Successful Treatment of an Aggressive Tracheal Malignancy With Immunotherapy

Abstract

Immune checkpoint inhibitors are emerging as therapeutic options for oncology patients in whom conventional treatment regimens have failed. These immunotherapies counteract tumor-induced tolerance and have been shown to be effective in thoracic malignancies, including non-small cell lung cancer (NSCLC). This report highlights the successful use of nivolumab—an immunotherapeutic agent that binds to proteins involved in T-cell proliferation—for the management of recurrent tracheal squamous cell cancer after exhaustion of conventional surgical, chemotherapeutic, and radiation therapy options. Observations provide a strong indication of the potential value of checkpoint inhibitors for managing a wide array of thoracic malignancies.

Immune checkpoint blockade is emerging as a promising therapeutic option for patients with cancer [1]. Clinical trials are exploring the effectiveness of immunotherapies as first-line options in tumors with favorable biological characteristics [2]. Immune checkpoints target cell surface receptor pathways, which can suppress immune function and T-cell–associated cytotoxicity to facilitate tumor escape from host immune responses [1].

Programmed death-1 (PD-1) is a coreceptor that when bound by ligands (programmed death ligand-1 [PD-L1] or programmed death ligand-2 [PD-L2]) can shut down T-cell proliferation and cytokine production. Anti-PD-1/PD-L1 antibodies have been shown to counteract this tumor-induced tolerance. In clinical trials, these antibodies have shown clinical response in advanced-stage malignancies, including non-small-cell lung cancer (NSCLC) [3, 4]. Nivolumab, an inhibitory PD-1 antibody, has been successful in trials against traditional chemotherapy agents, prompting US Food and Drug Agency approval for melanoma and NSCLC [2]. However, the experience with tracheal tumors has not been reported. We report the application of nivolumab for managing a recurrent locally aggressive tracheal squamous cell carcinoma after real-time polymerase chain reaction and immunohistochemical analysis demonstrated PD-L1 expression on tumor cells.

A 67-year-old man with a 40–pack-year smoking history presented with hemoptysis in June 2007. Imaging evaluation, which included positron emission tomography/computed tomography, revealed a 3.2 × 1.3 cm tracheal mass with no metastases. Bronchoscopic biopsy results confirmed the diagnosis of a moderately differentiated invasive tracheal squamous cell carcinoma. After laryngotracheal resection and reconstruction involving resection of approximately 4 cm of trachea (negative margins confirmed on pathologic examination), the patient received 5,040 cGy of cord-sparing, intensity-modulated radiotherapy (180 cGy per session). In 2010, he underwent a left lower lobe segmentectomy for a separate lung primary tumor, which on pathologic examination was also found to be squamous cell carcinoma.

In December 2011, 4 years after tracheal resection, surveillance bronchoscopy revealed recurrent disease (2-cm squamous cell carcinoma) at the location of the previous surgical margin. Attempted resection revealed extensive involvement of the remnant trachea, and the procedure was aborted. Despite additional radiation (3,060 cGy), chemotherapy with cetuximab (in 2012) and then paclitaxel/carboplatin (10 cycles in 2013–2014), and multiple bronchoscopic debulking procedures for emergent management of life-threatening airway obstruction (5 procedures in 2013–2015), the tumor grew to 6.5 cm, occupying 40% to 80% of the tracheal lumen (Figs 1, 2A) and spreading locally to involve the esophagus. A feeding gastrostomy tube was placed for nutrition given progressive dysphagia as the tumor grew in size.

Fig 1.

Tracheal squamous cell carcinoma (A) before and (B) after 9 months of immunotherapy with nivolumab. Note improvement of tracheal luminal patency and overall decrease in size of mass.

Fig 2.

Bronchoscopic images of tracheal tumor. (A) Before core was out on April 16, 2013 at time of presentation for acute respiratory compromise. (B) Seven months after initiation of immunotherapy on surveillance bronchoscopy (November 6, 2015).

Through real-time polymerase chain reaction and immunohistochemical analysis in 2015, the tumor was found to have significant expression of PD-L1 (Fig 3). Accordingly, nivolumab immunotherapy was initiated (3 mg/kg every 2 weeks). Surveillance imaging demonstrated significant decreases in tumor size after 2 months (4.2 cm) and 9 months (2.0 cm) (Fig 1). Bronchoscopy after 7 months revealed no gross disease (Fig 2B), with biopsy results demonstrating focal squamous metaplasia without malignancy. Clinically, the patient experienced significant improvement in dyspnea and resolution of his dysphagia, complaining only of mild fatigue throughout the nivolumab treatment period. His G-tube was removed in March 2016 in the setting of good oral intake.

Fig 3.

(A) Squamous cell carcinoma infiltrating desmoplastic stroma exhibits strong membrane immunoreactivity for programmed death ligand-1 (PD-L1) (×100, staining performed with 5H1 mononuclear antibody [mAb]). (B) High-magnification view showing well-differentiated squamous cell carcinoma with strong diffuse epithelial membrane immunoreactivity for PD-L1 (×400, staining performed with 5H1 mAb).

Comment

The patient’s course illustrates the successful use of nivolumab to treat a recurrent locally aggressive tracheal squamous cell carcinoma. Treatment with this PD-L1 inhibitor provided a novel therapeutic option for a patient with a very aggressive tumor. The case is proof of principle that immune checkpoint inhibitors may have efficacy against a broad range of solid tumors. Efficacy may be particularly good in tobacco-related malignancies that likely harbor a large mutational load, especially those located higher up in the aerodigestive tract [1, 5]. Although PD-L1 expression does not predict a benefit from nivolumab in lung squamous cell carcinoma [3], whether PD-L1 biomarkers will be important for predicting efficacy across tumor types—including tracheal tumors—remains to be discovered.