Trial Information

The Value of Early PET/CT in Patients With Metastasising Cancer of Unknown Primary

Background:

Every year, 800-1000 patients in Denmark are classified with a diagnosis of metastasising
cancer of unknown primary (CUP). This corresponds to approximately 3 % percent of all new
cancer cases on a national scale. The number is probably higher, since this is a
heterogeneous group of patients that is not registered consistently. The prognosis is poor;
the average survival is only approximately one year.

CUP is characterized by the finding of a metastasis the starting point of which (the primary
tumour) is unknown. Typically, one finds an enlarged lymph node in the neck, a swelling in
the throat or in the stomach, a filling in the skin or a tumour detected somewhere in the
body during an X-Ray examination, an endoscopy or the like. In spite of a search applying
multiple techniques, the primary tumour remains unknown in 70-80% of the patients.

A great number of patients experience a long and discontinuous examination sequence marked
by various contacts with doctors, many examinations dispersed over many days and locations,
as well as a lot of time wasted, because there exists no single option or institution that
takes care of the patient and handles diagnostic procedures and treatment efficiently.

Treatment is often initiated too late, typically as a combination of several
chemotherapeutics in order to cover different types of cancer simultaneously, but modern
chemotherapeutical regimes have not increased the survival rate. The bad prognosis is
undoubtedly due to the fact that the patients are diagnosed in an advanced phase.
Alternatively, the primary tumour is not detected at all. This, in part, is due to the
absence of any single agency in possession of the competence and responsibility to implement
the work-up without delay, and maybe because one does not offer examination by the modality
(PET/CT) which is most likely to detect the presence of cancer, its starting point and
dispersion in an early stage.

Methods:

Patients will be randomized 1:1 to the diagnostic arms 'conventional diagnostics incl. CT'
or 'early PET/CT' at study entry. Before study start, a randomization list will be prepared
according to which the assignment of patients to the treatment arms will be performed.

The early PET/CT examination will be performed at the Department of Nuclear Medicine at
Odense University Hospital (OUH) using the tracer [18F]-fluorodeoxyglucose (FDG). Patients
will be requested to appear in fasting state (minimum 6 hours) and will be administered
intravenously FDG which is a radioactively labeled glucose-analog which enters cells by
known glucose transport systems. The usage of FDG as cancer tracer is based on the increased
metabolism and glucose demand of rapidly growing and proliferating cells. FDG remains within
cells since it does not metabolize.

The patients will be scanned from the base of the scull to mid thigh by an integrated PET/CT
scanner (GE Healthcare DiscoveryTM STE). A standardized CT protocol is used (Smart mA 30-400
mA with a noise index of 18.0 and rotation time of 0.8 s., kV 120, reconstruction thickness
of 3.75 mm), followed by a PET examination (recording time is 2.5 min pr. field of view). CT
scanning will be done with intravenous contrast medium (Ultravist 370 mg I/ml). The
effective dose will be 18-20 mSv from CT and 5-6 mSv from FDG PET. Every patient at the
Department of Nuclear Medicine has their height and weight measured before PET/CT and the
PET/CT examination must be started in the interval 60 ± 5 min. after injection of FDG. Serum
glucose concentration is measured before injection of FDG and must not exceed 8 mmol/L (150
mg/dL) The first 40 patients with a negative FDG-PET/CT will have an extra, late scan
(without new contrast and with the same FDG-injection). One half (20 patients) will be
scanned after 3 hours and the second half (20 patients) will be scanned 4 hours after the
injection of FDG. This is to examine whether there is late focal uptake in some patients due
to slow and only slightly increased glucose uptake. If so, the standard time point of
scanning will in the remaining patients be at 3 or 4 hours after the injection of FDG in
order to optimize the chance of detecting also slow growing tumours and metastases.

Identification of the primary tumor:

The primary tumor will be confirmed by histopathological examination of relevant biopsy
specimens.

Endpoints:

In order to evaluate the hypotheses, the following data will be collected for all patients
retrospectively from the local patient report filing system FPAS:

1. Detection of primary tumor possible: yes/no (primary endpoint)

2. Time frame from inclusion into the study to detection of primary tumor.

3. Time frame from inclusion into the study to referral to palliative or curative
treatment.

4. Time frame from inclusion into the study to end of follow-up or death.

5. Total score of Quality of Life instrument "SF-36".

Population:

All patients are recruited from the Emergency Department based on subjective selection at
the discretion of a trained internal medicine specialist (KKP). The expected number of
patients will be 220.

Ethics:

The risk of PET/CT consists in the extra radiation dose (5-6mSv, p 4), which the
PET-examination adds to the patient beyond the dose from CT (18-20mSv). The dose of
radiation from PET is insignificant (a total estimated risk: 1/10.000), while the estimated
risk from the radiation dose of CT is 1/1000. The lifetime risk of developing cancer is 25%.
Performing the PET/CT scan increases the lifetime risk from 25% to 25,1%.

The radiation dose which is used has never been proven to cause adverse effects. The
increase in lifetime effect is considered acceptable when compared to the improvement in
diagnostic yield, patient course and targeted treatment.

Patient information describing the study and providing sufficient information for patients
to make an informed decision about their participation will be handed out to patients in
written form.

The patients will have 24 hours to think it over before making the final decision whether or
not to participate. Participation is voluntary and consent can at anytime be withdrawn
without any consequences for the patient's future treatment.

The Informed Consent form will be signed by all participating patients and stored at the
Department of Nuclear Medicine