Transbronchial Cryoablation as Local Treatment for Central Airway Malignant Tumor Open Access

Endoscopic treatment of central airway malignant tumors has conventionally included tumor debulking, yttrium aluminum garnet laser, electrocautery, coring, photodynamic therapy, and argon plasma-coagulation [1]. No study has reported transbronchial cryoablation as local treatment for malignant tumors of the central airway. Here, we report the novel local treatment of transbronchial cryoablation in 2 patients with a central airway malignant tumor.

An 86-year-old woman underwent bronchial artery embolization and radiotherapy (60 Gy/30 Fr) of intratracheal metastases to treat hemoptysis associated with postoperative recurrence of lung adenocarcinoma, pT2aN0M0 (Fig. 1a1–a3). She was followed up after treatment only because she did not want to undergo chemotherapy. However, recurrence was detected 6 months later. Bronchoscopy showed recurrent lesions in the membranous portion (Fig. 1b1). Contrast-enhanced computed tomography (CT) showed irregular wall thickening in the dorsal trachea with contrast effect (Fig. 2). Transbronchial cryoablation was performed as an additional treatment, as follows. The patient was first sedated with midazolam and fentanyl, and then orally intubated. A flexible bronchoscope (BF-1T 290™; Olympus, Tokyo, Japan) was inserted into the endotracheal tube, after which a high-frequency electrosurgical snare was inserted through its working channel. After resection of a stalked tumorous lesion via a high-frequency electrosurgical snare, a cryoprobe was inserted, with an ERBECRYO^® 2 (ERBE, Tubingen, Germany) cryotherapy unit and a flexible cryoprobe (ø 2.4 mm, length 900 mm). The cryogen was carbon dioxide, and the temperature of the cryoprobe was set at −41 to −44°C (Level 2). The flexible cryoprobe was applied three times for 30 s per cycle to all recurrent lesions in the visible range (Fig. 1b2, b3). Two months after the first transbronchial cryoablation, bronchoscopy showed recurrence (Fig. 1c1). A second transbronchial cryoablation was performed using the same procedure as the initial treatment (Fig. 1c2, c3). Three months after the second transbronchial cryoablation, bronchoscopy showed recurrence. A third transbronchial cryoablation was performed using the same procedure as previously (Fig. 1d1, d2). Five months after the third cryoablation, bronchoscopy showed no obvious recurrence (Fig. 1e). Minor bleeding was the only complication related to transbronchial cryoablation.

An 83-year-old man had undergone a right middle and lower lobectomy for treatment of squamous cell carcinoma, pT2aN0M0, 4 years previously. Six months after the surgery, CT revealed a nodule of diameter 8 mm in the right bronchus intermedius (Fig. 3a). Positron emission tomography–CT showed nodular accumulations of ¹⁸F-fluorodeoxyglucose (maximum standardized uptake = 5.8) suggesting recurrence of lung cancer (Fig. 3b). Bronchoscopy revealed a tumor in the bronchus intermedius (Fig. 4a1). Transbronchial cryoablation was performed as in Case 1, as follows. Sedation and intubation were performed as in Case 1. A flexible bronchoscope (BF-1T 290™; Olympus, Tokyo, Japan) was inserted into the endotracheal tube, and a high-frequency electrosurgical snare was inserted through its working channel. After resection of the tumor via a high-frequency electrosurgical snare (Fig. 4a1, a2), a flexible cryoprobe was inserted. The cryotherapy unit was the same as in Case 1. The flexible cryoprobe was applied to all recurrent lesions in the visible range four times for 30 s per cycle (Fig. 4a3, a4). One month later, bronchoscopy showed no obvious recurrence (Fig. 4b1, b2). Twelve months later, the patient underwent radiation and chemotherapy for a metastatic brain tumor. CT performed at that time found no evidence of tumor recurrence in the trachea. Minor bleeding was the only complication related to transbronchial cryoablation, as in Case 1.

The first successful treatment of malignant tumor using low temperatures was achieved in the mid-19th century [2]. Following advances in cryosurgical instrumentation, cryoablation is currently being applied as a relatively minimally invasive treatment, especially in breast cancer and renal cell carcinoma [3, 4]. The therapeutic effect of cryoablation may be related to the abscopal effect as well as to tumor necrosis caused by freezing. The abscopal effect of cryoablation has been recognized since the 1970s and may contribute to the control of metastatic tumors [5]. Several recent studies have reported the efficacy of cryoablation for lung cancer (mainly early stage disease) [6, 7], although its application remains limited. Conventional cryoablation techniques involve percutaneous puncture and freezing of malignant tumors. However, cryoablation carries a high risk of adverse events such as pneumothorax and bleeding. Spray cryotherapy is another cryoablation procedure [8], in which liquid nitrogen is sprayed into lesions in the airway; however, the rapidly spreading cryogens can cause barotrauma and hypoxemia. As an alternative technique, Gu et al. [9] have reported the efficacy and safety of transbronchial cryoablation. In their clinical trial, transbronchial cryoablation was performed successfully in 9 patients, but only for peripheral lung cancer, not for central lesions.

Of the 2 patients in whom we performed transbronchial cryoablation, Case 1 had no recurrence 5 months after the third cryoablation, and Case 2 had no recurrence 12 months after the first cryoablation. As yet, no criteria have been established for transbronchial cryoablation as local treatment for central airway malignant tumor. However, we think that any lesion that is judged superficial on contrast-enhanced CT and is visible on bronchoscopy may be amenable to treatment, regardless of the number of lesions.

Regarding the safety of transbronchial cryoablation, we performed three to four cycles of cryoprobe freezing of the tumor at 30 s per cycle and location. There was only minor bleeding after the procedure and no serious complications. This procedure was developed based on the study of Jung et al. [10], which reported the efficacy of bronchoscopic cryotherapy for treating recurrence of post-intubation tracheal stenosis. They performed three cycles of cryotherapy for 30 s in each direction for tracheal stenosis and reported its safety. Gu et al. [9] demonstrated the safety of transbronchial cryoablation of peripheral lung using a porcine model, with the temperature at the tip of the flexible cryoprobe set to −150°C. They performed two or three transbronchial cryoablations of peripheral lesions, each with a freezing time of 10 or 15 min, and examined changes in histopathology at periods of 24 h, 4 weeks, and 3 months after cryoablation. Over time, the specimen changed from massive hemorrhage to fibrous hyperplasia accompanied by chronic inflammation, and interestingly, the bronchial cartilage remained intact. In their clinical trial, they reported one minor complication and no procedure-related deaths. Although at present there are no established cryoablation techniques for central airway malignant tumor, we consider that the methods proposed by Gu et al. [9] and Jung et al. [10] would be applicable for this purpose. In particular, heat-based ablation has been avoided for tumors on the posterior wall of the trachea due to the high risk of perforation and fistula formation. However, transbronchial cryoablation differs from heat-based ablation in its mechanism of action and has a slow necrotic effect. Therefore, it is worth considering a cautery technique for the posterior tracheal wall.

Limitations exist regarding the ability to interpret the findings of this case report. Transbronchial cryoablation is likely to be effective and safe for central airway tumors. However, as we have presented only 2 cases, it is necessary to assess its efficacy and safety in a greater number of cases in multicenter trials. In conclusion, transbronchial cryoablation deserves consideration as a local treatment for central airway malignant tumors.

The authors thank FORTE Science Communications (https://www.forte-science.co.jp/) for English language editing.

This study was granted an exemption from ethics approval by the Research Ethics Committee of Kurashiki Central Hospital. The authors declare that appropriate written informed consent was obtained for publication of this manuscript and the accompanying images.

All authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

M.H. wrote the manuscript. T.N., Y.F., T.Y., and T.I. contributed to data collection. All authors read and approved the final manuscript.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.