Nuclear Medicine Resources Manual

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CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

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(b) The surgeon should excise the breast mass first, which will also include

the radioactivity injected around the tumour or intradermally. This will

lower the background activity.

sentinel node in the axilla and determines that it is the same node

visualized with the Methylene Blue technique to trace the lymphatic

system. In the case of a discrepancy, both nodes should be excised.

(d) Using the surgical probe, the background activity in the area is defined.

Any node with activity higher than twice the background activity should

be excised.

(e) If the primary tumour was not removed and the purpose of surgery is only

to excise the sentinel node, the site of injection should be shielded with

lead in order to decrease the background activity and to avoid saturation

and electronic jamming of the detector.

(f) The axilla should be scanned carefully using the surgical probe.

(g) If an internal mammary node is the only one detected or if it is visualized

in addition to the axillary node, the institution’s own procedures should

be followed. Internal mammary lymph nodes can be excised from the

third and fourth intercostal space next to the outer border of the sternum.

5.9.5. Procedure manual for sentinel node localization in malignant

melanomas

5.9.5.1. Patient selection

Only cases with the following characteristics should be investigated:

—Early stage malignant melanomas of the skin of no more than 3 mm in

thickness;

—No invasion of the subcutaneous tissue and no clinically palpable regional

lymph nodes present;

—Referral usually after an excisional biopsy or a wide surgical excision of

the lesion.

5.9.5.2. Radiopharmaceuticals

The following radiopharmaceuticals are used for sentinel node locali-

zation:

—Technetium-99m antimony tin colloid;

5.9. SPECIAL PROCEDURES IN ONCOLOGY

351

—Technetium-99m filtered (0.22 mm) or unfiltered SC (filtered SC is

preferred, although both work well);

—Technetium-99m HSA or dextran.

These can be used for fast visualization of the lymphatic channels and

sentinel nodes provided the patient is due to enter the operating room soon.

The first node seen after injection is the sentinel node and this should be

properly marked on the skin.

The following procedure should be observed:

(a) Route of injection:

—Intradermal injections, within 1 cm of the edge of the lesion or the scar

at four corners and 90

apart, can be used.

—For larger lesions or scars, multiple injections around the lesion can be

used, provided they are not more than 1

in (25.4 mm) apart.

(b) Dose and volume injected:

—Patients undergoing same-day surgery require 9–12 MBq (0.3–

0.4

mCi).

—Patients undergoing surgery the following day require 37 MBq

(1.0

mCi).

—The volume used is 1.0 mL injected at multiple sites, for each site about

0.2 mL intradermally and enough to form a bleb in the skin and induce

pressure inside the lymphatic system.

—A single head, large FOV gamma camera is recommended.

—Collimator: low energy, high resolution.

—Matrix size: 128 ¥ 128.

(d) Mode of acquisition:

—An anterior dynamic image should be taken every 30 s for 45 min,

followed by static images for 5 min in the anterior and lateral projec

tions.

—Transmission images should be acquired for both dynamic and static

images to outline the body contours.

(e) Region to be imaged:

Depending on the location of the lesion, clinical judgement should be

used in identifying the region to be imaged. These regions are:

—For lesions near the midline of the trunk, both the inguinal and axillary

regions;

—For the axilla, the supraclavicular region;

—For the inguinal region, the iliac and pelvic nodes;

CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

352

—For the head and neck, the supraclavicular regions;

—For the lower limbs, the corresponding inguinal region;

—For the upper limbs, the corresponding axillary region.

Markers over the site of the sentinel node should be attempted using a

point

Co source, and an ink mark on the skin should be performed.

(f) Reporting:

Details should be included on the site of injection and the radiopharma-

ceutical used, as well as on the location and number of sentinel nodes

visualized.

(g) Preparation for the surgical probe:

—The battery of the probe should be fully charged.

—A quality control has to be performed before using a calibration source.

—Adjustments should be made to the window and the energy range

according to the radionuclide used.

—The amplification and the time window should be adjusted according to

the level of radioactivity.

—The probe has to be sterilized according to the manufacturer’s recom-

mendation. Most probes are currently covered by disposable, sterile

plastic tubing for use in the operating room, usually supplied by the

manufacturer or obtained commercially.

BIBLIOGRAPHY TO SECTION 5.9.5

KESHTGAR, M.R.S., ELL, P.J., Sentinel lymph node detection and imaging, Eur. J.

Nucl. Med. 26 (1999) 57–67.

5.9.6. Radioimmunoscintigraphy

5.9.6.1. Principle

Radioimmunodetection or radioimmunoscintigraphy uses tumour

targeting antibodies or antibody fragments, labelled with a radionuclide

suitable for external imaging, for the detection of specific cancers.

Monoclonal antibodies have been developed against a variety of antigens

associated with tumours and have been shown to target tumours with minimal

side effects. Numerous radionuclides suitable for external imaging have been

conjugated to antibodies, or antibody fragments, and the radioimmunoconju

gates have been shown to be stable in vivo.

5.9. SPECIAL PROCEDURES IN ONCOLOGY

353

Antibody fragments clear the circulation more rapidly than intact

immunoglobulin. Antibody fragments have been conjugated with

99m

Tc,

allowing same or next day imaging. Intact immunoglobulin conjugated with

111

In permits imaging as late as a week after administration.

5.9.6.2. Clinical indications

Radioimmunoscintigraphy has been shown to be of benefit in the

detection of occult disease, in the management of patients with potentially

resectable disease, and for the evaluation of lesion recurrence and therapeutic

response. Radiolabelled antibody imaging in prostate cancer has been shown to

be useful in risk stratification and in patient selection for loco-regional therapy.

5.9.6.3. Contraindications

The following points should be borne in mind:

—Pregnancy and/or lactation is an absolute contraindication.

—A known hypersensitivity to foreign proteins is a relative contraindi-

cation.

—The safety of these agents in children has not been conclusively demon-

strated.

5.9.6.4. Equipment

The following items of equipment are required:

—A SPECT gamma camera;

—A low energy collimator for

99m

Tc (or

123

I) labelled antibodies;

—A medium energy collimator for

111

In labelled antibodies.

5.9.6.5. Radiopharmaceuticals

Currently approved antibodies for imaging are conjugated with

99m

Tc and

111

In. Both

99m

Tc and

111

In have been labelled to immunoglobulins, while

99m

has also been labelled to Fab´ fragments. The route of administration is

intravenous and the doses (for an adult of 70 kg) are 750–1000 MBq (15–25

mCi)

99m

Tc and 185–220 MBq (5–6 mCi)

111

In labelled antibodies.

The nuclide characteristics are as follows:

CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

354

Tc-99m: T

1/2

= 6 hours (140 keV gamma photons),

In-111: T

1/2

= 2.8 days (178 and 245 keV photons).

5.9.6.6. Protocols

It is important to obtain at least two, and preferably three, sets of images.

For

99m

Tc labelled antibodies these are usually obtained at 10 min, 4 hours and

24 hours following administration. The time interval between image sets is

longer for

111

In labelled antibodies, typically from the day of administration to

4 days after.

To evaluate the abdomen optimally, it is advisable to clear the bowel,

usually by administration of 10 mg of bisacodyl taken orally, four times a day,

but this may increase non-specific intestinal uptake. An enema on the day of

delayed imaging is useful for

111

In labelled antibody imaging.

Whole body images at 8 cm/min with a high resolution acquisition matrix

are optimal for the early image sets; delayed images should be acquired at a

slower speed, typically of 6 cm/min. Spot images of at least 1 000 000 counts are

also useful, in addition to whole body images. Serial squat views are essential

for colorectal and prostate cancer.

SPECT images of the abdomen and pelvis are particularly useful. For

99m

Tc labelled antibodies, these are carried out on the day of administration

and at 24 hours. For colorectal and prostate cancer, serial SPECT images of the

pelvis are recommended. Indium-111 labelled antibody SPECT may be carried

out at multiple time points. These should be acquired in a matrix of 64

¥ 64, for

40 seconds per angle for a minimum of 64 angles over 360

5.9.6.7. Interpretation

Specific uptake increases with time over 24 hours, whereas non-specific

uptake after the initial distribution decreases with time as the antibody or

fragment clears from the blood. Thus, the image at 10 min acts as a reference

with which to compare later images. The use of change detection analysis,

comparing the early and late images as a probability map of significant changes,

allows the detection of lesions down to 3.5 mm size in normal nodes (1 cm or

less) found radiologically.

BIBLIOGRAPHY TO SECTION 5.9.6

GOLDENBERG, D.M. (Ed.), Cancer Imaging with Radiolabelled Antibodies, Kluwer

Academic Publishers, Dordrecht (1990).

5.9. SPECIAL PROCEDURES IN ONCOLOGY

355

PERKINS, A.C., PIMM, M.V. (Eds), Immunoscintigraphy: Practical Aspects and

Clinical Applications, Wiley Liss, New York (1991).

5.9.7. Peptide receptor targeted scintigraphy

5.9.7.1. Background information

The high level expression of peptide receptors on various tumour cells as

compared with normal tissues or normal blood cells has provided the molecular

basis for the clinical use of radiolabelled peptides as tumour tracers in nuclear

medicine. In particular, binding sites for members of the somatostatin (SST)

receptor family (hSSTR1–5) are frequently found, and their expression has led

to therapeutic and diagnostic attempts to target these receptors specifically.

SST receptor (SSTR) scintigraphy using

111

In-DTPA-(D)Phe

-octreotide has a

high positive predictive value for the vast majority of neuroendocrine tumours

and has gained its place in the diagnostic work-up as well as follow-up of

patients with these tumours. Clear evidence suggests that scintigraphy with SST

receptor imaging agents is superior to CT, MRI or FDG PET in the primary

detection of neuroendocrine tumour sites. In a large number of patients,

additional (previously unknown) tumour sites are identified by SSTR scintig

raphy, which leads to a change in patient management in about 10% of patients.

In recent years, technetium based radiopeptide ligands have been implemented

to study SSTR expressing tumours. One of these,

99m

Tc-NEOTECT, has been

approved for non-small-cell lung cancer.

5.9.7.2. Radiopharmaceuticals

Native SST exists in two forms (with 14 or 28 amino acids), but it is

readily attacked by aminopeptidases and endopeptidases, and has a short in

vivo half-life. Consequently, synthetic SST analogues, which incorporate a Phe-

(D)Trp-Lys-Thr (or similar sequence) and which are metabolically stabilized at

both the N and C terminals, were developed for clinical applications. So far,

three commercially available SST analogues (i.e. octreotide ((D)Phe-Cys-Phe-

(D)Trp-Lys-Thr-Cys-Thr(ol)), lanreotide ((D)ß-Nal-Cys-Tyr-(D)Trp-Lys-Val-

Cys-Thr-NH

) and vapreotide ((D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-Trp-

)) have been shown to be effective in controlling the growth of some

human tumours. These three SST analogues have similar binding profiles for

four of the five hSSTR subtypes (i.e. a high affinity for hSSTR2 and hSSTR5, a

moderate affinity for hSSTR3 and a very low affinity for hSSTR1), but

lanreotide and vapreotide also have a moderate affinity for hSSTR4, whereas

octreotide has little or no affinity for this hSSTR.

CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

356

(a) Iodine-123-Tyr

-octreotide

This was the first radiopeptide tracer for which proof of principle was

obtained. It is no longer frequently used but may be produced in a functional

radiopharmacy laboratory. Clinical results are not as good in the abdomen as

those with the

111

In labelled compound, due to higher hepatobiliary clearance.

(b) Indium-111-DTPA-(D)Phe

-octreotide

This is the commercially available radiopeptide tracer of choice for the

detection and follow-up of neuroendocrine tumours (OctreoScan®, Tyco). It

can be conveniently prepared using a kit: 10

mg DTPA-(D)Phe

-octreotide are

labelled with approximately 120–150 MBq

111

In-Cl

. No further purification

steps are necessary.

This is synthesized using the commercially available lanreotide (Somat-

uline®) and 1,4,7,10-tetraazacyclo-dodecane-N,N´,N´´,N´´´-tetraacetic acid

(DOTA) as starting materials. It can be obtained from the University of

Vienna. Results are similar to those of the octreotide based peptide tracers.

(d) Indium-111-DOTA-(D)Phe-Tyr

-octreotide

This is currently under investigation at several sites with results even

better than those of

111

In-DTPA-(D)Phe

-octreotide.

(e) Technetium-99m-NEOTECT (

99m

Tc-P829)

This is an SSTR receptor based radiopharmaceutical which, in contrast to

octreotide based ligands, also binds to hSSTR3 with high affinity. It is available

from GE-Amersham in Europe and Schering in the USA.

5.9.7.3. Clinical indications and patient selection

Indium-111-DTPA-(D)Phe

-octreotide is used in patients clinically

suspected to bear an SSTR expressing tumour such as a carcinoid, insulinoma,

glucagonoma or paraganglioma (primary tumour localization) and

99m

Tc-

NEOTECT in patients with non-small-cell lung cancer in order to evaluate the

solitary pulmonary module and to assess the extent of the disease. It should

also be used in the follow-up of cancer patients known to bear a tumour which

5.9. SPECIAL PROCEDURES IN ONCOLOGY

357

expresses SSTR. Such follow-up scintigraphies should be performed every six

months.

A scintigraphic evaluation should be performed before primary surgery.

Patients refractory to conventional treatment strategies may be referred

for potential treatment evaluation with

Y-DOTA-lanreotide/octreotide (see

also Section 6.12).

5.9.7.4. Patient preparation

In all patients, diagnosis and disease staging should be established

according to WHO criteria. The location and size of primary tumours and/or

spread of metastases should be investigated by conventional CT or MRI,

radiography, colonoscopy or surgery.

Patients receiving treatment with long acting SST analogues should stop

treatment for at least three days prior to scintigraphy.

Patients should be informed that they will have to come for the scinti-

graphic acquisitions at several time points, usually at 4–8 and 24 hours post-

injection. When abdominal activity is present, acquisitions may also become

necessary after 48 hours.

If there is marked intestinal activity, the patient may be asked to take

laxatives. No additional special preparation is necessary.

5.9.7.5. Gamma camera imaging and analysis

(a) Indium-111-DTPA-(D)Phe

-octreotide scintigraphy

The peptide tracer should be injected as a bolus, usually in the morning.

The patient is then asked to come for acquisition in the afternoon. The peptide

tracer can also be injected in the afternoon, and acquisitions performed the

next morning. For planar and SPECT studies, a large FOV gamma camera

equipped with a medium energy, general purpose collimator is required. There

is no need to perform sequential images.

Planar images should be obtained at two time points:

—Early acquisition at 4–8 hours post-injection;

—Late acquisition at 24–48 hours post-injection.

Planar images (thorax and abdomen) should be gathered in the

anterior, posterior and lateral views (matrix at least 128 × 128 pixels,

(150

000–300 000 counts, scanning time 10–20 min). Both energy peaks are

used for scanning (set at 173 and 247 keV) with a 20% window.

CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

358

When searching for a neuroendocrine tumour, it is absolutely mandatory

that at least one abdominal SPECT acquisition be performed. This should be

either early or delayed, at 6 or 24 hours post-injection, respectively. A chest

SPECT is indicated occasionally if the patient is clinically suspected to have a

tumour and the abdominal images are negative.

SPECT imaging should always be done in a 360° orbit, using 6° steps with

″ per step.

The scintigraphic data should be filtered with a Wiener filter and recon-

structed in three planes (with a slice thickness of about 7 mm).

(b) Technetium-99m-NEOTECT (

99m

Tc-P829) scintigraphy

The primary indication for NEOTECT scintigraphy is non-small-cell lung

cancer. Other indications such as endocrine orbitopathy associated with the

thyroid are under investigation.

The radiotracer should be injected as a bolus.

For planar and SPECT studies, a large FOV gamma camera equipped

with a low energy, general purpose or high resolution collimator is required.

Planar images can be obtained as early as 15 min post-injection. It is

recommended that acquisition should start not earlier than 1 hour post-

injection and should be completed within 3 hours post-injection. In all patients,

chest SPECT images are required.

Planar images (thorax and abdomen) should be gathered in the anterior,

posterior and lateral views (a matrix of at least 128 × 128 pixels, 300 000 counts,

scanning time 10 min).

SPECT imaging should always be done in a 360° orbit, using 6° steps with

″ per step.

The scintigraphic data should be filtered with a Wiener filter and recon-

structed in three planes (with a slice thickness of about 7 mm).

5.9.7.6. Side effects

No acute or chronic side effects have been reported so far. In a few

patients, however, antibodies have been demonstrated which may interfere

with octreotide scintigraphy.

5.9.7.7. Comments

Other peptide tracers, such as vasoactive intestinal peptide (VIP) based

peptide tracers, may become available in the near future. These may even gain

5.10. HAEMATOLOGY

359

a broader clinical application as VIP receptors are expressed on more common

tumours such as colorectal cancer and breast cancer.

BIBLIOGRAPHY TO SECTION 5.9.7

KRENNING, E.P., et al., Localization of endocrine-related tumours with radio-

iodinated analogue of somatostatin, Lancet 1 (1989) 242–244.

SMITH-JONES, P., et al., Indium-111-DOTA-lanreotide: A novel tumour diagnostic

and therapeutic somatostatin analog, Endocrinology 140 (1999) 5136–5148.

VIRGOLINI, I., PANGERL, T., BISCHOF, C., SMITH-JONES, P., PECK-

RADOSAVLJEVIC, M., Somatostatin receptor subtype expression in human tissues:

A prediction for diagnosis and treatment of cancer? Eur. J. Clin. Invest. 27 (1997)

645–647.

VIRGOLINI, I., et al., Indium-111-DOTA-lanreotide: Biodistribution, safety and

radiation absorbed dose in tumour patients, J. Nucl. Med. 39 (1998) 1928–1936.

5.10. HAEMATOLOGY

5.10.1. Introduction

The role of nuclear medicine in haematology covers the following:

(a) Determination of blood volume, both red cell volume and plasma

volume;

(b) Mean red cell lifespan;

(d) Megaloblastic anaemias, especially the vitamin B

absorption test

(Schilling test);

(e) Iron metabolism;

(f) Radiolabelled platelets;

(g) Radiolabelled granulocytes;

(h) Splenic function;

(i) Bone marrow imaging.