FSRT Combines With Bevacizumab for Multiple Brain Metastases in Lung Adenocarcinoma

Official title

Fractionated Stereotactic Radiotherapy Combines With Bevacizumab for the Treatment of Multiple Brain Metastases in Lung Adenocarcinoma: a Prospective Controlled Phase III Study

Overview

For non-small cell lung cancer brain metastases, stereotactic radiotherapy is gradually replacing whole brain radiotherapy as the standard treatment. When patients have multiple brain metastases or larger tumors (diameter\>2cm), single session stereotactic radiotherapy (SRS) may cause significant neurological damage, so fractionated stereotactic radiotherapy (FSRT) is often used. The recent objective remission rate of FSRT is about 50%, and the 1-year intracranial control rate is about 45%, but intracranial progression remains the main factor affecting long-term survival of patients. Bevacizumab is a recombinant humanized monoclonal antibody against vascular endothelial growth factor, which can improve the efficacy of cranial radiotherapy by normalizing neovascularization and improving the hypoxic state of tumor cells. In addition, bevacizumab can improve the abnormal permeability of neovascularization, reduce exudation and extracellular brain edema, thereby further alleviating the toxic side effects associated with brain radiotherapy. Based on this, this prospective, controlled phase III study will explore the efficacy and safety of the combined use of fractionated stereotactic radiotherapy and bevacizumab in multiple brain metastases of lung adenocarcinoma.

Detailed description

This prospective, controlled phase III study will explore the efficacy and safety of the combined use of fractionated stereotactic radiotherapy and bevacizumab in multiple brain metastases of lung adenocarcinoma.

Patients will be randomly assigned to three groups in a ratio of 1:1:1. The FSRT+beva group receives FSRT radiotherapy+bevacizumab treatment; FSRT targets visible intracranial lesions with a total dose of 30Gy, administered once a day for a total of 5 days, with a fraction dose of 6Gy. Bevacizumab starts on day 1 (one week before FSRT treatment), q3w， A total of 4 treatment courses, intravenous injection, with a dose of 7.5mg/kg. The FSRT group receives simple FSRT radiotherapy; FSRT is targeted at visible intracranial lesions, with a total dose of 30Gy, administered once a day for a total of 5 days, and a fraction dose of 6Gy for segmentation. The WBRT group receives whole-brain radiotherapy (WBRT) with a simultaneous integrated boost (SIB) to visible intracranial lesions. The prescribed doses are: 40 Gy total to gross lesions and 25 Gy total to the whole brain, delivered in 10 daily fractions.

Interventions

• Drug Bevacizumab
  Bevacizumab starts on day 1 (one week before FSRT treatment), q3w，a total of 4 treatment courses, intravenous injection, with a dose of 7.5mg/kg.
• Radiation FSRT
  The FSRT group received simple FSRT radiotherapy; FSRT is targeted at visible intracranial lesions, with a total dose of 30Gy, administered once a day for a total of 5 days, with a fraction dose of 6Gy.
• Radiation Whole brain radiotherapy
  The WBRT group received whole brain radiotherapy and locally increased dose radiotherapy for visible intracranial lesions, with a total dose of 40Gy for local lesions and 25Gy for the whole brain, once a day for a total of 10 days.

Primary outcome measures

• Intracranial progression free survival [Time frame: 2 years]

Secondary outcome measures (5)

• Progress free survival [Time frame: 2 years]
• Overall survival [Time frame: 2 years]
• The quality of life (QOL) [Time frame: 2 years]
• Treatment related side effects [Time frame: 2 years]
• Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall (DR) failure [Time frame: 6 months]

Eligibility criteria

Inclusion criteria

• Age ≥ 18 years old;
• Cellular or histopathological confirmation of lung adenocarcinoma;
• Prior to enrollment, brain enhanced magnetic resonance imaging shows (1) 1-2 brain metastases, with at least one measuring ≥3 cm in diameter; or (2) 3-10 brain metastases, with at least one measuring ≥2 cm in diameter; or (3) 11-20 brain metastases; and deemed unsuitable for single-session SRS by radiation oncologists;
• At the time of enrollment, the extracranial disease status is stable;
• Eastern Cooperative Oncology Group (ECOG) physical fitness status score 0-2 points
• Normal liver, kidney, and bone marrow function within 14 days prior to enrollment: peripheral blood white blood cell count ≥ 4 × 10\^9/L; neutrophil count ≥ 1.5 × 10\^9/L, platelet count ≥ 100 × 10\^9/L, hemoglobin ≥ 100g/L, serum creatinine<1.5 times the upper limit of normal values; Bilirubin<1.5 times the upper limit of normal value; Transaminase<2 times the upper limit of normal value;
• The patient and their family agree and sign an informed consent form.

Exclusion criteria

• There are contraindications for bevacizumab, such as a history of cardiac and/or thromboembolic events, or uncontrolled hypertension;
• Meningeal metastasis or extensive intracranial metastasis are not suitable for FSRT;
• Bleeding tendency or coagulation dysfunction;
• Patients with hemoptysis (≥ 1/2 teaspoon of fresh blood per day) within the past month;
• Use full dose anticoagulant therapy within the past month;
• Has experienced severe vascular disease in the past 6 months;
• Have experienced gastrointestinal fistula, perforation, or abdominal abscess within the past 6 months;
• Has experienced hypertensive crisis, hypertensive encephalopathy, symptomatic heart failure (New York Class II or above), acute myocardial infarction, cerebral infarction, cerebral parenchymal hemorrhage, or other active cerebrovascular or cardiovascular diseases within the past 6 months;
• Patients with a history of arterial aneurysm or arteriovenous malformation;
• Having undergone major surgery within 28 days, or minor surgery or needle biopsy within 48 hours;
• Urinary protein 3-4+, or 24-hour urinary protein quantification>1g;
• Simultaneously accompanied by serious and uncontrolled other diseases.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun yat-sen University Cancer Center — Guangzhou

Publications

• Yuan X, Liu WJ, Li B, Shen ZT, Shen JS, Zhu XX. A Bayesian network meta-analysis of whole brain radiotherapy and stereotactic radiotherapy for brain metastasis. Medicine (Baltimore). 2017 Aug;96(34):e7698. doi: 10.1097/MD.0000000000007698. PMID 28834873
• Boothe D, Young R, Yamada Y, Prager A, Chan T, Beal K. Bevacizumab as a treatment for radiation necrosis of brain metastases post stereotactic radiosurgery. Neuro Oncol. 2013 Sep;15(9):1257-63. doi: 10.1093/neuonc/not085. Epub 2013 Jun 27. PMID 23814264
• Jiang T, Zhang Y, Li X, Zhao C, Chen X, Su C, Ren S, Yang N, Zhou C. EGFR-TKIs plus bevacizumab demonstrated survival benefit than EGFR-TKIs alone in patients with EGFR-mutant NSCLC and multiple brain metastases. Eur J Cancer. 2019 Nov;121:98-108. doi: 10.1016/j.ejca.2019.08.021. Epub 2019 Sep 27. PMID 31569068
• Zustovich F, Ferro A, Lombardi G, Zagonel V, Fiduccia P, Farina P. Bevacizumab as front-line treatment of brain metastases from solid tumors: a case series. Anticancer Res. 2013 Sep;33(9):4061-5. PMID 24023350
• Socinski MA, Langer CJ, Huang JE, Kolb MM, Compton P, Wang L, Akerley W. Safety of bevacizumab in patients with non-small-cell lung cancer and brain metastases. J Clin Oncol. 2009 Nov 1;27(31):5255-61. doi: 10.1200/JCO.2009.22.0616. Epub 2009 Sep 8. PMID 19738122
• Barrett OC, McDonald AM, Thompson JW, Bredel M, McGwin G, Riley KO, Fiveash JB. Distant brain recurrence in patients with five or more newly diagnosed brain metastases treated with focal stereotactic radiotherapy alone. J Radiosurg SBRT. 2017;4(4):255-263. PMID 28626600
• Aoyama H, Shirato H, Tago M, Nakagawa K, Toyoda T, Hatano K, Kenjyo M, Oya N, Hirota S, Shioura H, Kunieda E, Inomata T, Hayakawa K, Katoh N, Kobashi G. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006 Jun 7;295(21):2483-91. doi: 10.1001/jama.295.21.2483. PMID 16757720
• Mekhail T, Sombeck M, Sollaccio R. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. Curr Oncol Rep. 2011 Aug;13(4):255-8. doi: 10.1007/s11912-011-0180-1. No abstract available. PMID 21584645

Identifiers

NCT: NCT07058428 · GASTO-10137

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗