Recurrent Drug‐Induced Pneumothorax Associated With Lenvatinib: A Case Report

ABSTRACT

We present a patient with recurrent pneumothorax induced by lenvatinib, used for the treatment of thymic carcinoma. A 76‐year‐old Japanese man, who is a current smoker, was diagnosed with thymic carcinoma with pulmonary metastasis and pleural dissemination. Lenvatinib was initiated as third‐line chemotherapy in April 2022. He was subsequently admitted to our hospital in August and October 2023 for recurrent left‐sided pneumothorax. Following the second left pneumothorax, lenvatinib was discontinued, and he has remained free of pneumothorax for over a year. Clinicians should be aware of the potential adverse effects of lenvatinib in patients with pulmonary metastasis or pleural dissemination.

We present a rare case of a patient with recurrent pneumothorax induced by lenvatinib, used for the treatment of thymic carcinoma. Clinicians should be aware of the potential adverse effects of lenvatinib in patients with pulmonary metastasis or pleural dissemination.

1. Introduction

Thymic carcinoma is a rare malignancy, with an incidence of approximately 0.02 patients per 100,000 person‐years. Approximately 30% of patients with thymic carcinoma present with advanced disease and poor prognosis at the time of diagnosis [1]. Cytotoxic chemotherapy has traditionally been used to achieve disease control in these patients [2]. Recently, lenvatinib, a multitargeted receptor tyrosine kinase inhibitor, has shown high antitumor efficacy against thymic carcinoma [1], gaining attention as a promising treatment option for patients with this malignancy. Common side effects of lenvatinib include fatigue, hypertension, weight loss, diarrhoea, and anorexia [3]; however, reports of pneumothorax as an adverse event remain exceedingly rare. We herein present the first patient with recurrent pneumothorax following lenvatinib treatment for thymic carcinoma.

2. Case Report

A 76‐year‐old Japanese man with no significant medical history was admitted to our hospital in February 2013 after an abnormal shadow was detected during a routine medical check‐up. He was a current smoker with a 30 pack‐year history. Computed tomography (CT) revealed an anterior mediastinal mass, bilateral pulmonary, and subpleural nodules. A thoracoscopic biopsy of the subpleural nodules confirmed a diagnosis of thymic carcinoma, of the basaloid subtype. He was diagnosed with thymic carcinoma with pulmonary metastasis and pleural dissemination. The patient initially underwent first‐line combined chemotherapy with carboplatin and paclitaxel in June 2013. The thymic carcinoma, bilateral pleural metastasis, and pleural dissemination all progressed. Owing to insufficient tumour control, second‐line therapy with TS‐1 was initiated in April 2014. While the thymic carcinoma remained stable for an extended period, a right pleural effusion and pleural dissemination developed, leading to pleurodesis in September 2020. Although pleural effusion did not recur, some pleural dissemination gradually progressed. As a result, third‐line therapy with lenvatinib (24 mg/day) was initiated in April 2022. On the third day of lenvatinib administration, the patient developed Grade 3 hypertension, leading to a dose reduction to 20 mg/day. Two months later, Grade 3 hypertension recurred, and 3–6 months later, the patient experienced Grade 2 loss of appetite and hand‐foot syndrome. The lenvatinib dose was gradually reduced and eventually stabilised at 8 mg/day (Figure 1). Although a dose reduction of lenvatinib was necessary owing to side effects such as hypertension, hand‐foot syndrome, appetite and body weight loss, reductions in pulmonary metastasis and pleural dissemination were observed.

FIGURE 1.

Timeline of the patient's medical history. Tumour responses 9 (A) and 13 (B) months after the initiation of lenvatinib treatment. The left pleural dissemination lesions (red circles) show no significant changes. First (C) and second (D1 + D2) left pneumothorax events 16 and 18 months after lenvatinib initiation, respectively. The left pleural dissemination lesions (red circles) have changed to small subpleural cavitary lesions (red circles) (D2).

Lenvatinib treatment continued, and the patient showed left‐sided pneumothorax in August 2023 (16 months after starting lenvatinib) (Figure 1C). Left chest drainage resulted in rapid improvement, and his left chest tube was removed 8 days after insertion. However, 2 months later (18 months after starting lenvatinib) (Figure 1D), the patient was readmitted with recurrent left pneumothorax. Left chest drainage was reapplied, and given the possibility of lenvatinib‐induced pneumothorax, lenvatinib was discontinued. His left pneumothorax soon improved, and the left chest tube was removed 6 days after chest tube insertion. Given the risk of recurrence, surgical treatment of the pneumothorax was considered after the second episode; however, the air leak resolved spontaneously with drainage, and no further procedures were required. Following consultation with a thoracic surgeon to discuss his options, the patient decided not to undergo surgery or pleurodesis. Fortunately, the patient remained free from pneumothorax recurrence for over a year.

3. Discussion

Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that targets vascular endothelial growth factors 1–3, fibroblast growth factor receptors 1–4, platelet‐derived growth factor receptor α, and the RET and KIT signalling networks. A phase 2 trial conducted in Japan demonstrated the efficacy of lenvatinib in the treatment of advanced or metastatic thymic carcinoma [1]. In this trial, the most common Grade 3 treatment‐related adverse events were hypertension (64%) and hand‐foot syndrome (7%), with no fatalities attributed to these adverse events [1]. One of 42 patients (2.4%) in this trial discontinued treatment because of pneumothorax, although the specific details remain unclear [1].

To the best of our knowledge, six cases of pneumothorax associated with lenvatinib have been reported (Table 1) [4, 5, 6, 7, 8], all of which involved anaplastic thyroid cancer. The present case is the first case of lenvatinib‐induced pneumothorax in a patient with thymic carcinoma. Among these seven cases, two involved life‐threatening bilateral pneumothoraxes, both requiring surgical intervention. In our case, the absence of bilateral pneumothorax was likely to have been attributable to the previous right pleurodesis for right pleural effusion. Sakamoto et al. suggested that malignant pleuritis increases the risk of lenvatinib‐related pneumothorax and recommended pleurodesis before treatment [8].

TABLE 1.

Reported patients with pneumothorax occurring during lenvatinib treatment.

Patients	Age (y)/ sex	Smoking status/pack years	Primary disease	Chest CT findings		Number of the occurrence of pneumothorax	Time from starting lenvatinib treatment to pneumothorax	Pneumothorax site	Treatment	Outcome	First author [ref.]
				Multiple nodular shadows	Cavity regions
1	63/M	Unknown	Anaplastic thyroid cancer	+	−	2	34 days	Right	Chest drainage	Improved	Yamazaki [4]
							56 days	Right	Chest drainage → Pleurodesis	Improved
2	73/M	Unknown	Anaplastic thyroid cancer	+	+	1	2 months	Bilateral	Chest drainage → Surgery	Improved	Kazzaz [5]
3	77/M	Unknown	Anaplastic thyroid cancer	+	+	1	50 days	Bilateral	Chest drainage → Surgery	Improved	Lee [6]
4	Unknown	Unknown	Anaplastic thyroid cancer	Unknown	+	Unknown	Unknown	Unknown	Unknown	Unknown	Murayama [7]
5	Unknown	Unknown	Anaplastic thyroid cancer	Unknown	+	Unknown	Unknown	Unknown	Unknown	Unknown	Murayama [7]
6	78/M	Unknown	Anaplastic thyroid cancer	Unknown	Unknown	1	40 days	Right	Chest drainage → Surgery	Improved	Sakamoto [8]
7	76/M	Smoker/30	Thymic carcinoma	+	−	2	16 months	Left	Chest drainage	Improved	Present patient
							18 months	Left	Chest drainage	Improved

Several potential mechanisms have been proposed for the development of a pneumothorax in the context of lung metastasis with pulmonary emphysema. First, our patient had a 30 pack‐year smoking history, and CT revealed emphysematous changes with bullae. Vascular endothelial growth factor inhibitors like lenvatinib impair wound healing [9], potentially increasing the fragility of bullae. Thus, lenvatinib may have contributed to the secondary pneumothorax in our patient. Second, these include rupture of the subpleural necrotic tumour metastatic nodules, direct invasion of the pleura by the subpleural tumour, and involvement of a check valve mechanism in tumour nodules located at the periphery of the lungs [6]. Murayama et al. reported that pulmonary cavity lesions developed in 12 of 26 patients (46.2%) treated with lenvatinib for anaplastic thyroid cancer with lung metastasis. Pneumothorax occurred in two of these patients, and subpleural tumour cavitation due to tumour necrosis was speculated to have contributed to their pneumothoraces (Table 1, cases 4 and 5) [7]. Pneumothorax related to lenvatinib usually developed within approximately 2 months after lenvatinib initiation in the previous reports. However, pneumothorax in our patient occurred over a year after lenvatinib treatment initiation, probably because of (1) a considerably reduced lenvatinib dose due to adverse effects (e.g., hypertension, fatigue), leading to a slower antitumor response, and (2) the underlying thymic carcinoma, which may show lesser antitumor responsiveness than did anaplastic thyroid carcinoma in the previous reports. High‐resolution CT performed for our patient revealed that the subpleural nodules observed before pneumothorax (Figure 1A,B, circled in red) changed to small subpleural cavitary lesions at the time of follow‐up (Figure 1D, circled in red); this suggested tumour necrosis and cavitation induced by lenvatinib that may have contributed to the left pneumothorax.

Considering these findings, clinicians should remain vigilant for the occurrence of pneumothorax in patients receiving lenvatinib, including those with thymic carcinoma and particularly in those with pulmonary metastasis and pleural dissemination.

Author Contributions

R.T. wrote the draft of the manuscript. K. Yamasaki, Y.I., T.S., R.H. and K. Yatera revised it critically. All authors read and approved the final manuscript.

Ethics Statement

The authors declare that written informed consent was obtained for the publication of this manuscript and accompanying images using the consent form provided by the Journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analysed in this study.