The purpose of this study is to explore the efficacy and safety of different doses of bevacizumab injection in the treatment of malignant pleural effusion in patients with advanced non-squamous non-small cell lung cancer.

This study is a prospective, multicenter, randomized, phase II clinical study. 87 patients will be recruited.

Group A (low dose group)

Intrapleural injection of bevacizumab 2.5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard.

Group B (medium dose group)

Intrapleural injection of bevacizumab 5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard.

Group C (high dose group)

Intrapleural injection of bevacizumab 7.5mg/kg/times, d1, d8; 21 days for a course of treatment. Subjects will received two courses of treatment if there is no termination of treatment listed in the standard.

Main evaluation criteria: pleural effusion objective response rate(ORR) (WHO standard)

Secondary evaluation criteria: pleural fluid time to progression (TTP), overall survival (OS), ORR, QOL scores (Quality of Life Questionnaire-lung cancer) and KPS, and safety (NCI CTCAE V4.03)

Inclusion Criteria:

1. Voluntarily sign informed consent;
2. Non-squamous non-small cell lung cancer, newly diagnosed or previously treated with systemic chemotherapy and / or epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors treatment;
3. B ultrasound, chest X-ray or CT examination to a large number of pleural effusion, with a cytology confirm of malignant pleural effusion;
4. Aged 18-75 years;
5. Eastern Cooperative Oncology Group (ECOG) score ≤ 2;
6. Survival is expected to exceed 8 weeks

Exclusion Criteria:

If any of the following criteria is met, the subject shall be excluded:

1. Squamous cell carcinoma (including adenosquamous carcinoma) and small cell lung cancer (including small cell carcinoma and non-small cell mixed lung cancer);

2. In the past 2 weeks, there have been systematic anti-tumor treatment including chemotherapy (including thoracic chemotherapy), radiotherapy (excluding radiotherapy of metastatic lesions outside the thoracic radiation field), targeted therapy, immunotherapy and biotherapy;

3. The subject had received anti-vascular endothelial growth factor (VEGF) small molecule tyrosine kinase inhibitors or monoclonal antibodies in the past 4 weeks;

4. The subject had participated any clinical trials in the past 4 weeks;

5. The subject had previously received bevacizumab of pleural perfusion therapy;

6. Laboratory results:

   • White blood cell count <3 × 109 / L, neutrophil count <1.5 × 109 / L, platelet <75 × 109 / L, or hemoglobin <8g / dL;
   • Coagulation abnormalities (INR > 1.5 or prothrombin time (PT) > ULN + 4 seconds or activated partial thromboplastin time (APTT) > 1.5 ULN), with bleeding tendency or being treated with thrombolysis or anticoagulation;
   • Serum total bilirubin ≥1.5 ULN; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 ULN in the absence of liver metastases; ALT or AST ≥5 ULN in liver metastases;
   • Serum albumin <30g / L;
   • Serum creatinine ≥ 1.5 ULN or creatinine clearance <40ml / min;
   • Urine routine urinary protein ≥ ++, or 24 hours urine protein ≥ 1.0 g;

7. Hypertension cannot be controlled by drugs;

8. Heart disease with significant clinical symptoms, such as: congestive heart failure, coronary heart disease with symptom, arrhythmia hardly be controlled by drugs, myocardial infarction in 6 months, or heart failure;

9. Imaging (CT or MRI) showed a tumor lesion 5 mm away from the large vessels, or the presence of invasive central vasculature of the central tumor; imaging (CT or MRI) showed significant cavitation or necrosis of the lung tumor; Other diseases that may cause haemoptysis;

10. Imaging (CT or chest radiograph) showed significant pneumothorax, fluid pneumothorax;

11. Bilateral pleural cavity to a large number of effusion or encapsulated pleural effusion;

12. Obvious cough blood in 6 months, or daily hemoptysis amounted to half a teaspoon (2.5ml) or more;

13. Significant bleeding symptoms or with definite bleeding tendency within 12 months before randomization, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, occult blood ++ and above, intracerebral hemorrhage, vasculitis, or with congenital or acquired coagulopathy disorders;

14. Thrombosis, cancer thrombosis (including arteriovenous thrombosis, tumor thrombus, pulmonary embolism, transient ischemic attack, etc.) occurred within 12 months;

15. There are gastrointestinal obstruction, peptic ulcer, Crohn's disease, ulcerative colitis and other gastrointestinal diseases or other diseases may cause gastrointestinal bleeding or perforation;

16. Severe respiratory diseases, or need long-term oxygen, corticosteroid treatment of diseases such as chronic obstructive pulmonary disease, interstitial lung disease and respiratory failure;

17. The toxicity of previous antineoplastic therapies has not yet recovered to below grade 2 or has not fully recovered;

18. Patients with uncontrolled central nervous system metastasis;

19. There are serious uncontrolled systemic diseases, such as nephrotic syndrome, infection, poorly controlled diabetes;

20. Patients with active HIV（human immunodeficiency virus）, HBV（hepatitis B virus）, or HCV（hepatitis C virus） infection;

21. Patients had undergone surgery (<28 days) or did not heal completely, or had other unhealed wounds before the study;

22. Patients known to be allergic to bevacizumab or any of the components of the drug;

23. Pregnant or lactating female patients, or unwilling to take contraceptive measures of reproductive age patients (including men);

24. There is a serious psychological or mental abnormality, or lack of compliance;

25. The investigator determines other circumstances that may affect the conduct of clinical studies and the determination of findings.