Phase II trial of lung chemoembolization

Introduction

Lung chemoembolization is a new treatment option for lung tumors [1–3], but the optimal embolic, drug, and technique are unknown. A recent phase I trial of chemoembolization of lung metastases used Lipiodol, mitomycin, and Embospheres [4]. This was the first lung chemoembolization trial in the United States, and also the first trial to examine both the bronchial and pulmonary artery blood supply to lung metastases.

The phase I trial showed that lung chemoembolization can safely treat large and multifocal lung tumors (including mediastinal lymph nodes), in patients with limited treatment options. There were no serious adverse events, and the metabolic response rate was 40%. All lung metastases were hypervascular, and lipiodol was preferentially retained in the tumors. After chemoembolization, the initial tumor-to-plasma mitomycin concentration ratio was 380, and this high intratumoral drug concentration allowed successful treatment of tumors that were refractory to systemic chemotherapy. Given the encouraging results of the phase I trial, a phase II trial has been started, to examine local progression-free survival.

ClinicalTrials.gov identifier: NCT05672108

Materials and Methods

Trial design

This single-arm, phase II trial is being conducted at 2 sites (City of Hope and Memorial Sloan Kettering Cancer Center).

Study population

Non-small cell lung cancer (any stage), with lung, endobronchial, pleural, or mediastinal tumors that are progressing on systemic therapy (or the patient cannot tolerate systemic therapy), and that are not amenable to resection, thermal ablation, or ablative radiation therapy.

Interventions

Bronchial or pulmonary artery chemoembolization using Lipiodol, mitomycin, and Embospheres. Repeat or staged lung chemoembolization procedures allowed after 4 weeks; up to 4 procedures allowed per patient. Concurrent systemic therapy and local therapies outside the lung are allowed.

Lung chemoembolization procedure

Most lung tumors are supplied by the bronchial artery, but they can also be supplied by a non-bronchial systemic artery, or the pulmonary artery [4]. Many lung tumors appear to have a feeding pulmonary artery on CT, but most of those tumors are actually supplied by the bronchial artery based on catheter angiography [4].

In this study, bronchial angiography is generally performed first. If the tumors are not supplied by bronchial or non-bronchial systemic arteries, then pulmonary angiography is performed to identify the blood supply.

Chemoembolization is performed via the artery supplying the tumor (bronchial, non-bronchial systemic, or pulmonary). For localized disease, chemoembolization should be performed as selectively as possible, while still treating the target tumors completely. For multifocal disease, up to one lung can be treated per session via the bronchial artery, and up to one lobe can be treated per session via the pulmonary artery. 2 F microcatheters are helpful for selecting branches of the bronchial artery.

Cone beam CT or helical CT (in an integrated angiography / CT suite) must be performed to confirm that the artery supplies the tumor and does not supply esophagus or spinal cord. Enhancement of bronchi or mediastinal lymph nodes is not a contraindication to chemoembolization. Typical scan delays are: 5 seconds after the start of contrast injection for bronchial artery, and 3 seconds for pulmonary artery.

Mitomycin powder (5 mg/m²) is dissolved in lipiodol at 2 mg/ml (maximum lipiodol volume 10 ml). A water-in-oil emulsion is formed by adding water-soluble contrast (50% of the lipiodol/mitomycin volume), and pumping through a 3-way stopcock.

The lipiodol / mitomycin emulsion is typically injected in ~0.2 ml boluses (for the bronchial artery). Chemoembolization is performed until there is reduced flow, and no residual tumor blush. Embospheres should be delivered at the end, to help retain the lipiodol / mitomycin in the tumor (100–300 micron for pulmonary artery, and 300–500 micron for bronchial artery).

Follow-up

Chest CT, spirometry, laboratory tests (CBC and CMP), and clinic visit are performed 4–6 weeks after the procedure. At least 6 months of follow up imaging are obtained after the initial TACE procedure.

Primary endpoints are local progression free survival at 6 months, and safety. Exploratory endpoints include quantitative evaluation of changes in blood flow to the tumor and lung during chemoembolization.

Local progression free survival is defined as time from the initial TACE treatment, to progression in a completely treated territory, or death from any cause. The treated area is determined based on angiography and CT performed during the chemoembolization procedure. Progression is determined by RECIST 1.1 criteria, compared to the scan immediately prior to treatment of that territory, using the 2 largest measurable lesions per treated territory.

Complications will be evaluated prior to discharge after the procedure, and at the 4–6 week post-procedure clinic visit. The safety assessment period ends 3 months after the last chemoembolization procedure. Complications will be classified using the NCI Common Terminology Criteria for Adverse Events version 5.0. Change in oxygen saturation, FVC, and FEV1 pre- and post-procedure will be evaluated.

Common side effects of lung chemoembolization include cough, dyspnea, nausea / vomiting, fever, pain, and fatigue. Serious and rare potential complications include spinal cord injury and esophageal necrosis.

Sample size

30 patients

Figure 1.

Study schema. Between 1 and 4 lung chemoembolization treatment procedures can be performed per patient. The example above shows a potential schedule for 2 treatments.

Table.

Eligibility Criteria

Main inclusion criteria

Non–small cell lung cancer (any stage), with lung, endobronchial, pleural, or mediastinal tumors that are progressing on systemic therapy (or the patient cannot tolerate systemic therapy) and that are not amenable to resection, thermal ablation, or ablative radiation therapy

Lung-dominant disease (majority of active tumor volume is in the chest)

Main exclusion criteria

Eastern Cooperative Oncology Group performance status of >2

Oxygen saturation of <92% on room air

Forced expiratory volume in 1 s of <60%

No measurable treatable disease (eg, unable to measure tumor size on CT scan, or lung nodules are all <1 cm)

Pulmonary embolism within 3 mo

Pneumonia within 1 mo