Ga-68-DOTA-RGD2 PET/CT in patients with head and neck cancer: a potential tracer to image angiogenesis in tumors.

Head and neck cancer includes malignancies arising in the oral cavity, oro- and
hypopharynx and larynx. 90% of all head and neck cancer are squamous cell
carcinomas (HNSCC). With an incidence of 2955 in 2014, HNSCC is the 8th and 9th
most common cancers in the Netherlands for men and women, respectively. The
choice of treatment of HNSCC depends on size and site of the tumor, stage of
the disease, and expected oncological and functional outcomes. Whereas early-
and locally advanced tumors are treated with surgery or radiotherapy, treatment
of advanced HNSCC tumors often includes combinations of surgery, radiotherapy
and chemotherapy.

When treating patients with HNSCC, quality of life is an important factor to
consider. Early non-invasive monitoring of treatment response would allow
clinicians to determine whether the treatment should be adjusted. This could
consequently improve patient outcome in the future as well as enhance patients*
quality of life by avoiding further side effects of treatments that are
ineffective. Monitoring treatment response may also avoid unnecessary health
care costs. There is currently an unmet need to identify biomarkers or imaging
tools that can steer treatment decisions.

Angiogenesis is a crucial process for tumor growth and metastasis in head and
neck cancers and other types of solid tumors. Non-invasive methods to monitor
angiogenesis in the tumor can be of great value for treatment selection and
response monitoring to steer treatment decisions.

Preclinical studies carried out by us and other research groups have focused on
using RGD-based imaging peptides. RGD-peptides bind integrin *v*3, which is
expressed on newly-formed blood vessels. Radiolabeled RGD-peptides can image
expression of integrin *v*3, which is overexpressed on newly formed tumor
endothelial cells. Tumor uptake of radiolabeled RGD-peptides may act as a
biomarker for tumor growth.

Our preclinical experiments with human tumor xenografts proved that
radiolabeled DOTA-RGD2 can be used as an angiogenesis-specific tracer. We
showed that in HNSCC integrin *v*3 is only expressed on the neovasculature of
tumors, rather than on the tumor cells themselves and thus the tracer
accumulates in tumors with newly formed blood vessels only. Furthermore, in one
of our preclinical experiments we showed that DOTA-RGD2 could serve as a
clinical tool to monitor angiogenic responses after radiotherapy. The FaDu
xenograft models showed a decreased uptake of DOTA-RGD2 after tumor
irradiation. Using Ga-68-DOTA-RGD2 as an imaging biomarker of angiogenesis may
act as an early biomarker of response to therapy for HNSCC patients.
Furthermore, guiding treatment decisions in an early stage can improve patient
outcome, it can minimize the side effects, and it may also avoid unnecessary
health care costs.

In this study we aim to determine whether this novel imaging tracer
(Ga-68-DOTA-RGD2) can monitor responses early after initiation of therapy.
First, we will determine whether it is feasible to image tumor angiogenesis in
tumors with Ga-68-DOTA-RGD2 and this uptake correlates with the expression of
the integrin *v*3. Secondly, the uptake of Ga-68-DOTA-RGD2 as a non-invasive
clinical imaging tool during (chemo)radiotherapy will be determined.

The primary objective of the study is to ascertain the feasibility and safety
to image tumor angiogenesis in head- and neck cancer patients using
Ga-68-DOTA-RGD2 PET/CT. Secondary objectives are to determine the
pharmacokinetics and biodistribution of Ga-68-DOTA-RGD2 and to validate
Ga-68-DOTA-RGD2 as an imaging biomarker of angiogenesis.

This is a prospective, observational non-randomized feasibility study. The
patients will undergo a Ga-68-DOTA-RGD2 PET/CT scan 1-7 days before their
planned surgery. Ga-68-DOTA-RGD2 (200 MBq, 70 µg) will be injected
intravenously. In the first cohort of five patients three static PET/CT scans
will be acquired at 30, 60 and 90 minutes post injection (p.i.) (study A). The
five patients in the second cohort will undergo a dynamic PET/CT scan during 60
minutes (study B). In the remaining 15 patients a 30-minute static
Ga-68-DOTA-RGD2 PET/CT scan will be acquired starting at the optimal scan time
as determined in study B (study C).

In this study, the feasibility and safety of the radiotracer Ga-68-DOTA-RGD2
will be determined. There is a small chance of damage because of study
participation. This risk consists of unknown side effects of Ga-68-DOTA-RGD2
administration. The chance of damage is small considering the preclinical
toxicity studies. Furthermore, extensive clinical experience using
radiopharmaceutical compounds in experimental studies is present at the nuclear
department.
The risk of adverse events is limited and serious side effects are not
expected. Because this is the first time this tracer is used in clinical
practice, vital signs, pharmacokinetics and liver- and kidney functions will be
monitored during this study. An adverse event that may occur during the
procedure of this study is bruising after venous puncture. The surgery will not
be an extra risk or burden to the patient as surgery will be performed conform
standard of care.
The radiation dose to the patient is based on the combination of the radiation
dose from Ga-68-DOTA-RGD2 injection and from the CT portion of the study. The
estimated effective dose of administration of Ga-68-DOTA-RGD2 is 4.5 mSv. This
effective dose is in the range of commonly applied oncologic tracers, such as
18F-FDG (7.4 mSv for an adult). The effective dose from the CT portion range
from 1-4.5 mSv.

- Patients in study A will receive three low-dose whole-body static CT scans,
which will give a radiation dose of approximately 4.5 mSv. The combination of
Ga-68-DOTA-RGD2 PET and low-dose CT will expose these patients to a dose
equivalent of maximally 9 mSv.
- Patients in study B will receive one low-dose CT scan of the head and neck
region, which will give a radiation dose of maximally 1 mSv. The combination of
Ga-68-DOTA-RGD2 PET and low-dose CT will expose these patients to a dose
equivalent of maximally 5.5 mSv.
- Patients in study C will receive one low-dose CT scan of the head and neck
region, which will give a radiation dose of maximally 1 mSv. The combination of
Ga-68-DOTA-RGD2 PET and low-dose CT will expose these patients to a dose
equivalent of maximally 5.5 mSv.

The combination of Ga-68-DOTA-RGD2 PET and low-dose CT is the only test these
patients will receive in addition to their normal work-up. This study
corresponds to the risk category IIb as defined by the International Commission
on Radiation Protection (minor to intermediate level of risk).

Because the surgery will take place at least one day after administration of
Ga-68-DOTA-RGD2 the surgeon and other medical staff will not be exposed to
radiation burden, since Ga-68 has a half-life of 68 minutes.

The subjects who are included will not directly benefit from participating in
this study. However, imaging angiogenesis shows the potential to monitor and
steer treatment decisions in patients with head and neck cancer. Therefore,
this study is justified.

According to the NFU risk classification it is assumed that the added risk of
study participation within this study is negligible.