The feasibility of the deep hypothermal cryotherapy plus immune checkpoint inhibitor for treatment of severe malignant central airway obstruction
Original Article

The feasibility of the deep hypothermal cryotherapy plus immune checkpoint inhibitor for treatment of severe malignant central airway obstruction

Zhibing Luo#, Changwen Deng#, Shaoyong Gao, Xiaodong Wu, Xia Fang, Xiaoping Zhu, Qiang Li, Wujian Xu

Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China

Contributions: (I) Conception and design: Q Li, W Xu; (II) Administrative support: None; (III) Provision of study materials or patients: S Gao, X Wu; (IV) Collection and assembly of data: Z Luo, C Deng; (V) Data analysis and interpretation: X Zhu; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Qiang Li, MD; Wujian Xu, MD. Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, School of Medicine, Tongji University, No. 150 Jimo Road, Pudong New Area, Shanghai 200120, China. Email: liqressh1962@163.com; wujian_xu@163.com.

Background: The recurrence shortly after interventional therapy poses a great challenge in managing malignant central airway obstruction (MCAO). While cryotherapy has shown potential benefits when combined with immunotherapy in lung cancer, its effectiveness for improving local control of malignant central airway tumors is not well understood. This study aims to evaluate the clinical efficacy and safety of combining these strategies.

Methods: A total of 12 patients with MCAO who had been treated with a combination of cryotherapy and immune checkpoint inhibitors (ICIs) were compiled for analysis in a tertiary hospital in Shanghai East Hospital, China. The primary endpoint is the duration of efficacy (DoE) for MACO after the combined therapy, which was defined as the time interval of the airway stayed patency without additional repeated interventional treatment. Secondary endpoints encompassed an assessment of objective response rate, overall survival and the adverse events.

Results: Twelve patients received a combination therapy between January 2021 and December 2023. Median age was 66 years, 91.7% male. Fifty percent were squamous carcinoma. 50.0% had medium to low programmed cell death-ligand 1 (PD-L1) levels. 41.7% patients’ performance status scored higher than 2. 91.7% (11/12) of the patients objectively respond to the combined therapy, with a median DoE of 10.0 (95% confidence interval: 3.7–21.7) months. The 6-, 12- and 18-month survival rate was 75.0%, 50.0% and 41.8%, respectively. The most common adverse event was granulation. Other events included mild rash, pneumonitis, and hypothyroidism. No severe procedure-related adverse events occurred.

Conclusions: In patients with endoluminal or mixed MCAO, our findings suggest that combining endobronchial cryotherapy with ICIs may help maintain airway patency, offering a promising preliminary signal for this therapeutic approach.

Keywords: Cryotherapy; immunotherapy; malignant central airway obstruction (MCAO); bronchoscopy; lung cancer


Submitted Jun 05, 2024. Accepted for publication Oct 23, 2024. Published online Dec 26, 2024.

doi: 10.21037/cco-24-74


Highlight box

Key findings

• Combining deep hypothermal cryotherapy with immunotherapy resulted in a median duration of efficacy of approximately 10 months for malignant central airway obstruction (MCAO). An objective response was achieved in 91.7% of patients, with a 1-year survival rate of 50.0%.

What is known and what is new?

• Traditional interventional therapy for patients with MCAO typically results in a relapse within about three months. Among various interventional techniques for MCAO, cryotherapy has been reported to have a synergistic effect with immunotherapy.

• Using a novel catheter-based cryo-balloon, a combination of deep hypothermal cryotherapy and immunotherapy achieved a high objective response rate and long-term control of MCAO, with no new safety concerns.

What is the implication, and what should change now?

• Cryotherapy should be considered for MCAO to attain a longer control of local airway lesions when considering combination with immunotherapy.


Introduction

Approximately 20–40% lung cancer patients have central airway involved, which may cause difficulty in patients’ ventilation. Among the patients with severe malignant central airway obstruction (MCAO), about 40% of them died of respiratory failure (1-3). MCAO is accompanied with high frequency of obstructive infection and adds risk to systemic anti-cancer therapy (1). More importantly, it worsens patients’ performance status (PS), which is a deciding factor for chemotherapy.

Rapid restoring the patency of the central airway is critical for the treatment of malignant airway stenosis (4,5). However, systemic anti-cancer treatment, including chemotherapy, target therapy and immunotherapy, is not sufficient to quickly re-open the occluded airway. Radiotherapy is a common treatment choice for malignant central airway stenosis (6). But it usually takes at least 1 week to complete the whole treatment course. Moreover, there is a high risk of aggravation of the stenosis caused by edema following radiotherapy in the early stage of treatment, which is especially fatal for tracheal tumors (7,8). In this situation, minimally invasive interventional therapies in the airway combined with systemic anticancer therapy is a reasonable choice for severe malignant airway stenosis (9).

Traditional interventional techniques including high-frequency electrocautery, laser resection and metallic stenting have been widely used to remove the airway tumor tissues and restore the patency of the airway (10). However, patients with MCAO often suffered recurrence of the airway lesions shortly after these procedures, with a median overall survival (OS) of nearly 3 months (1). Endobronchial cryotherapy, including cryodebridement, is a widely utilized technique for removing central airway lesions. When applied to granulation, cryotherapy is more conducive to the inhibition of granulation tissues’ proliferation than heat techniques (11). Recently, immune checkpoint inhibitors (ICIs) such as Programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies have been widely used in the treatment of lung cancer (12). Some observational studies have shown that cryotherapy has a potent synergistic effect with ICIs by promoting the release of tumor antigens and infiltration of immune cells (13,14). For the treatment of MCAO, whether the combination of deep hypothermia in the airway with systemic ICIs treatment has better local control of airway lesions deserves further investigation. In the present study, we retrospectively analyzed the patients’ data who had received nitrogen-based deep hypothermal cryotherapy plus systemic ICIs simultaneously for the control of their malignant airway stenosis. We aimed to observe the clinical efficacy and safety of the combination strategies. We present this article in accordance with the STROBE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-24-74/rc).


Methods

Patients

This was a single-unit retrospective study conducted in Shanghai East Hospital, China. From January 2021 to December 2023, patients who had received a combination of cryotherapy under bronchoscopy and ICIs in our center were included for data analysis. Severe central airway stenosis was defined as the severity of stenosis of the trachea or bronchus of more than 50% or obvious airway stenosis-related symptoms occurred in patients (15). The airway tumor should be classified as endoluminal or mixed airway obstruction under bronchoscopy (16). Patients who had previously received radiotherapy for the airway tumor, or immunotherapy with PD-1 or PD-L1 were excluded for analysis. All patients provided informed consent on data collection to participate in the study. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and approved by the ethics committee of Shanghai East Hospital (No. 2024YS-086).

Bronchoscopy and deep hypothermal cryotherapy

Patients with lung cancer were scheduled for bronchoscopy for diagnosis and treatment when the chest CT indicated central airway involvement. For interventional treatment of airway stenosis, high-frequency electrocautery was performed to remove the endoluminal lesions. For mixed obstruction, metallic stent was then placed to sustain the patency of the airway if it remains stenotic after the resection. After that, endobronchial cryotherapy was conducted to the residual lesions. The stent would be removed if the local tumor was fully controlled during the follow-up.

For deep hypothermal cryotherapy, it was performed by using a cryo-balloon treatment system (Ningbo Senscure Biotechnology Co., Ltd., China) under general anesthesia. The cryo-balloon catheter can pass through the 2.8 mm working channel of an Olympus T290 bronchoscope. The system uses nitrogen as the cooling source (17). The surface temperature of the cryo-balloon can rapidly drop to −160 ℃. Freezing time was set to 10 s for 1 cycle in one position. Normally, 2 to 4 positions were chosen for a patient to fully cover the whole residual lesions. We routinely performed bronchoscopy within one week to clear the necrotic tissues after cryotherapy.

Systemic anti-cancer therapy

Systemic anti-cancer therapy strategies were made following the National Comprehensive Cancer Network (NCCN) guideline according to the patients’ clinical condition (18). Patients with high PS score (PS >2) or high PD-L1 levels (≥50%) were given only ICIs, either PD-1 antibody or PD-L1 antibody. Otherwise, patients were treated with immunotherapy plus chemotherapy if they had proper PS score (PS ≤2) and non-high PD-L1 expression.

Outcome measurement

The primary endpoint was the duration of efficacy (DoE) of the treatment for the malignant central airway stenosis, which was defined as the time interval from the combined therapy to the recurrence of the airway tumor that needs further treatment including radiotherapy or interventional treatment. Secondary endpoints include objective response rate, progression-free survival and OS. The safety of the combined treatment was evaluated by recording the adverse events.

Statistical analysis

For each patient, the total follow-up time was calculated from the date of cryotherapy to the earliest of the date of death or to December 31, 2023. SPSS 25.0 was used for data analyses. Continuous data were presented as median [95% confidence interval (CI)] and categorical data as frequencies and proportions.


Results

Baseline characteristics

Twelve patients received a combination of cryotherapy and immunotherapy between January 2021 and December 2023. The baseline characteristics were described in Table 1. Half of the patients were diagnosed as squamous lung cancer. Others included one small cell lung cancer (SCLC), two large cell carcinomas and one sarcomatoid carcinoma. 41.7% of the patients had a PS score higher than 2 points, indicating worse baseline conditions. The PD-L1 levels varied among patients. Although 50.0% were PD-L1 highly expressed, six patients were medium to low levels, and one had PD-L1 status unknown (Table 1).

Table 1

Baseline characteristics

Characteristic Values (n=12)
Age, years 66.0 (55.5–71.0)
Age ≥65 years 7 (58.3)
Sex
   Male 11 (91.7)
   Female 1 (8.3)
ECOG performance status score
   ≤2 7 (58.3)
   3 3 (25.0)
   4 2 (16.7)
Pathology
   Adenocarcinoma 2 (16.7)
   Squamous carcinoma 6 (50.0)
   Large cell carcinoma 2 (16.7)
   Small cell lung cancer 1 (8.3)
   Sarcomatoid carcinoma 1 (8.3)
Stage
   III 6 (50.0)
   IV 6 (50.0)
PD-L1 TPS
   ≥50% 5 (41.7)
   <50% 6 (50.0)
   Not evaluable 1 (8.3)

Data are presented as median (range) or n (%). ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed cell death-ligand 1; TPS, tumor proportion score.

The right main bronchus was the most affected airway in our series. Seven had right main bronchus involved, two had left bronchus affected, and two patients had co-stenosis of the right main bronchus and bronchus intermedius. 58.0% of patients had previously been treated with chemotherapy. Cryotherapy was successfully performed in all patients. Metallic stents were placed in eight patients after local resection. In four of the eight patients, the stents were successfully removed after full control of the local airway tumors. All of the twelve patients received PD-1 antibody. Nine of them also received chemotherapy simultaneously (Table 2).

Table 2

Detailed treatment information of the 12 patients receiving cryotherapy combined with ICI

No. Pathologic type TNM stage Previous treatment PD-L1 level (TPS, %) ICI Location, length (mm) Stenosis severity* Interventional treatment
1 s-NSCLC IVA (T4N0M1a) Surgery, Chemo 20% Sintilimab RMB + RIB, 50 3 Cryotherapy
2 Sarcomatoid IVA (T4N2M1a) None 50% Camrelizumab RMB + RIB, 73 5 Cryotherapy + stenting
3 s-NSCLC IIIA (T2bN2M0) None 50% Camrelizumab RMB, 17 4 Cryotherapy
4 s-NSCLC IVA (T2aN2M1b) Chemo <1% Sintilimab RMB, 32 5 Cryotherapy + stenting
5 s-NSCLC IIIA (T4N1M0) Chemo <1% Sintilimab RMB, 25 4 Cryotherapy + stenting
6 a-NSCLC IIIB (T3N2M0) Chemo 10% Pembrolizumab RMB, 29 3 Cryotherapy + stenting
7 s-NSCLC IVB (T4N2M1c) Chemo 50% Camrelizumab RMB, 20 3 Cryotherapy
8 a-NSCLC IIIB (T1N3M0) None 50% Sintilimab LMB, 18 5 Cryotherapy + stenting
9 s-NSCLC IVA (T4N2M1a) None 50% Pembrolizumab LMB, 19 4 Cryotherapy + stenting
10 SCLC IIIB (T3N2M0) Chemo <1% Serplulimab RMB, 20 5 Cryotherapy + stenting
11 LCLC IVA (T2N2M1a) Chemo + ICI <1% Serplulimab RMB, 20 4 Cryotherapy + stenting
12 SCLC IVA (T4N3M1a) Chemo unknown Serplulimab RIB, 15 5 Cryotherapy

*, stenosis grade: 1: <25%, 2: 25–49%, 3: 50–74%, 4: 75–90%, 5: >90%. s-NSCLC, squamous non-small cell lung cancer; SCLC, small cell lung cancer; LCLC, large cell lung cancer; Chemo, chemotherapy; ICI, immune checkpoint inhibitor; RMB, right main bronchus; RIB, right intermedius bronchus; LMB, left main bronchus; TNM, tumor, node, metastasis; PD-L1, programmed cell death-ligand 1; TPS, tumor proportion score.

Efficacy

After a median follow-up of 23.0 months (95% CI: 8.0–not reached), the median DoE was 10.0 months (95% CI: 3.7–21.7). Eleven of the 12 patients responded to the combination therapy, with 1 complete release, 9 partial release and 1 stable disease (Figure 1). The percentage of patients with objective response was 91.7% in these patients. One patient had completed release of the cancer. He was diagnosed as squamous lung cancer with PD-L1 expression of 90.0%, and was treated with four cycles of chemotherapy plus ICI, followed by pembrolizumab maintenance treatment (Figure 2). The patient with large cell lung cancer did not respond to the combined therapy. One year ago, she received a lobectomy of the right upper lobe. However, her cancer relapsed with right main bronchus involved. Therefore, she went into four cycles of platinum-based chemotherapy before cryotherapy. Her endoluminal tumor recurred 2 months later after cryotherapy plus serplulimab and platinum-based chemotherapy. She died 4 months later after the combined therapy.

Figure 1 Swimmer plot for individual patients in the case series. DoE, duration of efficacy; OS, overall survival.
Figure 2 Representative chest CT images and bronchoscopy findings of the patient with complete remission. The patient was diagnosed as squamous lung cancer originated from the right upper lobe with right main bronchus, intermedius bronchus and mediastinal lymph node invaded (A,B). The patient was firstly treated with high frequency coagulation and stenting, but the tumor relapsed quickly after 2 weeks and caused obstructive pneumonia (C,D). So, a metallic stent was placed (E) cryotherapy was performed to the residual tumors of the right bronchus after endobronchial resection (F). The patient received four cycles of chemotherapy and pembrolizumab followed with pembrolizumab maintenance. Two months later, the endobronchial tumor reduced obviously (G,H), so the metallic stent was removed (I). The patient remained CR after up to 35 cycles of ICI treatment (J). CT, computed tomography; CR, complete remission; ICI, immune checkpoint inhibitor.

For this group of patients, the 6-, 12- and 18-month survival rate was 75.0%, 50.0% and 41.8%, respectively. Again, the highly PD-L1 expressed patients had the longest OS, but two patients with negative PD-L1 expression also survived more than 12.0 months (Figure 1).

Safety

A summary of the safety events was given in Table 3. A total of 15 events occurred among the patients, and 86.7% of them were grades 1 to 2. Four events were associated with chemotherapy or ICIs, including rash, pneumonitis, and hypothyroidism. Eight events related to interventional therapy, but none of them need specific interventional treatment. Granulation was the most frequent adverse event, which might relate to metallic stenting. There was no perforation, massive bleeding, airway injury or bronchomalasia after cryotherapy. There were three death events, but none of them related to cryotherapy or ICIs. The first patient was diagnosed as squamous lung cancer with left main bronchus completely occluded and left pulmonary artery invaded. His PD-L1 level was 90% and received a combination therapy of cryotherapy, stenting, immunotherapy and chemotherapy. He died of massive bleeding 2 months later due to rapid regression of the tumor after two cycles of immunotherapy. Another patient died of foreign body aspiration during the coronavirus disease 2019 (COVID-19) pandemic at home. The third death was attributed to the progression of her primary large cell lung cancer.

Table 3

Summary of adverse events

Adverse events Patients (N=12)
Grade 1–5 Grade 3–5
Any grade adverse events
   Grade 3 or 4 0 0
   Grade 5 2 2
Procedure-related adverse events
   Perforation 0 0
   Bleeding 1 0
   Pain 0 0
   Dyspnea 0 0
   Tracheobronchomalacia 0 0
   Re-occlusion 1 0
   Stent migration 1 0
   Infection 0 0
   Granulation 5 0
   Mucus impaction 0 0
Immune-mediated adverse events
   Hypothyroidism 2 0
   Pneumonitis 1 0
   Hyperthyroidism 0 0
   Colitis 0 0
   Hepatitis 0 0
   Rash 1 0
   Pancreatitis 0 0
   Infusion reactions 0 0

Discussion

In this retrospective study, 12 lung cancer patients with severe airway stenosis received a combination treatment of deep hypothermal cryotherapy and immunotherapy. Most of the patients showed a persistent local control of airway tumor lesions under limited side effects, therefore, acquired longer survival.

The combination therapy made it possible for the patients with poor PS to undergo further anti-cancer therapy. More than 40.0% of the patients had a PS score higher than 2 in our case series. Normally, these patients are suggested to receive best supportive therapy instead of systemic anti-tumor treatment (19). Previous studies had shown that the average OS for this group of patients was less than 3 months (1,19). In the present study, the percentage of patients with objective response was as high as 91.7% after cryotherapy and immunotherapy. The combination therapy quickly re-opened the occluded airway and greatly improved the patients’ performance, which allowed them to endure the systemic treatment, such as chemotherapy and anti-angiogenesis. One stage IIIA patient with main bronchus involved achieved complete remission of the local lesions after the combined treatment. This preserved his lung function compared to the strategy of whole lobe resection if he took surgery as his original choice.

The long DoE suggests that the combination therapy had a persistent effect on local control of airway tumors. Relapse shortly after interventional therapy is a great challenge for the treatment of malignant central airway stenosis (20). The residual tissues, which often manifest as inner-luminal type after thermal cutting such as high-frequency electrocautery or laser, are the source for tumor recurrence. Great risks exist if heat cutting is continuously performed on the residual tumor tissues, because it might lead to airway perforation or massive bleeding. In this condition, cryotherapy has many advantages compared to heat ablation in cancer treatment (21,22). Traditional cryotherapy using CO2 (−78.5 ℃) or nitrous oxide (−89.5 ℃) as the cryogenic materials can reach a working temperature as low as −40 ℃, which is sufficient to cause tumor cell death. However, more endobronchial devices using liquid nitrogen are being developed. Apart from its easy availability and safety in use, liquid nitrogen has proved to be the most useful for its low temperature (−195.6 ℃) (23). Modern liquid nitrogen endobronchial device is also highly efficient. Due to its balloon-shaped design, the cryo-balloon, when filled with liquid nitrogen, offers a larger contact area and higher treatment efficiency compared to the traditional cryoprobe, allowing for more effective treatment of target lesions.

Half of the patients in our case series had medium to negative PD-L1 expression who were normally less likely to benefit from immunotherapy, especially for SCLC patients (24,25). However, their endobronchial lesions responded well to the combination therapy in our series. A possible explanation could be the enhanced antitumor immunity following cryotherapy. Thermal ablation techniques, including microwave ablation and cryotherapy, have been shown to induce an abscopal effect in various cancers (26,27) and may reverse resistance to immunotherapy (28). Recent research has demonstrated that cryotherapy can trigger an antitumor immune response in lung cancer and enhance the effectiveness of immunotherapy (29). Animal studies further support this, showing a significant increase in the ratio of mature dendritic cells in the tumor microenvironment (TME) after cryotherapy, as well as a 100-fold increase in CD8+ cytotoxic T cells (30). At the same time, the inhibitory immune cells, including myeloid-derived suppressor cells and regulatory T cells in the TME were all reduced. Taken together, these studies suggest that cryotherapy might turn the cold tumor to the hot tumor by improving the TME, and promoting the efficacy of immunotherapy through synergistic effect.

The combination treatment did not obviously increase the rate of complication. No severe procedure-related adverse event emerged in the combination therapy. However, Concerns should be taken towards the time intervals of cryotherapy to avoid cold injury, bleeding, or even airway perforation due to the super low temperature as shown in our previous animal experiment (17,31). One patient died of massive hemoptysis. This patient had left pulmonary artery invaded before treatment. As his PD-L1 level was as high as 90%, he responded quite well after pembrolizumab therapy, and his tumor relieved so quickly that the artery ruptured before the third cycle of immunotherapy. This case reminds us that patients who have mediastinal major blood vessels invaded should be closely monitored as they were at high risk of hemoptysis, especially for the squamous lung cancer patients.

Although our data showed preliminary privilege of combined strategy in malignant central airway stenosis patients, the present study also had some limitations. First, due to its retrospective design, heterogeneity in patients’ pathology, PD-L1 levels and response to anticancer therapy all may affect the patients’ duration of effects. Second, lack of controls makes it difficult to accurately assess the importance of cryotherapy in the combination therapy, especially among the high PD-L1 patients. Third, the amount of residual tissues might also affect the duration of effects, as skilled interventional pulmonologists may achieve better clearance of the local tumors before cryotherapy. In this way, well-balanced and controlled perspective trial should be conducted in the future to fully elucidate the effects of combination therapy.


Conclusions

In conclusion, endobronchial cryotherapy combined with ICIs provides an effective and safe treatment to control local tumors of MCAO.


Acknowledgments

Funding: This work was supported by the Shanghai Science and Technology Innovation Action Plan (No. 22Y11901100) and The Top-level Clinical Discipline Project of Shanghai Pudong (No. PWYgf2021-05).


Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-24-74/rc

Data Sharing Statement: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-74/dss

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-24-74/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-24-74/coif). All authors report that the study was funded by the Shanghai Science and Technology Innovation Action Plan (No. 22Y11901100) and The Top-level Clinical Discipline Project of Shanghai Pudong (No. PWYgf2021-05). All cryo-balloons were proved by Ningbo Senscure Biotechnology Co., Ltd. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the ethics committee of Shanghai East Hospital (No. 2024YS-086). All patients provided informed consent on data collection to participate in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.


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Cite this article as: Luo Z, Deng C, Gao S, Wu X, Fang X, Zhu X, Li Q, Xu W. The feasibility of the deep hypothermal cryotherapy plus immune checkpoint inhibitor for treatment of severe malignant central airway obstruction. Chin Clin Oncol 2024;13(6):84. doi: 10.21037/cco-24-74

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