Nitroglycerin as a Sensitizer in the Treatment of Non Small Cell Lung Cancer: a Phase II Trial
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 发起方
- 入组人数
- 47
- 试验地点
- 1
- 主要终点
- Increase of 2 year overall survival of 15% vs historical controls
研究概览
简要总结
Nitroglycerin is a nitric oxide donor which is mainly known as a vasodilating agent used in ischemic heart disease. It has also been shown to increase tumor blood flow in animal and human tumors.
The addition of nitroglycerin to chemotherapy in non small cell lung cancer has been shown to generate very favorable response rates with respect to standard treatment schedules[5]. Theoretically nitroglycerin might reduce resistance to chemotherapy via a plethora of different effects: better tumor perfusion, direct effects of NO on cancer cells, increase in activated p53 protein and via an increased blood flow in the tumour with as consequence a higher drug concentration in the tumor [6] .
In mice, nitric oxide donors such as isosorbide dinitrate have been shown to decrease tumor hypoxia by better tumor perfusion, which could enhance radiotherapy responses [7].
To date these combined effects have not been tested in humans. In this trial we would like to demonstrate the effect of nitroglycerin on tumor perfusion and hypoxia in non small cell lung cancer (using DCE and HX4 scanning), providing a rationale for further study and to test the effect of combining nitroglycerine to standard treatment of NSCLC (radiotherapy/chemotherapy).
详细描述
Namely, the failure of many different tumor types to show a lasting response chemotherapy or radiotherapy might be attributable to a lack of oxygen supply (called "hypoxia" from hereon) in a large part of the cancer cells.
Tumor hypoxia is a well-known factor negatively influencing outcome in many solid tumors, including lung cancer, head and neck cancer, etc. Hypoxic cells are more radio-resistant, more chemo-resistant and more prone to develop distant metastases than normoxic cells.
Nitroglycerin, due to it's vasoactive effects, tends to redistribute the blood supply to the tumor, increasing tumor blood flow, hereby theoretically decreasing hypoxia.
It has been shown that NO donating drugs can alter tumor blood flow and oxygenation status in animal models [7]. In a randomized phase 2 trial by Yasuda nitroglycerin has been successfully combined at a dose of 25 mg daily for 5 days each chemo cycle with cisplatin and vinorelbine in non small cell lung cancer, enhancing chemotherapy response, possibly due to better delivery of the anti-cancer drugs in the tumor[5]. The toxicity profile between the 2 arms was not significantly different.
The effects of nitroglycerin or other donating drugs on cancer have been found to be numerous: not only is there an increase in tumor bloodflow, also direct effects on stabilization of p53 and degradation of Hif-1 alpha have been found[6]. Decreased hypoxic biomarkers (eg VEGF, P-glycoprotein) have been found in patients with NSCLC treated with nitroglycerin patches for 3 days prior to surgery when compared to non-treated individuals [8]. There might also be a supplementary effect on the MHC-molecules, rendering tumor cells more "visible" to the immune system [9].
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Non-small cell lung cancer stage IB-IV amenable for radiotherapy with curative intent.
- •(Stage IV patients with oligometastic (1-4 metastases) NSCLC are regularly treated radically in the IKNL region).
- •Patients not included in the PET-Boost or the Lucanix trial.
- •WHO performance status 0-
- •Willing and able to comply with the study prescriptions.
- •18 years or older.
- •Ability to give and having given written informed consent before patient registration.
- •No recent (< 3 months) severe cardiac disease (NYHA class >1) (congestive heart failure, infarction).
- •No radiotherapy in 4 weeks prior to this study.
- •No treatment with investigational drugs in 4 weeks prior to or during this study.
- •No known allergy to nitroglycerin or nitroglycerin patch.
- •No known allergy to iodine based contrast agents
- •No use of Levitra, Viagra or Cialis at the time of application of the nitroglycerin patch.
- •No conditions necessitating the use of ergot alkaloids, alpha blockers (eg tamsulosine), betablockers or calcium channel blockers on the day of nitroglycerin patch application).
- •No other active malignancy.
- •No major surgery (excluding diagnostic procedures like eg mediastinoscopy) in previous 4 weeks.
- •Adequate renal function: calculated creatinine clearance at least 60ml/min.
排除标准
- 未提供
研究组 & 干预措施
Nitroglycerin
干预措施: Nitroglycerin patch (Drug)
结局指标
主要结局
Increase of 2 year overall survival of 15% vs historical controls
时间窗: 2 years
次要结局
- Demonstrate the effect on enhancement of tumor oxygenation(3 days)
- Toxicity(7 weeks)
- Evaluating the possible value of Perfusion CT and hypoxia scans on treatment with nitroglycerin of NSCLC(2 years)
- Demonstrate effect on enhancement on tumor perfusion(3 days)