Apatinib monotherapy for early non-small cell lung cancer: a case report

Abstract

Stage I non-small cell lung cancer (NSCLC) accounts for about 15% of incident cancer cases. Prognosis is poor, with a metastasis and recurrence rate of 38% within 2 years of surgery and an overall 5-year survival rate of 54–60%. Here, we report successful apatinib monotherapy of early NSCLC in a patient who had declined surgery, radiofrequency ablation, and immunotherapy. The patient received apatinib for 64 months without clinical, laboratory, or radiographic evidence of disease progression. The curative effect was judged to be stable and safe.The role of apatinib as monotherapy for patients with early stage NSCLC who are not candidates for surgery or radiotherapy, or as an adjunct to standard therapy, deserves further study.

Introduction

Lung cancer exhibits the highest incidence and the highest mortality rate of all malignant neoplasms [1]. Non-small cell lung cancer (NSCLC) is the most prevalent histopathologic type of lung cancer, accounting for 80 to 85% of cases. Stage I NSCLC has a poor prognosis, with a metastasis and recurrence rate of 38% within 2 years of surgery and an overall 5-year survival rate of 54–60% [2,3,4,5]. Comprehensive treatment based on surgery is the mainstay of treatment. However, surgery may be unacceptable to some patients and contraindicated in those with severe comorbidities such as advanced cardiopulmonary diseases. Alternative treatment of these patients is difficult and poses formidable challenges to many experts in the field of thoracic surgery.

Angiogenesis is critical for tumor growth and metastasis. Vascular endothelial growth factor (VEGF) signaling plays an important role in angiogenesis. Vascular endothelial growth factor receptor (VEGFR), a tyrosine kinase, is a key regulator of this process. As a tyrosine kinase antagonist, Apatinib impedes angiogenesis and tumorigenesis by inhibiting VEGFR-2 [6, 7]. Apatinib has been approved for the treatment of advanced gastric cancer that has failed second-line treatment [8], but its application in the treatment of lung cancer is still in the phase III clinical trial stage. Apatinib has demonstrated good efficacy and safety in the treatment of advanced NSCLC after first-line chemotherapy [9]. However, to our knowledge, apatinib therapy of early NSCLC has not been reported. We report successful apatinib monotherapy of a patient with early NSCLC who refused invasive treatments such as surgery and stereotactic radiotherapy, and whose lung cancer-related target gene tests were negative. The patient received Apatinib monotherapy for 64 months, and did not exhibit clinical, laboratory, or radiographic evidence of disease progression. The curative effect was judged to be stable.

Case report

On January 17, 2018, a 61-year-old postmenopausal woman was admitted to the cardiovascular department of our hospital with a chief complaint of chest tightness and pain for more than 1 year, and dizziness for 3 days. She had a 40-year history of hypertension that was well controlled by oral valsartan 80 mg daily. Computerized tomography (CT) of the chest revealed a 13 mm×14 mm pulmonary nodule in the anterior segment of the left upper lobe with irregular edges and short burrs and moderate enhancement, with a CT value of about 59 Hounsfield units. Multiple 2–6 mm ground-glass nodules were present in the posterior and anterior segments of the left upper lobe, the right oblique cleft, the right middle lobe, and bilateral lower lobes. No hilar or mediastinal lymphadenopathy was observed (Fig. 1A-B). No evidence of metastasis was found in brain magnetic resonance imaging, abdominal and pelvic CT, and superficial lymph node color ultrasound.Past history: myomectomy, history of lacunar cerebral infarction, meningioma, family history of hypertension; denial of history of other diseases and denied history of smoking.

Fig. 1

Computerized tomography (CT) of the chest revealed: (A) a 13 mm×14 mm pulmonary nodule in the anterior segment of the left upper lobe with irregular edges and short burrs and moderate enhancement, with a CT value of about 59 Hounsfield units. Multiple 2–6 mm ground-glass nodules were present in the posterior and anterior segments of the left upper lobe, the right oblique cleft, the right middle lobe, and bilateral lower lobes. (B) No hilar or mediastinal lymphadenopathy was observed

CT-guided percutaneous pulmonary nodular biopsy combined with histopathological examination revealed a right lung adenocarcinoma (Fig. 2A-B). Immunohistochemical staining disclosed: TTF (+), Napsin A (+), CK7 (+), CK5/6 (-), P53 (+), Ki-67 (-), CK (pan) (+). Lung cancer target gene test results were negative for ALK (D5F3) rearrangements and mutations of EGFR exons 18, 19, 20, and 21. The patient received a diagnosis of adenocarcinoma of the right upper lobe, cT1bN0M0 stage IA. Due to personal reasons, the patient refused surgical treatment, stereotaxic radiotherapy, and other invasive treatments. After prolonged discussions with her caregivers that addressed her medical condition, personal willingness, and treatment options, she accepted oral apatinib monotherapy, The dose was 0.25 g once daily, and no other anti-tumor drugs were taken during the treatment.

Fig. 2

Patient was diagnosed with adenocarcinoma of lung. H&E staining results at (A) 40× and (B) ×200 objective

Chest CTs obtained 5 and 9 monshs after the initiation of therapy disclosed stable disease (SD; 21.4% reduction) (Fig. 3A-B). Apatinib monotherapy was continued, and comprehensive re-examinations were conducted at 17, 24, 30, 36, 40, 47, 51, 57, and 64 months that demonstrated SD (Figs. 4A-B-C-D and 5A-B-C-D-E).The patient had a previous history of hypertension and during apatinib monotherapy, regular oral valsartan 80 mg once daily, regularly monitored good blood pressure. Complete blood counts, liver and renal function tests, serum electrolyte levels, urinalyses, and other indicators were monitored repeatedly during therapy. Proteinuria (3+) was observed on one urinalysis during the 40th month of therapy, but resolved spontaneously. No abnormalities were found in other indicators. The patient died of severe coronavirus 2019 disease (COVID-19) on June 2, 2023.

Fig. 3

(A-B) Small nodules in the anterior segment of the upper lobe of the right lung, smaller than the anterior segment, significantly reduced solid components, short burrs can be seen at the edge, and the adjacent pleura is pulled

Fig. 4

The size of small nodules in the anterior segment of the upper lobe of the right lung did not change much compared with before, (A-B) about 11 mm×11 mm, (C) 13 mm×10 mm, (D) 14 mm×17 mm. The solid composition was the same as before, short burrs could be seen at the edges, and the adjacent pleural stretch was the same as before. The two lungs were scattered in multiple ground glass small nodules, which did not change much compared with before

Fig. 5

(A-B-C) The size and shape of the small nodules in the anterior lobe of the upper lobe of the right lung did not change much compared with before. The nodules of the anterior segment of the upper lobe of the right lung were larger than the anterior segment, with a size of about (D) 20 mm×14 mm, (E) 15 mm×15 mm, multiple patchy, patchy density exudation was observed in both lungs

Discussion

The standard therapy of early NSCLC is surgery-based comprehensive treatment. Stereotactic radiotherapy and immunotherapy are usually offered to patients who refuse surgery and those with surgical contraindications. However, the overall treatment efficacy is poor and the long-term survival rate is still low. According to statistics, stage I non-small cell lung cancer (NSCLC) accounts for about 15% of new cases, and the overall 5-year survival rate is about 54% [4]. Studies show that the 5-year survival rate of patients with stage I lung cancer is about 60%, and the metastasis and recurrence rate reaches 38% within 2 years after surgery, and the prognosis is still poor [5]. For patients with early NSCLC who cannot undergo surgical treatment, their 5-year survival rate is less than 50% [10]. How to make reasonable treatment of early lung cancer patients has always been the focus and difficulty of research.

Apatinib belongs to oral anti-tumor neoangiogenesis drugs, the main target is VEGFR2, by blocking downstream signal transduction to inhibit tumor angiogenesis, so as to achieve the purpose of anti-tumor [11]. Apatinib induces autophagy and apoptosis in NSCLC through VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling [12]. Main side-effects are hypertension, gastrointestinal symptoms, and proteinuria, but most are of grade I to II severity and can be controlled through conservative management [13]. Studies have shown that apatinib achieves better disease control and survival benefits after failure of multiline treatment for advanced lung cancer, and the adverse effects can be tolerated [14]. Apatinib can reduce the expression of drug-resistant protein ABCG2 and vascular endothelial growth factor receptor 2, accelerate the apoptosis of tumor stem cells, kill residual tumor stem cells, reverse drug resistance, and improve clinical efficacy [15]. However, combination chemotherapy or immunotherapy is often used in clinical treatment. At present, there are few reports about apatinib monotherapy in the treatment of lung cancer, especially early non-small cell lung cancer.

Based on this, the patient in this case belongs to early lung adenocarcinoma. After being treated with apatinib alone, the total survival time reached 64 months, Her cause of death was severe COVID-19 pneumonia. Her disease was stable throughout comprehensive evaluations during the entire treatment course, and her only side-effect was transient proteinuria, remission after symptomatic treatment.The efficacy of apatinib on tumor inhibition was confirmed by imaging.As this case is a case report and has few data, the clinical effect of single-agent apatinib treatment for early non-small cell lung cancer still needs to be supported by more clinical data. The relevant clinical and experimental studies should still be carried out in the future to explore the suitable population for apatinib treatment.

Conclusion

We report a case of early NSCLC that responded to apatinib monotherapy, with a sustained response for over 64 months. Apatinib may represent a safe and effective oral targeted agent for patients with early NSCLC. The role of apatinib as a monotherapy for patients who are not candidates for surgery or radiotherapy, or as an adjunct to standard therapy of stage I NSCLC, deserves further study.