1

PET SCAN IN ONCOLOGY

DR. ARNAB BOSEDept. of RadiotherapyNRS Medical College, Kolkata

2

Imaging often is the best means of noninvasively identifying and assessing tumors. With information gleaned from imaging studies, the prognosis can be established and treatment decisions made with greater certainty.

Broadly stated, cancer imaging can be performed using anatomic or functional imaging methods.

3

The traditional imaging of the patient with cancer, and the most established methods, are based on anatomic imaging.

However, interest is increasing in more functionalmethods in cancer imaging.

Further, several anatomic imaging methods offer functional components that complement the anatomic

method. Hybrid images, derived from and displaying both functional and anatomic data, also are becoming more

widely available, often coming from the same hybrid imaging

machine.

4

Anatomic imaging normally detects a phenotypic alterationthat is sometimes, but not invariably, associated with cancer—a mass. However, with anatomic imaging, we often do not know whether masses are the result of malignant or benign etiologies, as in solitary pulmonary nodules or borderline-size lymph nodes.

Similarly, small cancers are undetectable with traditional anatomic methods, because they have not yet formed a mass.

5

After surgery, it is even more difficult to assess for the

presence of recurrent tumor with anatomic methods.

Post-treatment scans are complicated by the need for

comparisons with normal anatomy to detect altered morphologic findings as a result of cancer.

Anatomic methods do not predict the response to treatment

and do not quickly document tumors responding to therapy.

6

Positron Emission Tomography ( P E T ), a functional imaging method, helps to address many of the

limitations of anatomic imaging, and when combined with anatomic images in fusion

images, is emerging as a particularly valuable tool, providing

both anatomic precision and functional information in a

single image set.

7

PET provides information on the metabolic function of organs or tissues by detecting how cells process certain compounds such as glucose. Most cancer cells

metabolize glucose at a much higher rate than normal tissues. By detecting increased radio-labelled glucose metabolism

with a high degree of sensitivity, PET identifies cancerous

cells, even at an early stage, when other imaging modalities may

miss them.

8

In a typical PET study, one administers a positron emitting

radionuclide by intravenous injection. The radionuclide circulates through the bloodstream to reach a

particular organ.

The positrons emitted by the radionuclide travels a distance

of a few millimeters in tissue before it collides with a negatively charged electron. This collision annihilates

the entire mass of the positron and electron, generating

two photons with energy of 511 KeV each.

9

These two photons travel at the speed of light in exactly opposite directions (i.e.180 degrees apart). Coincident detection of these two photons by two oppositely positioned detectors in the PET scanner results in images with a much higher resolution compared with the conventional, single-photon nuclear medicine studies and produces the possibility of quantitative measurement of the tracer uptake in

a volume of interest.

10

PET machines are composed of a ring of detectors within which the patient is positioned .

The gamma photons emitted travel at the speed of light. Rather than register the gamma photons as two separate events, the PET machine registers them as a paired event. It does this through the establishment of time windows. If two gamma photons are detected within the same (small) time window, the camera records them as coming from the same annihilation event. As the gamma photons travel at 180 o to each other, the camera draws a line of flight between the two events and determines that the annihilation must have occurred along this line.

detector array

positron

radiotracer

gamma photon

11

The PET machine generates transverse images depicting the distribution of positron emitting radionuclides in the patient and uses annihilation coincidence detection to obtain projections of the activity distribution. The transverse images are obtained through the process of filtered back-projection.

Detectors used for coincidence detection in modern PET machines are scintillators made of bismuth germanate (BGO) or lutetium oxyorthosilicate doped with cerium (LSO:Ce) that transform the 0.511 MeV gamma ray energy into visible photons detected by photomultiplier tubes (PMTs).

12

The radionuclides used in PET studies are produced by

bombardment of an appropriate stable nuclide with protons

from a cyclotron, thereby producing positron emitting radionuclides that are subsequently attached to

clinically useful biological markers.

13

The 18F radionuclide attached to the 2-fluoro-2-deoxy-D-glucose (FDG) molecule is the

biological marker most commonly used in studies involving

glucose metabolism in cancer diagnosis and treatment (2-[18F] fluoro-2-deoxy-d-glucose).

Tumor imaging with FDG is based on the principle of increased glucose metabolism of cancer cells.

14

Like glucose, FDG is taken up by the cancer cells through

facilitative glucose transporters (GLUTs).

Once in the cell, glucose or FDG is phosphorylatedby hexokinase to glucose-6-phospate or FDG-6-

phosphate,respectively.

Expression of GLUTs and hexokinase, as well as the affinity

of hexokinase for phosphorylation of glucose or FDG, is generally higher in cancer cells than in normal cells.

15

Glucose-6-phosphate travels farther down the glycolytic oroxidative pathways to be metabolized, in contrast to FDG-6-phosphate, which cannot be metabolized.

In normal cells,glucose-6-phosphate or FDG-6-phosphate can be dephosphorylated and exit the cells. In cancer cells, however, expression of glucose-6-phosphatase is usually significantly decreased, and glucose-6-phosphate or FDG-6-phosphate therefore can become only minimally dephosphorylated and remains in large part within the cell.

Because FDG-6-phosphate cannot be metabolized, it is trapped in the cancer cell as a polar metabolite, and it constitutes the basis for tumor visualization on PET.

16

NORMAL TUMOR

Over expression of Glucose transportersHigher levels of HexokinaseDown-regulation of Glucose-6-phosphatase Anaerobic glycolysis, less ATP per glucose molecule, more glucose molecules needed for ATP productionGeneral increase in metabolism from high growth rates

17

A potential range of clinical scenarios in oncology for which

18F-FDG-PET has shown to be worthwhile includes:

i) The non-invasive characterization of the likelihood of malignancy of mass lesions, which are not readily

amenable to biopsy, or for which biopsy attempts have already

failed.

ii) The detection of cancer in patients at significantly increased

risk of malignancy on basis of elevated tumor markers, clinical

symptoms or signs but in whom routine tests have failed to

detect a cancer.

18

iii) Staging of high-risk malignancy amenable to potentially curative therapy for which disease extent is critical to treatment selection.

iv) Planning of highly targeted therapy where delineation of disease is critical to efficient and safe treatment delivery and thereby, therapeutic success.

v) Assessment of therapeutic response in diseases with a significant likelihood of treatment failure, and for which earlier demonstration of therapeutic failure may benefit the patient.

vi) Surveillance of high-risk malignancies or evaluation at clinical relapse where salvage therapies exist and for which early intervention may be curative or prolong life.

19

It is important to recognize that, being a tracer of glucose metabolism, 18F-FDG is not a ‘specific’ radiotracer for imaging malignant disease.

There are several benign conditions and many physiological processes that lead to increased uptake of this tracer.

These include, but are not limited to, normal wound healing, infection and inflammation, active muscle contraction during the uptake period, and activated brown fat.

20

Normal organs, including the brain, liver, kidneys and bone marrow have relatively high 18F-FDG uptake, even underfasting conditions, and this provides background activity that may mask small lesions or malignancies with low glucose metabolism.

Such malignancies include some neuroendocrine tumors, mucinous tumors, differentiated teratomas, many prostate carcinomas, lobular breast cancer, some renal and hepatocellular carcinomas, and most bronchioloalveolar carcinomas.

The relatively poor 18F-FDG uptake of these tumors compromises the sensitivity of PET for the detection of tumor sites.

21

The standardized uptake value (SUV) is a semi-quantitative

measure of the tracer uptake in a region of interest that normalizes the lesion activity to the injected dose and bodyweight; SUV does not have a unit. Despite initial enthusiasm, it is generally accepted that

SUV should not be used to differentiate malignant from benign processes, and that the visual interpretation of PET studies

by an experienced reader provides the highest accuracy.

22

There are many factors influencing the calculation of SUV, such as the body weight and composition, the time between tracer injection and image acquisition, the spatial resolution of the PET scanner, and the image reconstruction algorithm.

Nonetheless, SUV may be useful as a measure to follow the metabolic activity of a tumor over time within the same patient and to compare different subjects within a research study under defined conditions. For example, the SUV of an individual tumor can be measured before and at different time points after therapy, and any change can be used as an index of therapeutic response.

23

Research in PET radiochemistry has provided access to many alternative tracers for oncology at the present time.

Many of these tracers have been evaluated in both pre clinical and clinical studies.

Some have the ability to uniquely characterize specific aspects of tumour biology and, as a result, to offer several diagnostic advantages in comparison with 18F-FDG in particular types of tumours.

24

25

Sensitivity describes how often the imaging test would give a “positive result” in a patient with cancer (i.e., true-positive [TP] finding). A test with high sensitivity has a low number of false-negative results.

Specificity is the frequency with which a test result is negative if no disease is present, or the true-negative (TN) ratio. A highly specific test has a low frequency of false-positive results

Accuracy is 100 * (TP + TN)/(TP + FP + TN + FN).A highly accurate test is one with a low prevalence of false-positive and false-negative results.

26

PET Scan in Lung Cancer

PET has an overall sensitivity of more than 90% and a

specificity of about 85% for diagnosing malignancy in primary

and metastatic lung lesions; the sensitivity of PET for bronchoalveolar lung cancer and carcinoid of the lung

is about 60%, and the specificity of PET for lung cancer is lower

in areas with a high prevalence of granulomatous lung

disease.

It is expected that the use of PET for diagnosing malignancy

in indeterminate lung nodules will continue to grow as more

patients are diagnosed with nodules on CT performed for other

indications or as a screening test.

27

FDG-PET is useful in staging of lung cancer by detecting

mediastinal nodal involvement PET has greater sensitivity and

specificity than CT, but it is still imperfect. Nodes that appear

involved by PET or CT should be sampled for confirmation of

their status when such information will lead to alterations in

clinical management, particularly when deciding whether to

consider resection.

FDG-PET has also been studied for evaluating the response

to pre-operative chemotherapy or chemo-radiation and for

distinguishing between viable tumor and fibrosis in patients

who have received RT or chemotherapy, or both, in assessing

local disease control in patients treated non-operatively.

28

PET is justified instead of a battery of other tests (e.g., bone

scan, CT, MRI) to assess for distant metastases.

PET is more sensitive (90% vs. 80%) and more specific

(90% vs. 70%) than bone scan in detecting bone metastases

from NSCLC; PET has a sensitivity and specificity of greater

than 90% in detecting adrenal metastases from NSCLC. Brain

CT or MRI is still needed because PET cannot reliably detect

brain metastases because of physiologically intense brain

uptake of FDG.

For patients with stage IV tumors, PET may be able to

indicate the most accessible site for biopsy.

29

PET is also useful in restaging NSCLC. In particular, PET appears to be more sensitive than CT

in differentiating post-irradiation change from local

recurrence, although differentiating these two entities remains a

challenge. The post-irradiation change in the chest can remain

intense on PET for up to several years. In differentiating local

recurrence from post-irradiation change, the intensity of uptake

and its shape should be taken into account

30

PET Scan in Lymphoma

Positron emission tomography (especially fused PET/CT) is

superior to conventional CT in staging of Hodgkin’s disease

and non-Hodgkin’s lymphoma; however, there is no definite

evidence that PET changes the initial management of lymphoma patients. Nonetheless, because most

recurrences occur at the sites of the primary disease, pre-

treatment PET appears helpful in identifying recurrence.

31

Hodgkin’s disease and high-grade NHL are mostly markedly

avid for FDG and almost always visible on PET, whereas low-

grade NHL can be only mildly intense and, in rare cases,

completely invisible on PET.

Intense spleen uptake (i.e., more intense than the liver)

before chemotherapy is a reliable indicator of its involvement,

but spleen involvement by lymphoma cannot be excluded with

normal uptake.

PET cannot be used to reliably evaluate bone marrow

involvement.

32

The most promising role of PET in lymphoma management

appears to be in therapy monitoring: early prediction of

response to chemotherapy (i.e., interim or midway PET) and

evaluation of a residual mass for active lymphoma at the

completion of chemotherapy (i.e., end-of-treatment PET).

The decrease of uptake associated with effective chemotherapy seen on interim PET precedes the

anatomic changes seen on CT by weeks to months. Overall,

metabolic changes on interim PET after one or a few cycles of chemotherapy are reliable predictors of response,

progression-free survival rates, and overall survival rates.

33

End-of-treatment PET has proven impact in patient care.

At the completion of chemotherapy, CT demonstrates a

residual mass at the initial site of disease in as many as 50%

of patients. On the end-of-treatment PET, these patients

demonstrate increased FDG uptake in the area of residual

lymphoma in contrast to those without active lymphoma. The

positive predictive value of residual uptake at the completion of

chemotherapy is more than 90%.

In follow-up of patients in remission, PET is more sensitive

than CT in detecting recurrent disease.

34

PET Scan in Head & Neck Cancers

In initial staging of head and neck tumors, PET has a sensitivity and specificity of about 90% for nodal staging, and PET therefore is more sensitive and specific than CT or MRI. Aweakness of PET is its low sensitivity (30%) for nodal diseasein patients with disease in the neck at clinical stage N0.

In addition to local staging, PET can detect synchronous cancers and distant metastases. In initial staging of head and neck cancers, a PET scan is overall most helpful in patients with locally advanced disease because these patients have a risk of 10% or greater for distant disease.

35

For restaging of head and neck tumors after radiationtherapy, PET is highly sensitive; however, the optimal

time toperform PET is a matter of debate. There is a higher likelihood of false-positive findings when

PET is performed earlier than 3 months after irradiation.

For patients presenting with metastatic neck nodes with unknown primary PET is useful in the search for the

original lesion.

36

PET Scan in Colorectal Cancers

PET is highly sensitive in detecting distant hepatic and extra-hepatic metastases.

Considering the higher sensitivity of PET in detectingdistant metastases and the introduction of intravenouscontrast media to the CT portion of fused PET/CT, it is conceivable that PET/CT will be increasingly employed

in pre-operative staging of colorectal cancer; the

contrast-enhanced CT portion of PET/CT can be used instead of conventional CT or MRI for evaluation of anatomic

resectability of liver metastases.

37

PET plays an important role in restaging of colorectalcancer and is even more important now that it is

known thattreatment of limited metastatic disease can be

curative.

PET can visualize the site of the local and distant disease

when recurrence is suspected based on the clinical findings,

findings on other imaging modalities, or an increasing CEA level with sensitivity and specificity higher than

90%

38

PET Scan in Breast Cancer

PET can increase the detectability of small primary breast

cancers and may be especially useful in evaluating patients

with dense breast tissue. Its role in routine patient care is

under investigation.

In evaluating the axillary lymph nodes, PET does not play

any role because of its low sensitivity (60%) despite relatively

high specificity (80%). In contrast, PET is relatively sensitive

(85%) and specific (90%), and it is superior to CT (sensitivity of

54%, specificity of 85%) in evaluation of the internal mammary

chain lymph node for metastases.

39

The main role of PET in breast cancer lies in the investigation of distant metastases and response

monitoring.

Compared with CT, PET has a higher sensitivity (90% vs.

40%) but lower specificity (80% vs. 95%) in detecting metastatic disease.

Overall, PET has the same sensitivity as bone scan in detecting bone metastases (both about 90%), but PET

appears to be somewhat more sensitive than bone scan for

osteolytic lesions and somewhat less sensitive than bone scan for osteoblastic lesions. PET has a higher specificity than

bone scan in detecting bone metastases (95% vs. 80%).

40

In patients with advanced breast cancer undergoing neo-adjuvant chemotherapy, PET may differentiate

respondersfrom non-responders as soon as the first cycle of

therapy hasbeen completed. This may help improve patient

managementby avoiding ineffective chemotherapy and supporting

thedecision to continue dose-intensive pre-operative chemotherapy in responding patients.

41

In esophageal and gastric cancers, PET is useful to assess for

distant disease. PET is routinely used in the staging of esophageal cancer, and it has the potential to be used

for monitoring the effect of neo-adjuvant therapy. In ovarian, uterine, and cervical cancers, PET is used to

assess for recurrent disease. In cervical cancer, PET plays an important role in nodal staging and can have a role in radiotherapy planning. In malignant melanoma, PET is used to evaluate the

presence of distant metastases. In sarcoma, the most intense

areas on PET have usually the highest grade and should be

considered in planning the biopsy.

42

This is a very interesting case of a 67 year old gentleman with

three pulmonary nodules on CT scan. He was referred for PET/CT, which showed only one of the three

nodules was FDG avid.

A subsequent biopsy of the FDG avid

nodule showed adenocarcinoma. The surgeon and the patient

decided to resect all three nodules. The pathology of the three nodules showed adenocarcinoma, a more peripheral area of infarct from tumor embolus and in the other lung a benign hamartoma.

In this particular case, PET/CT accurately identified the malignant nodule from the other two benign nodules.

43

thank you