Nitroglycerin as a sensitizer in the treatment of non small cell lung cancer: ;a phase II trial.

Tumor hypoxia is a well known factor negatively influencing the response of
numerous types of cancer to chemotherapy or radiotherapy. Tumor hypoxia is due
to many factors, which can be patient-related (eg. anaemia or vascular
insufficiency), but also tumor-related (eg. abnormal tumor vasculature).

The primary physiological function of the tumor vasculature is to support
perfusion, the nutritive flow of blood through the tissues. Vascular physiology
can be studied non-invasively in human subjects using imaging methods such as
positron emission tomography (PET), magnetic resonance imaging (MRI), X-ray
computed tomography (CT), and Doppler ultrasound (DU). [1-4] Tumor perfusion
has a prognostic value but is also a key process to allow drug penetration in
tumor tissues.

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 tumor with as consequence a higher drug
concentration in the tumor [6].

In mice, NO donors such as isosorbide dinitrate have been shown to decrease
tumor hypoxia by better tumor perfusion, which could enhance radiotherapy
responses [7].


The promising results of the combination of nitroglycerin with chemotherapy and
the theoretical and preclinical basis for a hypoxia reducing and
radiosensitizing effect on cancer cells, make this an interesting compound to
investigate in a phase II trial.

Primary endpoint of this trial will be to demonstrate a survival benefit of the
addition of nitroglycerin to radiotherapy for NSCLC.

Translational research will be a part of this trial: by performing in 10
patients upfront measurements of perfusion and hypoxia and quantifying the
effect of nitroglycerin on these measurements we hope to clarify the mechanism
of action of nitroglycerin in NSCLC.

During this trial, acute toxicity will be monitored closely during and after
radiotherapy

Demonstrate an increase of 2-year overall survival (OS) of 15 % (from 50% to 65
%) vs historical controls of the addition of nitroglycerin to radiotherapy
(±chemotherapy) of stage I-IV NSCLC.

Single centre non-randomized phase 2 trial.

* Day 1:
- Dynamic Contrast Enhanced (DCE) CT scan at radiology department before HX-4
scan
- Injection of HX-4 at nuclear medicine department
- Static HX-4 PET-CT scan 240 minutes post-injection

The baseline DCE-CT scans and the scans after nitroglycerin are to be kept a
minimum of 2 days apart to avoid renal impairment by consecutive IV contrast
infusions.

Practical:

Day 3/4:
- Nitroglycerin patch Transiderm Nitro 5 at 8.30 h.
- Dynamic Contrast Enhanced (DCE) CT scan at radiology department at 14:30 h.
- Injection of HX-4 at nuclear medicine department at 15 h.
- Static HX-4 PET-CT scan 240 minutes post-injection at 19 h.
- Removal of nitroglycerin patch after scanning is completed.

Patients will receive a standard low dose nitroglycerin patch, for 12 hours
daily during the whole course of radiotherapy.
2,5 months after treatment, an 18-FDG PET CT scan will be performed. These
findings will be correlated with the FDG/hypoxia PET-scans and perfusion CT
scans.

The extra burden in this trial consists of

- nitroglycerin patch from day 1 of radiotherapy to the last day of radiotherapy

2 DCE CT scans (1 with and 1 without nitroglycerin) AND 2 HX-4 PET-scans ((1
with and 1 without nitroglycerin) in 40 patients.
1 DCE CT scan and 1 HX-4 PET scan without nitroglycerin in 20 patients.

Risks: DCE-CT scans and HX-4 PET-CT-scans will add on average 7-7.5 and 20-25
mSV respectively to the radiation dose received [8]
When compared to the 65000 mGy which is on average administered to patients
treated with radiotherapy for NSCLC at Maastro Clinic, this added radiation
dose by the extra scans is negligible.

Contrast enhancement has the known risks of allergy and renal failure, which is
generally a low risk. To minimize the risk of renal impairment by a bolus
injection of contrast used in DCE-CT scanning, the DCE-CT scans are performed
with a minimum of 48 hours apart and patients are encouraged to augment their
fluid intake between scans.

Nitroglycerin has as most common side effects: headache (60% of patients),
light-headedness (6% of patients), syncope (4% of patients).

The combination of nitroglycerin with chemotherapy has been proven to be safe
in a large phase II trial and reports of toxicity of the combination of
nitroglycerin and radiotherapy have never been made. However, theoretically the
perfusion of normal tissue might also be influenced, leading to enhanced
radiosensitivity of normal tissue.

Therefore patients will be closely monitored for enhanced side effects during
and after radiotherapy. A stopping rule has been foreseen in case of excess
toxicity.