura), intraparenchymal (≥2 cm from pleura), or hilar (<1 cm from lobar artery or vein) on CT. The distance from the tumor to the closest vessel with a diameter of ≥3 mm was measured on CT, and categorized as >3 mm or ≤ 3 mm based on the criteria reported by Yashiro et al. [6].
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, since the pulmonary function after lung surgery has been reported to recover fully after 6 months and stabilize thereafter [15]. 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 once, 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, and number of needles used for each tumor.
Statistical analysis
Comorbidities were evaluated using the Charlson comorbidity index [16]. Postoperative complications were assessed using the Clavien-Dindo classification [17]. The optimal cut-off value for tumor size to predict local recurrence was determined using a receiver-operating characteristic curve and the Youden index. The Kaplan-Meier method was used to evaluate local control and overall survival period [18]. 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 <.05. All statistical analyses were performed using Microsoft Excel (version 10; Redmond, WA).