Bronchial Fistula: Rare Complication of Treatment with Anlotinib

Abstract

Background: Anlotinib is a newly developed small molecule multiple receptor tyrosine kinase (RTK) inhibitor that was approved for the treatment of patients with lung cancer in China. We aim to report 3 cases of rare complication of anlotinib-bronchial fistula (BF) during the treatment of lung cancer patients and summarize the possible causes.

Methods: We collected three patients who developed BF due to anlotinib treatment, and conducted a search of Medline and PubMed for medical literature published between 2018 and 2020 using the following search terms: "anlotinib," "lung cancer," and "fistula."

Results: Our literature search produced two case reports (three patients) which, in addition to our three patients. We collated the patients' clinical characteristics including demographic information, cancer type, imaging features, treatment received, risk factors for anlotinib related BF, and treatment-related outcomes. The six patients shared some common characteristics: advanced age, male, concurrent infection symptoms, diabetes mellitus (DM), advanced squamous cell and small cell lung cancers, centrally located tumors, tumor measuring ≥5 cm in longest diameter, and newly formed tumor cavitation after multi-line treatment especially after receiving radiotherapy. Fistula types included broncho-pericardial fistula, broncho-pleural fistula, and esophago-tracheobronchial fistula. Six patients all died within 6 months.

Conclusions: Although anlotinib is relatively safe, it is still necessary to pay attention to the occurrence of BF, a rare treatment side effect that threatens the quality of life and overall survival of patients. Anlotinib, therefore, requires selective use and close observation of high-risk patients.

Keywords: Anlotinib; Bronchial fistula; Broncho-pericardial fistula; Broncho-pleural fistula; Esophago-tracheobronchial fistula; Lung neoplasms.

1

Broncho-pericardial fistula (BPCF) appears in a patient with pulmonary squamous cancer after using anlotinib. A: Left hilar mass (28 mm×31 mm), before use of anlotinib; B: After use of anlotinib for 1.5 mon, a cavity was formed in the left upper lung tumor (yellow arrow: cavity); C: A fistula communicating with the left main bronchus and pericardial cavity with large gas buildup in it, suggesting BPCF (red arrow); D: After drained gas with catheter stetted into pericardium for 5 days, computed tomography showed significant reduction of gas and pericardium partially conglutinated; E: (Bronchoscopy) A huge fistula at the left main bronchus; F: (Bronchoscopy) A huge cavity was seen with heart beat visible on the inner wall.

2

Broncho-pleural fistula (BPF) appears in a patient with pulmonary squamous cancer after using anlotinib. A: Central right upper lung occupied mass (55 mm×65 mm) with the right main bronchus invasion and right upper lung obstructive pneumonia, before use anlotinib; B: A huge cavity formed in the upper right lung mass after 4 mon of use of anlotinib; C: Right BPF (red arrow) with liquid pneumothorax formation.

3

BPF appears in a patient with small cell lung cancer after using anlotinib. A: Upper left lung mass (92 mm×89 mm) with left upper lung atelectasis, along with mediastinal lymphadenopathy (short axis=46 mm), before use anlotinib; B: Thin-walled cavitation lesion in the left lower lung considered to be lung cancer metastases, before use anlotinib; C: Left lower lung atelectasis with a cavity wall incomplete and communicates with the pleural cavity, indicating broncho-pleural fistula (BPF, red arrow), which led to the formation of liquid pneumothorax.