Nitroglycerin as a Sensitizer in the Treatment of Non Small Cell Lung Cancer: a Phase II Trial
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 . 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. 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. 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
. There might also be a supplementary effect on the MHC-molecules, rendering tumor cells
more "visible" to the immune system .
Furthermore, hypoxia has been shown in vitro to increase the invasiveness of cancer cells in
an NO-mediated manner, which can be blocked by NO-donors. An interesting study in this
respect is a non-randomized phase 2 trial by Siemens et al, in which a very low dose of
nitroglycerin (Minitran 5 patch (18 mg) cut in 6 pieces, delivering 0.033 mg/h in stead of
0.2 mg/h normally) was given to patients with biochemical recurrence (PSA-failure) after
primary therapy. After 24 months the PSA doubling time was more than 31 months versus 12.8
months before the start of therapy, demonstrating the inhibitory effect of nitroglycerin on
prostate cancer cells. 
Due to these effects and the effect on tumor bloodflow and decrease of hypoxia nitroglycerin
might also be interesting as a radiosensitizing agent.
Currently a Mexican phase 2 trial is recruiting 40 patients to evaluate the efficacy of
nitroglycerin added to concurrent chemoradiotherapy in NSCLC stage III. (Clinical trials.gov
The aim of the present study is not only to demonstrate the effect of nitroglycerin on
perfusion and hypoxia through (HX4-)scanning of patients, but also documenting the efficacy
of the approach of giving nitroglycerin in an on/off (12h/12h) schedule to people receiving
(chemo-)/radiotherapy, whilst monitoring toxicity.
The on-off schedule is chosen because of the existence of a tolerance effect on the vascular
system, hence diminishing the effect of nitroglycerin already after the first 24 hours.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Increase of 2 year overall survival of 15% vs historical controls
Philippe Lambin, MD, PhD
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Nitroglycerin in NSCLC