Pilot Study assessing sildenafil effect on lung tumour blood flow

Patients with non-small cell lung cancer (NSCLC) have a 5 -year survival rate
of 15%. The worst prognosis is seen in stages IIIb and IV: 1-year survival of
23-46%. Combined chemotherapy with a platinumderivative and a 3rd generation
cytotoxic agent is currently the standard treatment of stages IIIb and IV. This
improves quality of life but only improves 1-year survival by 10%. There is
thus a great need to improve treatment outcome in patients with advanced or
metastatic NSCLC. One possible approach may be to (transiently) increase tumour
perfusion, as this should enhance chemotherapy delivery and thus efficacy. In
addition, hypoxic conditions due to vascular insufficiency exist in solid
cancers and appear to be associated with resistance to both radiotherapy and
chemotherapy. The associated improved tumour oxygenation may therefore also
lead to chemosensitisation and radiosensitisation.

Sildenafil is a highly selective phosphodiesterase type 5 (PDE5) inhibitor.
PDE5 is a member of the superfamily of phosphodiesterases that specifically
cleaves and thereby inactivates cyclic guanosine monophosphate (cGMP). cGMP is
the intracellular 2nd messanger of nitric oxide (NO) and the main mediator of
smooth muscle relaxation and vasodilatation. By inhibiting the cleavage of cGMP
sildenafil prolongs its action and thus augments smooth-muscle relaxation and
vasodilatation. Recently it has been shown to act on the pulmonary vasculature,
causing pulmonary vasodilatation, and has been approved for the treatment of
pulmonary arterial hypertension.

No previous studies have assessed whether sildenafil induced pulmonary
vasodilation leads to an associated increase in lung tumour perfusion. If this
were to be the case then sildenafil could potentially be a chemo-en/or
radiosensitiser as explained above.

The aim of this pilot study is to assess if the sildenafil leads to an increase
in tumour blood flow in NSCLC.

After inclusion baseline blood pressure, pulse and hematological, renal and
hepatic functions will be determined. Women of childbearing potential will
additionally undergo a pregnancy test. A baseline dynamic CT perfusion scan and
water-PET scan will be performed to assess baseline tumour perfusion. On the
treatment day patients will receive 50 mg sildenafil orally (time point 0). One
hour after administration a CT perfusion and water-PET scan will be performed
to assess tumour perfusion post sildenafil. By comparing the baseline and
post-treatment scans the effect on tumour perfusion will be estimated. Blood
pressure and pulse will be monitored at 0, 15, 30, 45, 60 and 120 mins to
assess for possible systemic hypotension.

Administration of 50mg sildenafil.

The extra burden for the patients consists of one extra hospital visit lasting
approximately 2 hours during which the patient receives a 50 mg tablet of
sildenafil and a dynamic CT perfusion and PET scan. De baseline perfusion scan
and bloods will be conducted during a previously planned visit as part of their
tmour staging/treatment. The extra radiation dose of the perfusion scan is
estimated at 1,3 mSv and the PET scan at 1.8mSv.

Sildenafil has a good safety profile. Common side effects are headache, nausea,
dyspepsia, rhinitis, flushing, dizziness and asymptomatic decrease in blood
pressure. Episodes of dose related abnormal vision (blurred vision, changes in
light perception and transient blue-green vision) have been reported but they
were usually reversible. Rare cases of non-arteretic ischaemic optic neuropathy
(NAION) have been reported in patients using sildenafil but a causative
relationship has not been established. To minimise this risk patients with a
history of visual loss and genetic degenerative retinal disease e.g. retinitis
pigmentosa will be excluded.