Role of Positron Emission Tomography/ Computed Tomography (PET… · 2011-06-19 · of tumor metabolism, differentiation between tumor recurrence and radiation necrosis, detection

Protocol for MSc. Essay Title:

Role of Positron Emission Tomography/

Computed Tomography (PET/CT) in radiotherapy treatment planning and target

definition Investigator:

Name: AHMED ABD-ELHADY ABD-ELRAHMAN ABD-ELRAHMAN MOSTAFA

Status: Resident of Clinical Oncology &Nuclear Medicine Mansoura University Hospital

Supervisors:

Assistant Prof. Dr. HALA MOHAMED AHMED EL-SHENSHAWY Assistant Prof. of Clinical Oncology & Nuclear Medicine

Faculty of Medicine, Mansoura University

Dr. MOHAMED ABD-ELRAHMAN MOUSSA DAOUD

Lecturer of Clinical Oncology & Nuclear Medicine Faculty of Medicine, Mansoura University

Principle Supervisor:

Assistant Prof. Dr.

HALA MOHAMED AHMED EL-SHENSHAWY Assistant Prof. of Clinical Oncology & Nuclear Medicine

Faculty of Medicine, Mansoura University

Protocol No.

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition

0. TABLE OF CONTENTS

PAGE CHAPTER 2- 18 1- INTRODUCTION19- 33 2- PHYSICS OF PET/CT34- 47 3- PET/CT & LUUG CANCERS48- 54 4- PET/CT & LYMPHOMAS

60- 83

5- PET/CT & HEAD AND NECK CANCERS WITH THYROID MALIGNANCIES

84- 106 6- PET/CT & BREAST CANCER FEMALE GENITAL SYSTEM

107- 124 7- PET/CT & GASTEROINTESTINAL MALIGNANCIES

125- 132 8- PET/CT & BRAIN TUMERS

133- 144 9- PET/CT & MALE GENITAL AND BLADDER CANCER

145- 147 148- 193

10- SUMMERY AND CONCLUSION11- REFERENCES

2


1- Introduction

3


INTRODUCTION

Many efforts have been made to improve imaging acquisition, the

accuracy of target volumes and the delineation of critical organs for the purpose

of radiation therapy (RT). In order to perfectly delineate the primary tumor and

to optimize radiation doses administered to normal tissues, it is necessary for

patients to undergo an imaging study (Bujenovic, 2004).

During the past two decades, many literatures have demonstrated the

relative usefulness of computed tomography (CT) and also magnetic resonance

imaging (MRI) in Diagnosing, staging, and re-staging of cancer, as well as the

monitoring and planning of cancer treatment. Spatially accurate medical

imaging is an essential tool in three dimensional conformal radiation therapy

(3DCRT) and intensity-modulated radiation therapy (IMRT) treatment planning.

CT imaging is the standard imaging modality for image based radiation

treatment planning (RTP). CT images provide anatomical information on the

size and location of tumors in the body. They also provide electron density

information for heterogeneity-based patient dose calculation. The major

limitation of the CT imaging process is soft tissue contrast, which is overcome

by using contrast agents or using another anatomical imaging modality like MRI

(Bar-Shalom, et al 2003).

One of the disadvantages of anatomical imaging techniques like CT

and MRI is its inability to characterize the tumor. Tumors need to be

characterized whether they are benign or malignant and if malignant it would be

helpful to know whether the proliferation is slow or fast. Necrotic, scar, and

inflammatory tissue often cannot be differentiated from malignancy based on

4

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition anatomic imaging alone. Anatomical imaging has high sensitivity for detection

of structural changes, but a low specificity for further characterization of these

abnormalities (Cohade, et al 2003).

The need for better accuracy in definition of the target volume and

normal tissues and their subsequent segmentation has led to the use of other

imaging modalities for acquisition of functional information (Wahl, et al 1994).

Positron emission tomography (PET), now more than 30 years after its

initial development, has become an established nuclear imaging modality that

has proved its usefulness in oncology. PET was invented at the Mallinckrodt

Institute of Radiology at Washington University in the mid 1970s and was soon

adopted into neurology and cardiology as a valuable research tool. However, it

took more than a decade for investigators to realize that PET also could be a

powerful tool for oncology (Landis, 2005).

Single photon emission computed tomography (SPECT) and positron

emission tomography (PET) are imaging techniques that provide information on

physiology rather than anatomy. These modalities have been used for evaluation

of tumor metabolism, differentiation between tumor recurrence and radiation

necrosis, detection of hypoxic areas of the tumor, and distinguish between

benign and malignant lesions when CT and MRI cannot. (Daisne, et al 2003)

It has been proved that, compared with CT, PET has higher sensitivity

(87% vs. 62%) and specificity (89% vs. 73%) for staging cancer, a higher

sensitivity (93% vs. 54%) and specificity (83% vs. 74%) for imaging recurrence,

and a higher sensitivity (84% vs. 60%) and specificity (95% vs. 39%) for

monitoring the effects of therapy (Gambhir, et al 2001)

5


Table 1 shows the timing of restaging with PET as well as the role of

PET in restaging, differentiation between recurrence and fibrosis , determination

of recurrence and its extent and assessment of response to therapy in different

type of cancers (Malik and Bruce , 2006).

Table 1: Timing and Role of Restaging with PET.

6


PET has incomparable abilities to determine the metabolic activity of

tissues but it needs the assistance of higher-resolution, anatomic information that

it cannot provide. CT is the easiest and highest-resolution tomographic modality

to integrate into PET imaging. The combination of the two offers the best of

both worlds in an integrated data set and thus improves diagnostic accuracy and

localization of many lesions (Landis, 2005).

Positron emission tomography/computed tomography (PET/CT)

combines two imaging technologies into one, PET provides sensitive

information regarding whether a growth within the body is cancerous or not. CT

provides detailed information about the location, size and shape of various

lesions but cannot differentiate cancerous lesions from normal structures with

the same accuracy as PET. The PET/CT scanner (Fig 1) is an open design with

two large rings and an open area in between, giving patients the ability to see the

area around them and allowing technicians patient access during the exam.

Initial attempts at combining PET/CT images involved visual comparison of

side-by-side or overlaid PET and CT images; however, exact alignment of the

two images is not possible, due to differences in image size or slice thickness

between PET and CT and differences in patient positioning between the two

separate examinations. There is software programs that now fuse (known as

PET/CT fusion) the images. Current PET/CT scanners integrate both scanning

techniques into a single device that allows scanning with both techniques in a

single session, without moving the patient between examinations. Also, the CT

scan involves an external radiation source, functioning as the transmission scan

for attenuation correction of PET data, thereby reducing the time required for

PET (Hayes, 2004).

7


Fig 1: PET/CT scanner

PET/CT can image tumor metabolism, proliferation, hypoxia, and

apoptosis with precise anatomic image fusion and become an essential tool in

the management of patients with cancer by its ability to stage, restage the

disease, better localization of the tumor for radiotherapy planning, and

assessment of the treatment response (Table 2) (Chang Gung, 2005).

PET-CT exceeds the sensitivity specificity and accuracy of PET alone.

In a study by Haney and coworkers in which patients with a wide variety of

malignancies were studied, PET-CT demonstrated sensitivity, specificity, and

accuracy of 98%, 99%, and 98%, respectively, compared with PET alone, where

the sensitivity, specificity, and accuracy were 90%, 93%, and 91% respectively

(Haney, et al 2002).

8


Studies on combined use of CT scan and PET imaging for treatment

planning have been performed, with use of interactive co-registration methods

so that every voxel of one modality (CT) has its counterpart in the other

modality (PET) (Scarfone et al, 2004). Using PET/CT, metabolic tumor

mapping, with integration of anatomical and metabolic images, greatly

influences the size and shape of both the gross tumor volume (GTV) and the

clinical target volume (CTV) (Fig 2) (Perez et al, 2002).

Fig 2: ICRU recommended treatment volume

The basis of PET imaging is the labeling of small biologically

important molecules such as sugars, amino acids, nucleic acids, receptor-binding

ligands or even water and molecular oxygen, with positron emitting radio-

nuclides. When these positron emitting tracers undergo radioactive decay, their

positions can be detected by the PET scanner. By imaging the temporal

distribution of these labeled compounds, we can create “physiologic maps” of

the functions or processes relevant to the labeled molecules. Because of this

PET offers substantial advantages over anatomic imaging modalities in

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition oncologic imaging and can often distinguish between benign and malignant

lesions when CT and MRI cannot. (Kubota, et al 1994 and Landis, 2005)

There are several positron-emitting radioisotopes that have been used

for PET imaging. The first four isotopes in table 2 are of particular note with

regard to imaging biological systems. Each of them has a pure positron-emitting

radioisotope, and none of them has an appropriate single-photon emitting

radioisotope. Fluorine, the fourth entry in the table, isn't a normal element in

biological systems but fluorine can often replace either a hydrogen atom or

hyroxyl moiety. It is also a pure positron-emitter and doesn't have a useful single

photon emitting isotope (Jadvar and Parker 2005).

F-18 fluoro-2-deoxy-D-glucose (FDG) is the most frequently used

radio-pharmaceuticals today and new F-18 labeled ligands are under

development. It has changed dramatically the management of numerous cancers

such brain tumors, head and neck cancers, thyroid cancer, parathyroid cancer,

lung cancer, esophageal cancer, lymphoma, pancreatic cancer, colorectal cancer,

and many others. PET-CT will be used with increasing frequency and will

become progressively used as a surrogate marker for disease response. Novel

ligands, labeled with F-18, will further increase the clinical utility of this

technology (Chang Gung, 2005).

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Table 2: Positron-emitting Radioisotopes used in PET

Isotope Half-life B+ energy (MeV)

Gamma energy (MeV)

C-11 20.4 m 0.385 (99.8%) N-13 9.97 m 0.492 (99.8%) O-15 122 s 0.735 (99.9%) F-18 110 m 0.250 (100%) K-38 7.64 m 1.216 (99.3%) 2.167 (99.8%) Cu-62 9.74 m 1.315 (97.6%) Cu-64 12.7 h 0.278 (17.9%) Ga-68 68.1 h 0.836 (8.79%),

0.352 (1.12%) 1.077 (3.0%)

Rb-82 75 s 1.523 (83.3%), 1.157 (10.2%)

0.776 (13.4%)

I-124 4.18 d 0.686 (11.3%), 0.947 (11.3%)

1.691 (10.4%), 7.228 (10.0%), 1.509 (3.0%), 1.376 (1.7 %), 1.325 (1.43%)

11


Table 3: selected tracers used in oncological PET

Table 3 shows the most common tracers and its labeling agents used in

oncologic applications of PET as well as the mechanism of its uptake by tumor

cells and its metabolism (Malik and Bruce, 2006).

12


The PET/CT planning scan

• Patient positioning Fundamental to the use of images for radiotherapy planning is the

requirement to scan the patient in the treatment position. The GE Discovery LS

PET/CT scanner has a minimum patient bore of 55 cm. This is significantly less

than radiotherapy simulators and large bore CT scanners specifically designed

for radiotherapy planning. This restricted bore creates challenges to patient set-

up in the treatment position for image data acquisition. However, it should be

recognized that use of CT scanners with comparable bore sizes has been

common practice in centers where diagnostic CT scanners are used for treatment

planning scans. The current generations of PET/CT scanners have increased

bore size; however, there will still be some restrictions on treatment position set-

up during imaging (Jarritt et al 2006).

Radiotherapy treatments are performed with patients on a flat couch,

whereas diagnostic scans are usually performed using a concave couch, with the

patient lying on a thin mattress. For PET/CT data to be used to guide

radiotherapy treatment, the scanner must be equipped with a flat-bed insert,

which are now routinely available (Fig. 3). It should be noted that addition of

this bed attachment reduces the patient port further and again restricts

positioning options (Jarritt et al 2006).

• Immobilization devices The use of immobilization devices in radiotherapy treatment is well

established and provides an effective mechanism for the reproducible

positioning of patients at each treatment episode. A locally modified Med-TEC

thorax immobilization board and a knee rest were used (Med-TEC, Orange City, 13

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition IA) in the pilot study. Patients were positioned with both arms above their head

to ensure that the arms were outside the treatment fields. The immobilization

board was modified with an additional T-bar grip to enable the patient’s arms to

be supported above their heads and to reduce the span across the patient’s arms

to facilitate positioning within the scanner (Fig. 4) (Jarrit, et al 2005).

Fig 3: Flat-bed insert on scanner couch.

Fig 4: Patient in treatment position passing through scanner.

14


• Planning scan acquisition

The principles and practices already established for RTP were

transferred to the acquisition of planning data using the PET/CT system. Two

therapy radiographers positioned the patient and provided verification that the

position during the data acquisition process could be reproduced during

treatment. A previous evaluation of staff radiation doses from routine

performing of FDG-PET scanning showed that the major component of the

accumulated dose is obtained through close proximity to the patient post

injection. To minimize dose to the therapy radiographers, the data acquisition

process was implemented as a two-stage process. (Carson, et al 2003)

‘‘Cold’’ set-up session Prior to injection of 18F-FDG, the patient was positioned on the couch

using the flat-top insert and immobilization devices as previously illustrated.

The patient was carefully positioned to ensure that they would be able to

maintain the position for the duration of the imaging process. This was of the

order of 40 min while a whole-body PET/CT scan was acquired, as the primary

purpose of the scan was for diagnosis and staging. In the subsequent study, a

diagnostic scan will be performed independently of the treatment planning

session. This will reduce the time for the radiotherapy planning PET/CT to 10–

15 min. During this session the therapy radiographers used the CT scanner

positioning lasers to establish anterior and lateral markers on the patient’s skin,

approximately at the position of the xiphisternum. Full details of the patient’s

position on the scanner and immobilization board were manually recorded to

permit rapid and accurate repositioning of the patient post injection. The patient

was then removed from the PET/CT scanner for the injection and uptake phase.

Although use of the internal scanner lasers proved acceptable during the pilot

study, further experience has shown that their use can be problematic for the

15

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition therapy radiographers depending on the shape and size of the patient. This

potentially increases the time required to set-up the patient and may lead to

increased radiation doses to the radiographers. The use of external room lasers

would reduce these problems and is recommended. However, additional quality

control testing of these lasers would be required to ensure the external lasers are

aligned with the scanner. In addition, the potential effects of sag of the scanner

couch during the investigation with the patient being set-up outside the scanner

bore and then being moved on the couch into the imaging position must be

investigated.

‘‘Hot’’ set-up session Following the injection and uptake period, the patient was repositioned

by the therapy radiographers using the pre-recorded set-up information. Radio-

opaque markers were attached over the skin marks previously identified and the

data acquisition process was completed. After the scan, the radiotherapy

radiographers permanently marked the patient’s skin at the position of the radio-

opaque markers to provide reference points between the CT images and the

treatment planning system.

• Respiratory gating for PET/CT data in Radiotherapy planning

In defining a volume on the PET image it is essential to understand the

acquisition process, especially in relation to physiological motion. For studies in

the head and neck, immobilization techniques should eliminate potential gross

movements and the alignment of PET and CT data from a combined PET/CT

study should be ‘‘exact’’. For studies of the chest and abdomen, the use of

immobilization devices will help eliminate gross patient movement. However,

there remains a significant discrepancy in the way that physiological movement

16

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition due to respiration and heartbeat impacts upon the PET and the CT images. The

increasing use of high-speed, multi-slice CT scanners enables images of the

chest to be acquired in periods of time which are short compared with the

respiratory cycle and effectively provide a ‘‘snapshot’’ of the lungs in time. This

technique can be further controlled by the use of breath-hold techniques.

However, this situation does not pertain for the acquisition of the PET data. Data

are acquired over a number of minutes and represent a time averaged

distribution based upon the dwell time of the activity at any point in space

during the study. Thus, objects which do not move with time will see no

degradation in activity concentration, whereas those objects which move

significantly will exhibit a reduced activity concentration due to the distribution

of activity throughout a larger apparent volume. It could therefore be argued that

these PET images inherently include a margin for physiological motion and that

no further allowance should be made in the definition of the PTV (Caldwell CB,

et al 2003). Other factors such as gross movement and repositioning errors will

remain. This, however, is not the only degrading factor. The presence of

respiratory motion introduces inaccuracies into the reconstructed images as a

result of mis-registration between PET and CT acquisitions (Visvikis, et al 2003

and Beyer, et al 2004). Since with these hybrid scanners, the CT maps are also

used for the correction of the attenuation effects in the emission data, an extra

inaccuracy may be introduced by using non-perfectly aligned CT and PET

datasets as a result of the respiratory motion (Erdi, et al 2004).

The definition of a PTV clearly remains a complex task and techniques

for the definition of a GTV may have a limited impact on the final definition of

a PTV, especially where significant physiological motion is known to occur.

These uncertainties have led to the investigation of diagnostic and treatment

methodologies which measure physiological motion and incorporate the data

into the treatment plan and the delivery system. The solutions that have been

17

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition proposed to date for taking into account the effects of respiratory motion

concentrate on the acquisition of respiration synchronized PET and CT datasets.

The use of breath hold protocols has been used as a means of improving

registration between the PET and CT (Goerres, et al 2002). However, these will

not aid in the delineation of target volumes as the radiotherapy treatment will be

delivered over a few minutes. There is a lot of interest in the use of respiratory

gating for both the PET-CT image acquisition and the treatment. Several studies

have been carried out to investigate the feasibility of respiratory gating of PET

of the upper chest and abdomen (Nehmeh, et al 2004, Boucher, et al 2004 and

Wolthaus, et al 2005) and also to quantify the impact of respiratory motion on

the underestimation of lesion activity. Different detector systems have been

proposed, including a transducer or an impedance electrocardiograph (ECG)

monitor measuring changes in abdominal or thoracic circumference, a thermistor

measuring the temperature of circulating air during patient respiration, a

spirometer measuring respiratory flow (Visvikis, et al 2003), the Varian Real

Time position management (RPM, Varian Medical Systems, Palo Alto, CA)

(Nehmeh, et al 2004) or the Polaris system tracking the displacement of

infrared reflective markers in the patient chest. (Nehmeh, et al 2002) An

alternative approach to gating is to use an image derived respiratory signal

through the acquisition of dynamic datasets or list mode data (Visvikis, et al

2005). One such respiratory correlated approach used a point source of 18F-

FDG attached to the patient’s skin to track respiratory motion. Identifying the

frames in which the point source fell within an operator defined region of

interest (ROI) allowed PET images corresponding to different points within the

respiratory cycle to be created. It was demonstrated that this technique produced

similar results to gating. Another approach which uses time activity curves

generated from a ROI drawn over a moving object in the image to recover the

breathing frequency is currently undergoing clinical validation (Visvikis, et al

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition 2003).The advantage of these techniques is that the data may be retrospectively

reconstructed for any breathing phase or amplitude.

Irrespective of the gating methodology implemented, the emission data

acquired in each of the temporally gated frames is reasonably free of respiration-

produced inaccuracies. However, the resulting individual frame images are of

reduced resolution, as well as overall quality, as they contain only a fraction of

the counts available throughout a PET acquisition. Some groups have attempted

to deal with this problem by acquiring gated data in 3D mode (Boucher, et al

2004). The need, therefore, exists for the development of correction

methodologies making use of the gated datasets, in order to obtain respiration

free PET images using all available data throughout a standard respiration

average PET acquisition. This approach will also remove the need currently

existing in terms of significantly increasing the time (over a factor of 3) of gated

PET acquisitions in order to compensate for the presence of reduced statistics in

the final reconstructed images. Very limited work is currently available in this

domain. First, an emission driven solution through the combination of

respiratory synchronized emission datasets and an iterative reconstruction

algorithm can be envisaged, in a similar fashion to the methodology that has

been previously suggested for SPECT cardiac imaging applications (Kyme, et

al 2003 and Lee, et al 2005).The second option is based on a realignment

methodology to ‘‘bring’’ all of the respiratory synchronized PET datasets to a

particular phase in the respiratory cycle. This methodology is potentially

applicable to both image and raw data domains, deriving the transformation

parameters from the corresponding respiratory motion synchronized CT frames

(Nehmeh, et al 2004 and Lamare, et al 2004)

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2-Physics of PET/CT

20


PET/CT is a new diagnostic imaging modality, which proves that

adding PET and CT is not merely additive, but highly synergistic. While PET

provides high sensitivity for lesion detection, CT provides the anatomic

backdrop, which frequently is important in order to make a specific diagnosis

(Gustav, 2004).

• Computed Tomography Imaging

CT images describe the electronic density distribution of cross sections

of the patient anatomy. CT systems provide gray scale display of linear

attenuation coefficients that closely relate to the density of the tissue. CT

imaging evolved from conventional planar radiographs. In planar X-ray film

imaging the three dimensional anatomy of the patient is reduced to a two

dimensional attenuation projection image and the depth information of the

structures are lost. In CT imaging several attenuation projection images for a

volume of tissue are acquired at different angles. These sets of projection images

are reconstructed by filtered back projection algorithm to generate two

dimensional attenuation cross-section of anatomy of the patient. A CT scanner

positions a rotating x-ray tube and detector on opposite sides of the patient to

acquire projection images. Early CT scanners used pencil beams of x-rays and a

combination of translation and rotation motion to acquire projection images

(Bushberg, et al 1994).

Modern CT scanners have a stationary or rotating detector array with a

rotating fan beam x-ray tube. There are also two types of scanning: axial and

helical CT scanning. In axial scanning the patient is moved step by step

acquiring sets of projection images for each slice. In helical scanning (Fig 5) the

patient table moves continuously while the x-ray tube acquires a series of

21

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition projection images. The projection images are acquired for a helical path around

the patient. In helical scanning to reconstruct a cross-sectional planar image, the

helical data is interpolated to give axial plane projection data before

reconstruction (Fig 6). By removing the time to index the table between slices

the total scan time of the patient is reduced. Also reconstruction can be done for

any slice thickness after acquiring the data. This helical scanning is available in

most of the current CT scanners (Wilting, 2004).

Fig 5: Helical scanning (Continuous scanning while table moves)

Fig 6: Helical interpolation

22


The reconstructed CT image is a two dimensional matrix of numbers,

with each pixel corresponding to a spatial location in the image and in the

patient. Usually the matrix is 512 pixels wide and 512 pixels tall covering a 50

cm x 50 cm field of view. The numeric value in each pixel represents the

attenuation coefficient as a gray level in the CT image. These numbers are called

Hounsfield units or CT numbers. CT number gives an indication of the type of

tissue. Water has a CT number of zero. Negative CT numbers are typical for air

spaces, lung tissues and fatty tissue. Values of µpixel greater than µwater

correspond to other soft tissues and bone. Radiologists occasionally make

critical diagnostic decisions based on CT number of particular regions of

interest. Also attenuation values given by CT numbers are used to calculate the

dose delivered to the tumor in RTP. CT number is an important parameter in CT

images which must be frequently checked for accuracy (Levin, 2003).

• Positron Emission Tomography Imaging

Positron emission tomography (PET) imaging generates images that

depict the distribution of positron emitting radionuclide in the patient body. PET

imaging often uses the F-18 fluoro-deoxy-glucose (FDG) radioactive tracer to

track increased glucose metabolic activity of tumor cells and to provide images

of the whole body distribution of FDG. When the positron is emitted by the

radioactive tracer it annihilates with an electron to generate two 511 kev photons

emitted in nearly opposite directions (Fig 7). These photons interact with the

ring of detector elements surrounding the patient (Fig 8). If both the emitted

photons are detected then the point of annihilation lies on the line joining the

points of detection. This line joining the points of detection is known as the line

of response (LOR). The circuit used by the scanner to record the detector

interactions occurring at the same time is called coincidence circuitry. This

23

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition whole process is called annihilation coincidence detection. Thus a PET scanner

uses annihilation coincidence detection instead of mechanical collimation like

gamma cameras to acquire projections of activity distribution in the patient.

Projections acquired at different angles are reconstructed using iterative

algorithms to generate cross- sectional images of activity distribution (Kinahan,

2003).

Fig 7: Annihilation event

Fig 8: Annihilation coincidence circuitry and PET detector geometry

24


The annihilation coincidence detection process allows many false

events to be acquired. Corrections are necessary for these false events before the

projections are reconstructed. The total events acquired are classified as trues,

random and scatter (Fig 9). A true coincidence is simultaneous interactions

occurring in the detectors resulting from emissions occurring in the same

nuclear transformation. Random coincidences occur when emissions from

different nuclear transformations interact in coincidence with the surrounding

detectors. Scatter coincidence occurs when one or both photons from

annihilation is scattered in the patient body and interact with the detector to give

a false LOR. The acquired annihilation events need to be corrected for random

and scatter events. Random coincidence events along any LOR may be directly

measured using the delayed coincidence method (Zaidi, et al 2003). The

delayed coincidence method uses two coincidence circuits. The first circuit

measures both true and random coincidence events. The second circuit has a

delay of several hundred microseconds inserted into the coincidence window, so

all true coincidences are thrown out of coincidence. The counts measured in the

second circuit are subtracted from the first to give true counts. Scatter correction

is done for the projection data by model-based scatter estimation. The scatter

correction factor is estimated by mathematical models and applied to the

projection data before reconstruction (Kinahan, et al 1998).

Annihilation photons emitted by nuclear transformation are attenuated

by the patient body. Hence correction for attenuation is also necessary to get an

accurate activity distribution. The probability of both photons escaping is the

product of the probabilities of each escaping. The probability of photons

interacting within the coincidence window is proportional to the probability of

photons escaping (Kinahan, et al 2003).

25


Fig 9: coincidence events A –True coincidence events B –Scatter coincidence events C –Random coincidence events

26


PET/CT imaging

Fused PET and CT images give better diagnostic evaluation than PET

or CT images used alone as the greatest limitation in using PET alone for

radiotherapy treatment planning (RTP) is its lack of anatomical information.

This limitation of PET is overcame by fusing PET and CT images together

(Cohade, et al 2003).

The necessity of accurate spatial registration of fused images requires

different fusion techniques for different image datasets. Software fusion and

hardware fusion are the two different approaches considered by the scientific

community (Townsend and Beyer, 2002&2003). Software fusion approach use

different transformation algorithms to fuse different modality images acquired at

different times. The transformation algorithms are classified as rigid and non-

rigid transformation algorithms. They are based on whether they fuse images of

rigid-body (e.g., head) or non rigid (e.g., abdomen) objects (Patton, 2001 and

Yap, 2002).

The hardware approach of image fusion is headed towards designing a

single imaging system to acquire simultaneously the different image modalities

required. Hardware fusion is partially achieved by construction of a hybrid

PET/CT scanner (Beyer et al, 2000 and Townsend et al, 2004) which acquires

different modalities sequentially. These hybrid scanners are two separate

scanners enabled to operate in sequence one after another to acquire the different

image modality datasets in a single imaging session. Although hybrid scanners

do not give a true hardware fusion and have not proven to be a better fusion

technique scientifically (Kalabbers et al, 2002).

27


• Dual Modality PET/CT Imaging

Dual-modality PET/CT was first built at the University of Pittsburgh

in collaboration with CTI (Knoxville, TN) and Siemens Medical Solutions

(Hoffman Estates, IL), combining separate PET and CT scanning devices into

one device (Beyer, 2000).

Image fusion was initially achieved by software fusion of anatomical

and functional images. Software fusion was generally successful with brain and

rigid body volumes. It encountered significant difficulties when fusing images

of the rest of the body. Alignment algorithms fail to converge the two image sets

due to problems of patient movement or discrepancies in patient positioning

between two scans. Also involuntary movements of internal organs arise when

patient are imaged on different scanners and at different times.

Dual modality PET/CT imaging is a combination of imaging

technologies helping to acquire accurately aligned anatomical and functional

images in the same scanning session (Fig 10). Also an additional advantage of

the combined PET/CT scanner is the use of CT images for attenuation

correction. CT images can be scaled in energy and used to correct the PET data

for attenuation effects (Kinahan et al, 2003)

28


Fig 10: PET/CT scanner

The PET/CT prototype consisted of a rotating partial ring PET system

and a single slice CT scanner mounted on the same rotating support. The CT

scanner combined with PET often uses helical scanning CT to enable fast patient

throughput, but new scanners with both helical and axial scanning are available

now. The CT data is usually acquired first, followed by PET acquisition. There

are typically two separate acquisition processing units for CT and PET, and an

integrated display workstation. The acquired CT and PET datasets are sent to the

reconstruction processing unit for reconstruction. Reconstructed images are

fused in the fusion workstation. CT and PET images can also be separately

viewed in the workstation.

29


General PET/CT scan Protocol

The protocol for PET/CT imaging starts with patient preparation. 5 –

15 mCi of FDG is injected into the patient 45 – 60 min before the start of image

acquisition. After 45 min, the glucose circulates through the body; the patient

gets ready for image acquisition by emptying the bladder. The patient is

positioned on the table for an initial topogram. The topogram is used to select

the scan range for PET/CT image acquisition. The scan range is selected as a

number of bed positions. Once the image acquisition region is selected in the

topogram, the helical CT scan is done first; it takes around 30 sec to acquire one

bed position. After completion of the CT portion, the scanner bed is moved to

the PET starting position and the emission scan is started.

The emission scan duration per bed position varies with the detector

technology used. With conventional bismuth germinate oxyorthosilicate (BGO)

system, acquisition times will range from 5 to 8 minutes per bed position. The

new lutetium oxyorthosilicate (LSO) technology reduces emission scans to 3 to

5 minutes per bed position. The CT data are used to perform attenuation

correction. Image reconstruction is completed a few minutes after the PET

image acquisition is completed. Since the CT data is used for attenuation

correction, the total scan duration for a PET/CT scanner is shorter than that for

stand-alone PET scanner, because the CT acquisition is much faster than a

conventional PET transmission acquisition (Humm et al, 2003).

For a typical “diagnostic” PET/CT scan using oral and intravenous

(IV) contrast for the CT, patients generally are given oral contrast and injected

with 18F-fluorodeoxyglucose (FDG) approximately 1 hour before scanning. The

30

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition patient subsequently is positioned in the PET/CT scanner and immobilized as

indicated (for instance, soft collars may be used to reduce neck movement in

patients with head and neck cancer or lymphoma with neck involvement). The

first step in a standard PET/CT protocol generally involves the acquisition of a

digital scout radiograph, in which the full patient is visualized and the area of

interest is selected (Fig. 11 [#1]). Patients then undergo the CT portion of the

examination (Fig. 11 [#2]), followed by the PET portion of the examination

(Fig. 11 [#3]). A common misconception is that the CT and PET data are

acquired simultaneously; however, the data are acquired sequentially, with CT

always performed first. Most scanners without a separate transmission rod

source will not allow PET acquisition only but will allow dedicated CT

acquisition. Because of the sequential data acquisition, there is still a high

probability of CT and PET image mis-registration if the patient moves between

the CT and PET portions of the examination (Fig.12). Once attenuation

correction (AC) and scatter correction are performed using the attenuation

coefficients from the corresponding CT portion of the scan (Fig. 11 [#4]), fused

accurately co- registered images are available for interpretation (Fig. 11 [#5])

(Todd et al, 2006).

31


Fig 11: Standard PET/CT Protocol. A digital scout radiograph is first acquired, in which the full patient is visualized and the area of interest is selected (1). Patients then undergo the CT portion of the examination (2), followed by the PET portion of the examination (3), Once attenuation correction and scatter correction are performed using the attenuation coefficients from the corresponding CT portion of the scan (4), fused, accurately co-registered images are available for interpretation (5).

Fig 12: Misregistration caused by patient movement. Misregistration of axial CT (A) and PET (B) images are shown on an axial PET/CT image (C). This type of misregistration is due to movement of the patient’s head to the right after the CT acquisition (during the PET acquisition).

32


Quality Assurance in PET/CT

As PET/CT imaging is gaining grounds in RTP, quality assurance

(QA) protocols to check the PET and CT as a combined device are needed. QA

for PET/CT is not well defined and there is research in progress to define a

standard methodology for checking their performance. Some research work has

analyzed the artifacts of helical CT and its impact on the attenuation correction

of PET images. These studies analyze the problems faced in PET/CT imaging

due to breathing and to artifacts from metal and oral contrast agents. Most of the

QA currently done in PET/CT scanner facilities are based on stand-alone PET

and CT QA protocols (Bujenovic et al, 2003 and Nehmeh et al, 2003).

PET scanner quality control includes system corrections such as normalization,

calibration and blank scans. Normalization correction compensates for variation

in efficiency in each line of response (LOR) in the sinogram. Calibration

correction is used to convert the reconstructed image pixel values into activity

concentrations. Both normalization and calibration correction are used to

compensate for sensitivity variation in the scanner. The blank scan typically is

acquired daily using a transmission rod source and it is used with patient

transmission data to obtain attenuation correction factor (ACFs). In PET/CT

scanners only the normalization and calibration scans need to be done; a blank

scan is not needed as CT scans provide ACFs. Blank scans are done during

regular CT daily QA instead of the transmission source blank scan used in

stand-alone PET scanners. Blank scans give the number of un-attenuated

photons (Io) reaching a detector from the x-ray tube. When used with the

number of photons detected (I) by a detector during CT imaging it gives the

ACF for CT energy photons (Cohade et al, 2003).

33


Daily and monthly QA for PET imaging in PET/CT scanners is done

by scanning a uniform 68Ge cylindrical phantom for a normalization scan. Both

normalization and calibration corrections are checked. The reconstructed PET

images are checked for variation in uniformity. This is done by checking the chi-

square value of the acquired data. The CT QA is done by checking CT number

for an electron density phantom. The CT phantom is a cylindrical hollow acrylic

phantom filled with water. Once CT images of the phantom are taken the CT

number values of acrylic, water and air are checked and recorded. Thus current

QA methods for PET/CT are more oriented to verify the performance as a stand-

alone device rather than as a combined device. Hence validation of the PET/CT

dataset has to be done in the scanner and also for the imported PET/CT dataset

in the RTP software (Nehmeh et al, 2003).

34


3- PET/CT& Lung cancers

35


Radiotherapy is a key treatment modality in the curative treatment of

patients with locally advanced non-small cell lung cancer (NSCLC).Recent

progress in combined modality treatments incorporating radio-chemotherapy,

with or without surgery, as well as the technical advances in radiation delivery,

have all led to significant improvements in treatment outcomes (Senan et al,

2005).

Three dimensional conformal radiotherapy (3DCRT) accurately

conforms the dose distribution to the planning target volume allowing the

radiation dose to the tumor with respect to normal tissue to be optimized. 3D-

CRT is widely used in the treatment of thoracic neoplasms, particularly non-

small cell lung cancer (NSCLC) (Armstrong et al, 2000). Conformal irradiation

techniques have shown advantages in comparison to conventional 2D approach

in terms of dose volume histograms of tumor and healthy tissues (Ragazzi et al,

1999, Graham et al, 1999, Kwa et al, 1998 and Rancati et al, 2003).

Careful staging and accurate delineation of target volumes are crucial

for preventing geographical misses as it is technically possible to produce

radiation dose distributions that tightly conform to the tumor volume. An

incorrect definition of the gross target volume (i.e. detectable tumor) or clinical

target volume (tumor plus a margin for microscopic extension) is a source of

systematic errors, which can lead to under-treatment and reduce the probability

of tumor control (Senan et al, 2005).

At present, the standard imaging modality for target volume definition

in 3D-CRT is computed tomography (CT), which presents limitation in

determining lymph-nodal involvement and in providing information on lesion

viability (Wahl et al, 1994).

36


Positron emission tomography (PET) has been a major innovation in

lung cancer imaging that exploits differences in the structure of tissues. Positron

emission tomography with 18F fluorodeoxyglucose ([18F] FDG-PET) is

showing increasing usefulness in staging and follow-up (Kostakoglu et al,

2003, Follen et al, 2003, Lai et al, 2004).

Clinical studies have mainly focused on the use of 18F-

fluorodeoxyglucose (FDG), a glucose analogue that is taken up due to the

enhanced glucose metabolism of lung cancer cells, leading to metabolic trapping

and accumulation in the cancer cell after phosphorylation by hexokinase

(Rempel et al, 1994).

In particular, in lung cancer, [18F]FDG-PET shows a higher accuracy

than CT in lymph-node staging, with sensitivity and specificity values of 85%

and 90% for positron emission tomography (PET), and 61% and 79% for CT,

respectively (Gould et al, 2003).

Data from a randomized trial in surgical patients with Stage I NSCLC

found that PET scans changed disease stage in 20% of patients, thereby

supporting the recent trend of performing FDG-PET scans in patients who are

candidates for curative radiotherapy for the same stage (Viney et al, 2004).

Post-radiotherapy survival has been reported to be superior in patients

who have undergone a staging PET scan, a finding that can be explained by the

exclusion of up to 30% of patients who have otherwise unsuspected distant

metastases (Hicks et al, 2001 and Bradley et al, 2004).

37


PET scanning may be useful in treatment planning, but only limited

prospective data are available from clinical trials. Nevertheless, significant

changes in the definition of target volumes have been reported in between 30

and 60% of patients with NSCLC. More recently, PET and CT combined images

have been shown to add important information on viable tumor tissue extent and

to considerably modify target volumes of 3D-CRT (Fig 13, 14) (Bradley et al,

2004).

Fig: 13 PET-CT scan of a tumor in the right lung. The information contained in separate CT and PET images (left) are better appreciated on co-registered images (upper right), which allow for easier contouring of target volumes (lower right). FDG uptake in the heart is also visible.

38


Fig: 14 Screen-shot of contoured target volumes on PET and CT images for a peripheral lung tumor.

39


PET/CT for defining target volumes in NSCLC

• Nodal target volumes :

Accurate identification of nodal metastases is crucial for planning

curative radiotherapy, particularly as routine elective nodal irradiation is no

longer recommend in NSCLC (Senan et al, 2004). Different meta-analyses have

shown FDG-PET to be superior to conventional mediastinal staging using CT

scans and esophageal ultrasound (Fischer BM et al 2001, Gould et al, 2003

and Toloza et al, 2003). A planning study reported that treating only FDG

positive mediastinal areas decreases radiation exposure of the lungs and the

esophagus sufficiently as to allow for radiation dose-escalation (Wel et al, 2005)

A prospective clinical trial using this approach reported isolated nodal

failures in only 1 of 44 patients. (DeRuysscher et al, 2006)

Although PET-defined mediastinal radiotherapy fields appears a

logical step, reported false positive findings occur in up to 39% of patient,

depending on the population studied and the equipment used (Graeter et

al,2003). As such, findings that can have a major impact on treatment policy

should ideally be confirmed by histology. In up to 70% of patients in whom

FDG-PET scans indicate nodal metastases, histological confirmation can be

obtained using endoscopic ultrasound-guided fine needle aspiration (EUS-FNA)

(Annema et al, 2004). As such, the combination of PET and EUS-FNA

qualifies as a minimally invasive staging strategy for defining involved-fields in

NSCLC.

40


The issue of whether digital fusion is superior to simple correlative

reading for staging lymph nodes is not entirely clear as the available data are

conflicting. Some authors report no significant differences in accuracy of

establishing either N stage or individual lymph node stations when digital

software fusion was used (Magnani et al, 1999). Others have reported

comparable sensitivity, but an improved specificity and accuracy, for digital

software fusion in identifying correct lymph node stations (Aquino et al, 2002).

A recent study reported that nodal staging using hardware fusion (i.e. PET-CT)

was significantly more accurate than only visual correlation. However, the latter

study has been criticized because of the reported accuracy for PET scans alone

(49%) were far below that reported in the meta-analysis. (Lardinois et al, 2003)

A recent retrospective analysis in NSCLC compared a hybrid CT-PET

with PET alone with visual matching, with the hybrid CT-PET read first in 129

patients, followed by the PET alone with visual CT matching 2 or more weeks

later. Histological verification of nodal stage was obtained in all patients, and

both a patient-and TNM-based analysis was performed. Hybrid CT-PET was

superior for stages II and III, and was significantly more accurate for both N2

nodes (96% versus 93%) and N1 nodes (90% versus 80%). With regards to

specific nodal stations, CT-PET was more sensitive at stations 4R, 5, 7, 10L, 11,

while it was more accurate at stations 7, 11 (Fig 15) (Shielda et al, 2000).

Overall, the findings of CT-PET were reported to change patient management in

9.3% of these patients (Cerfolio et al, 2004).

41


Fig: 15 regional lymph node stations. (Ao=aorta, PA=pulmonary artery).

42


43

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition • Target volumes for primary NSCLC:

Although FDG-PET scanning has an important role to play in the

differential diagnosis of pulmonary nodules (Vansteenkiste, 2004), the extent of

the primary tumor is usually assessed by thoracic CT scans, occasionally

supplemented by magnetic resonance imaging (MRI), e.g. for superior sulcus

lesions or when the relationship between the heart or the large vessels is of

importance (Bittner et al, 1998).

At present, FDG-PET scans offer little additional advantage over CT

or MRI scans for staging of the primary tumor because of its lack of precise

anatomical localization. The spatial resolution of modern CT scanners (typically

about 1 mm) is far superior to that of current PET scanners (6–8 mm), so that

the extra gain with fusion is expected not be large, unless PET scans can reliably

address tumor delineation caused by atelectasis or intra-tumor heterogeneity

(Jang et al, 2003 and Ciernik et al, 2003).

Specific issues that have to be addressed in order to clarify

the role of PET scans for contouring primary tumors include:

1. Low spatial resolution:

Despite a high contrast resolution, the relatively low spatial resolution

of images (presently in the range of 6–8 mm and physically limited to about 2

mm) remains a major drawback of PET scans. Tumor edges on PET scans are

indistinct, making contouring difficult and auto-contouring using predefined

SUV thresholds has been proposed as a solution. However, criteria for defining

tumor thresholds for contouring GTV’s requires data from studies correlating

44

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition PET data with pathological specimens. These studies are unfortunately

unavailable for NSCLC (Paulino et al, 2004).

2. Significance of hypodense regions:

Some reports have proposed modifying dose distributions to spare

‘hypodense’ regions on FDG-PET scans, and to boost regions showing a high

uptake. However, there is little pathological data to support the view that

‘hypodense’ regions represent exclusively sites of necrosis and/or atelactasis. In

additions to studies correlating pathology with PET imaging, studies of the

molecular characteristics of cancer cells showing different uptake values for

PET tracers are needed before the concept of modulating radiation dose-

intensity to tumors sub-volumes can rationally be tested in clinical trials

(Caldwell et al, 2003).

3. Tumor mobility:

As PET acquisition takes several minutes, tumor motion due to

respiration or cardiac action results in PET ‘GTV’s’ that incorporate at least

some effects of this motion. As such, PET scans correlate best with imaging

techniques that incorporate all mobility, such as slow CT scans (Lagerwaard et

al, 2001). Respiration-correlated, or 4D, CT scans are have been shown to be an

effective approach for evaluating tumor mobility, and incorporating mobility

into treatment planning (Underberg et al, 2004). These modified CT scanning

techniques are used almost exclusively in radiotherapy planning, and studies on

the fusion of such images with diagnostic PET scans (acquired during free-

breathing) are needed. Respiration-gated PET acquisition techniques have been

developed (Nehmeh et al, 2003), but their use implies that an appropriate

45

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition respiratory phase for radiotherapy (and PET scan) has first to be established. In

the near future, availability of respiration correlated PET-CT scans will limit the

variations and artifacts due to respiration, and studies investigating the clinical

gains from these approaches are awaited.

4. Timing of PET scans:

PET scans are increasingly performed during the initial staging process

for NSCLC, without attention to details relevant for radiotherapy planning

using for example customized immobilization devices or fiducial markers.

Mutual protocols between nuclear medicine specialists and radiation

oncologists allow patient positioning with the use of devices in an appropriate

way for both diagnostic and therapeutic purposes (Senan et al, 2005).

The assessment of response by conventional imaging is mainly based

upon changes in tumor volume. However, these changes do not necessarily

correlate with pathological complete remission rates and survival (MacManus

et al, 2003). Assessment of tumor response by metabolic parameters is

considered to be a promising approach. Studies evaluating the role of FDG-

PET scans for response assessment following radiotherapy generally reported a

poor agreement between post-radiation CT and PET scans. More patients were

judged as complete responders by PET than by CT scan, and PET responses

were a better predictor of survival (Hebert et al, 1996).

An evaluation of pre-and post-induction chemo-radiotherapy PET

scans in 23 patients with stage N2–3 NSCLC found PET to be of limited value

in predicting residual disease at 4–6 weeks after chemo-radiation. (DeYoung

et al, 2004) Approximately 80% of patients with a negative post–induction

PET at their primary site had in fact residual disease, and approximately 25%

46


of patients with a negative post-induction PET in the mediastinum had residual

tumor. Another report suggested that FDG-PET was better able to predict

pathological responses in patients with squamous cell cancer than those with

an adenocarcinoma, and found that the technique was less accurate in

predicting responses when concurrent chemo-radiotherapy, rather than

chemotherapy alone, was used as the induction scheme. Therefore, the utility

of PET in predicting pathologic response to chemo-radiotherapy remains

presently investigational. Due to concerns about false-negative scans arising

from radiation-induced inflammation, the current practice is to defer PET

reassessment to between 3 and 4 weeks after completion of chemotherapy, and

3 months post-radiotherapy (Cerfolio et al, 2004).

A large study looked at the pathology of 988 mediastinal lymph nodes

and their interpretation on CT and FDG PET-CT. On the basis of CT criteria

alone, 75% of the pathologically involved nodes would have been covered by

the GTV, whereas 89% of involved nodes would have been covered by the PET-

CT planned GTV (Vanuytsel et al, 2000). Conversely, one study showed that

irradiation field sizes to the involved mediastinal nodes alone were smaller if

PET-CT planning was used (9.9 +/- 4.0 cm3) vs. CT planning alone (13.7+/- 3.8

cm3) (Wel et al, 2005). DeRuysscher et al 2005 showed that irradiating these

PET-positive nodes alone resulted in only a single treatment failure in 44

patients. In a study by Kamel et al 2003, FDG PET scanning changed treatment

in 19% (eight) of patients. Three of the patients had their adjuvant radiotherapy

cancelled and five patients had their radiation fields changed.

• New PET/CT tracers:

47


Clinical experience with newer tracers is very limited but they may

hold promise for the future. A review of this large field is beyond the scope of

this article. The most extensive clinical data in lung cancer are available for 3-

deoxy-3-18fluorothymidine (FLT), a marker for DNA synthesis. A clinical

study reported that the uptake of FLT correlated better with proliferation of

lung tumors than the uptake of FDG. No FLT uptake was visible in non-

proliferating tumors, suggesting that FLT may thus be complementary to FDG

in the evaluation of NSCLC (Buck et al, 2003).

PET/CT for defining target volumes in small cell lung

cancer (SCLC) Patients with limited-stage lung cancer (LS-SCLC) are candidates for

concurrent chemo-radiotherapy, and must be distinguished from the more

common presentation of extensive disease. The available literature suggests

that that PET has diagnostic value in SCLC (Chin et al, 2002). SCLC is a

FDG-avid tumor, with mean SUVmax for primary and mediastinal nodal

lesions of SCLC reported to be similar to that seen in NSCLC (Bradley et al,

2004).

In the largest reported series of 120 patients, FDG-PET resulted in a

stage migration for 14 patients, correctly upstaging 10 patients to extensive

disease and down-staging 3 patients by not confirming metastases of the

adrenal glands suspected on the basis of CT scan (Brink et al, 2004) Only

1/120 patient was incorrectly staged by FDG-PET, owing to failure to detect

brain metastases. It has been suggested that PET can identify metastases to

regional lymph nodes in 25% of patients whose mediastinal CT was negative.

At the present time, further evaluation with imaging or biopsy should be

48


performed to clarify PET results in patients with LD-SCLC whose

management is likely to be altered as a result of the scan (Chin et al, 2002).

The benefits of staging FDG-PET scans have clearly been established

in NSCLC, and this information is of clinical benefit for selecting candidates for

curative radiotherapy. Non-randomized studies suggest that designing radiation

fields for the mediastinum with the aid of PET scans may be beneficial. Given

the uncertainties arising from image-fusion as well as the low spatial resolution

of PET scans, use of PET information for defining target volumes for primary

tumors is questionable. It remains to be seen whether the treatment of

‘biological target volumes’ defined using different PET markers will become a

clinical reality in the near future ( Ling et al, 2000).

PET/CT is changing this role by integrating the information on tumor

morphology provided by CT with that on its metabolism and, particularly, on the

number of neoplastic viable cells. This is demonstrated by the initial

applications of PET and co-registered CT imaging in the evaluation of patients

undergoing radical radiotherapy for locally advanced lung cancer. In these cases,

the addition of PET to the standard CT protocol appears to significantly change

treatment planning (changes of 22%–64% in the planning treatment volume

have been reported in 22–100% of patients (Dizendorf EV 2003 and Ciernik

IF, et al 2003).

49


4- PET/CT& Lymphomas

50


Although the World Health Organization/Revised European–American

Classification of Lymphoid Neoplasms (i.e., WHO/REAL) classification has 2

major categories of lymphoid malignancies, i.e., Hodgkin’s lymphoma (HL) and

the non-Hodgkin’s lymphomas (NHL) of B-cell or T-cell/natural killer (NK) cell

origin, (Harris et al, 1999) within each group there is very significant

variability in management and prognosis. Nevertheless, in both HL and NHL,

prognosis and treatment depend critically on histological type and disease stage.

Biological characteristics, including histologic grade, also may influence

outcome and can potentially be assayed by PET (Hasenclever et al, 1998).

Lymphomas represent a diverse range of diseases with manifold

presentations, outlook, and therapeutic approaches. Key to the modern

management of lymphoma is accurate delineation of the extent of disease. The

inability of computed tomography (CT) to identify the involvement of non-

enlarged nodes and its relatively poor sensitivity in the detection of extra-nodal

sites of involvement limit the performance of noninvasive staging techniques

(Hicks et al, 2003).

Functional imaging techniques such as Gallium-67 (Ga-67)

scintigraphy have been used for many years to improve the evaluation of

patients with lymphoma. Ga-67 scintigraphy was the imaging technique of

choice to assess response to treatment in HD and in high-grade NHL. While

providing complementary information to CT in many clinical settings,

functional imaging has never had sufficient accuracy or localizing ability to

seriously challenge conventional primary staging paradigms. However, it suffers

from low spatial resolution and a lack of specificity. Its sensitivity is low in

infra-diaphragmatic disease because of physiological uptake in the abdomen. Its

51

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition limitations in low-grade NHL also are well known. Moreover, a Ga-67

scintigraphy should always be performed before treatment to determine whether

the individual patient has a gallium-avid lymphoma (Front et al, 1995). In

addition FDG-PET is without any doubt the best noninvasive imaging technique

for response assessment in patients suffering from lymphoma (Bar-Shalom et

al, 2003 and Fischman et al, 2004).

Despite the important role of Ga-67 scintigraphy in response

evaluation, it appears now that FDG-PET is more sensitive for the detection of

nodal and extra-nodal sites of disease. Furthermore, FDG-PET also is

considered to be more convenient than Ga-67 scintigraphy because a PET study

can be performed 1 hour after the injection of 18F-FDG whereas the

scintigraphy must be performed several days after the administration of Ga-67.

18F-Fluoro-deoxy-glucose positron emission tomography (FDG-PET), however,

has been demonstrated to have both higher sensitivity and specificity than CT in

many comparative series. Second, the tumor-to-background ratio is higher for

PET than for gallium. Although probably adequate for imaging of the chest,

gallium suffers from decreased sensitivity for evaluation of the abdomen due to

high physiologic liver and bowl activity. Third, due to its lower anatomic and

spatial resolution, gallium imaging has decreased capability to detect small

lesions when compared to FDG-PET imaging. As a result of these limitations,

up to 36% of lesions seen on PET images may not be visible on gallium exams.

Also, negative post-therapy gallium scans are not useful unless a pre-therapy

scan demonstrating tumor accumulation of the agent were performed. Post-

therapy scans can also suffer from non-specific hilar uptake of gallium that can

be confused for recurrent disease (Rohren et al, 2004).

NHL is broadly grouped into low-, intermediate-, and high-grade

disease subgroups (Segall, 2001). There is a direct correlation between the

52

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition degree of FDG uptake and the histologic grade of lymphoma (Delbeke, 1999).

Treatment for NHL is based on several factors, including tumor grade. High-

grade tumors demonstrate greater metabolic activity (and greater FDG

accumulation) than low grade tumors (Romer et al, 1998). In fact, low-grade

lesions (including mucosa-associated lymphoid tissue lesions) may not

accumulate sufficient FDG to be visualized (Kostakoglu et al, 2003).

For Hodgkin's disease, the stage at presentation and tumor cell type

determine the patients overall prognosis and optimal method for treatment

(Guay et al, 2003). Because the anatomic extent of disease is the single most

important factor influencing relapse-free duration and overall survival in

patients with Hodgkin's disease, accurate staging prior to initiation of therapy is

essential for proper patient management (Hoh et al, 1997).

The more-than 35 clinico-pathologic entities described within the

spectrum of NHL can be divided into the more clinically useful groups of

“indolent” or “aggressive” lymphomas. The most common “indolent”

lymphomas are the follicle-center cell (“follicular”) lymphomas, and the most

common “aggressive” lymphomas are the diffuse large B-cell lymphomas. For

both “indolent” and “aggressive” NHL, stage has a critical role in the selection

of treatment. Noncontiguous lymph node involvement and extra-nodal

involvement, both uncommon in HD, are more common in patients with NHL

and, therefore, sensitive whole-body evaluation is likely to be of major

importance in accurately staging these diseases. In particular, bone marrow and

hepatic involvement are more common in patients with NHL than HD and may

be difficult to detect on conventional imaging. This is important because

prognosis is strongly influenced by the number of extra-nodal sites involved

(Shipp et al, 1993).

53


One of the difficulties in staging NHL is detection of focal, as opposed

to diffuse, bone marrow involvement because the former can potentially be

missed on bone marrow biopsy, particularly if suboptimal samples are obtained

for evaluation or if suboptimal evaluation methods used (Campbell et al, 2003).

Radionuclide bone scanning is relatively insensitive, and MRI is more sensitive

but may require multiple sequences to achieve adequate sensitivity (Yasumoto

et al, 2002). PET may have particular advantages for evaluating extra- nodal

involvement, including focal bone marrow disease (Fig. 17), splenic (Fig. 16,

18) and small bowel disease (Fig. 19).

Fig 16: on conventional staging this patient with low-grade (follicular) NHL had stage 2A disease. CT demonstrated left lower cervical and mediastinal lymphadenopathy. There was no splenomegaly, and bone marrow biopsy was negative. FDG PET/CT demonstrated abnormal uptake in non-enlarged

54

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition axillary and para-aortic nodes and intense splenic uptake, upstaging the patient from stage 1 to stage 3 disease and changing our treatment to chemotherapy.

Fig 17: This patient presented with weight loss and epigastric pain and was found to have an epigastric mass with abdominal para-aortic lymphadenopathy and splenomegaly on CT. Biopsy of the mesenteric mass was inconclusive, and bone marrow biopsy was negative. FDG PET confirmed known sites of abnormality and additional focal liver (horizontal arrows), bone (vertical arrow and other sites not displayed in these coronals.

Fig 18: In addition to its ability to detect diffuse splenic infiltration by virtue of diffusely and, often, intensely increased FDG uptake in the spleen relative to the liver, PET also can detect focal splenic

55

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition deposits, even in the absence of structural abnormality. As well as uptake in non-enlarged lesser curve and splenic hilar nodes, several focal splenic nodules are clearly apparent, particularly on fused PET/CT images.

Fig 19: This patient presented with abdominal pain, and bulky para-aortic lymphadenopathy was identified on CT. FDG PET demonstrated high uptake in multiple abdominal nodes as well a several discrete foci with slight elongation, suggesting small bowel involvement. Co-registered PET images and CT with oral contrast obtained contemporaneously on hybrid PET/CT demonstrate intense uptake corresponding to mural thickening of small bowel.

In the primary staging setting, detection of more extensive disease by

PET than by conventional imaging would be of major relevance for patients

with apparently limited stage HD in whom upstaging could alter management

from being radiation-based to chemotherapy alone or combined modality

therapy. It also may help to better define radiation treatment volumes in both

early and more advanced disease stages by better defining gross tumor volume.

If chemotherapy is not used to treat potential systemic microscopic disease in

HD, then the accurate tailoring of radiation therapy fields to cover all gross

disease becomes even more critical. Demonstration of disease in normal-sized

lymph nodes could be of particular importance for planning radiation therapy,

given that the quality of radiation therapy delivery has a major impact on overall

survival (Duhmke et al, 1996).

56


There was increasing recognition that wide-field radiation may play an

important role, alongside certain chemotherapy agents, in giving rise to second

malignancies in this patient population. To reduce this risk most schedules for

early Hodgkin’s disease and early non-Hodgkin’s lymphoma use a short course

of chemotherapy to contain microscopic regional disease and reduce bulk at the

known sites prior to involved field radiotherapy (Moody et al, 2000).

Freudenberg et al 2004 reported that PET/CT imaging with FDG is

accurate in restaging lymphoma and offer advantages over separate PET and CT

imaging. Data from the present study confirm the high value of PET/CT in

patients suffering from lymphoma in both initial staging and restaging. In both

situations, FDG PET/CT showed a high sensitivity of 100% and 97%,

respectively, as well as a high specificity 100% and 99%, respectively.

Freudenberg et al 2004 reported also that combined PET/CT to be superior to

PET and CT read side by side. Specifically, combined image reading changed

the stage of the disease in 14% of their lymphoma patients (2/14), compared

with a separate side-by-side interpretation of the same PET and CT data. the

combination of both methods either performed separately or read side by side or

performed with a hybrid PET/CT system detected significantly more malignant

lesions than did either CT or PET used as a single method. In addition, the

combination of PET and CT ruled out false positive findings of PET or CT,

which may have an important impact on staging as well as in selecting therapy

options.

PET/CT facilitated diagnosis, especially in the differentiation of

physiological bowel activity and pathological glucose utilization in the bowel;

such differentiation remains challenging without exact anatomical information

derived from simultaneously acquired CT, particularly given that bowel

displacement may occur between two separate examinations. In addition,

57

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition treatment planning of radiation therapy as well as of surgical biopsy may be

facilitated by the exact anatomical correlation of FDG positive findings

(Christian la Fougère et al, 2006).

Nevertheless, the value of PET/CT is mostly related to limited CT

image quality, as in, for example, CT of the thorax, which compromises the

interpretation of sub-centimetre nodules. Normal anatomical structures such as

blood vessels may present an ambiguous appearance (Allen-Auerbach et al,

2006). Optimized co-registration requires use of a normal expiration breath-hold

protocol for both CT acquisition and the PET portions of the examination.

Furthermore, suboptimal image fusion and attenuation correction may result in

misinterpretation of PET images (Bockisch et al, 2004).

In HD, bone marrow infiltration by malignant cells in BMB (Bone

Marrow Biopsy) occurs in up to 6.5% (Macintyre et al, 1987). Various

predictive factors, including B symptoms, peripheral low cellularity, age over 35

and inguinal involvement, have been established to predict possible bone

marrow infiltration by HD (Vassilakopoulos et al, 2005). However, BMB in

HD has a low yield and BMI (bone marrow involvement) alone does not define

a special high-risk group in which a different treatment approach is indicated

(Munker R, et al 1995); accordingly, the need for BMB in all HD patients is

questionable (Howard et al, 1995).

In NHL, bone marrow involvement occurs in 30%– 50% and is more

common in indolent histologies (Foucar et al, 1982 and Conlan et al, 1990).

Regarding the focal lymphomatous involvement of bone marrow, the value of

unilateral versus bilateral BMB remains controversial. It has been shown that

bilateral biopsy of the iliac crest enhances the diagnostic yield of BMB in HD

(22 bilateral BMBs were positive, versus 14 unilateral BMBs) and NHL (237

58

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition bilateral BMBs were positive, versus 24 unilateral BMBs) (Wang et al, 2002).

These data show that focal bone marrow infiltrations in NHL and HD can pass

undetected when using unilateral biopsy.

.

FDG-PET is superior to CT alone or in combination with unilateral

BMB in detecting bone marrow involvement in HD and NHL patients and leads

to upstaging in a relevant proportion of patients. In patients with FDG-avid bone

lesions, direct PET/CT-guided bone biopsy (Fig 20, 21) seems to be more

accurate than standard BMB in confirming bone involvement. In the future, the

decision to perform a BMB in patients with HD or NHL and the type of biopsy

procedure should thus be guided by the results of FDG-PET/CT as the initial

staging procedure.

Fig 20: PET/CT images of a 62- year-old woman with recurrence of HD. A) Axial PET/CT image showing increased FDG uptake in an inguinal lymph node (arrowhead) and the left proximal femur (arrow). B) FDG uptake was used for planning the CT-guided percutaneous bone biopsy. The needle tip (arrow) is in the lesion. Histology was positive for lymphomatous infiltration

59


Fig 21: PET/CT images for restaging in a 32-year-old woman with recurrence of HD. A) Coronal maximum intensity projection image showing intense FDG uptake in cervical (upper arrow), mediastinal (lower arrow), axillary (arrow at the left axilla) and iliac (lowest arrow) lymph nodes as well as an FDG-avid lesion in the spleen (short arrow). There are multiple lesions with FDG uptake in the bones (arrowheads; left humerus, pelvis, both proximal femora). B) Bone window of the axial CT image at the level of the upper thorax shows enlarge axillary lymph nodes (arrow) but normal bone structure of the scapula (arrowheads). C, D) Corresponding axial PET image (c) and fused PET/ CT image (d) demonstrate intense FDG uptake in enlarged axillary lymph nodes (arrow) and the scapula (arrowheads). BMB was negative in this patient

60


61


As regard to gastrointestinal lymphomas PET is superior to

morphologic imaging methods in the assessment of lymphoma and PET/CT has

already proved to be the most accurate imaging method (Ho CL, et al 2003),

even without a full-dose CT scan (Schaefer NG, et al 2004).

62


5- PET/CT& Head and

neck cancers with thyroid malignancies

63


1-Head and Neck Carcinomas

Most positron emission tomography (PET) imaging studies in head

and neck cancer are performed using the radiotracer 18-fluorodeoxyglucose

(18FDG). PET with FDG has become a standard clinical imaging modality in

patients with head and neck cancer. It contributes valuable information in

localizing a primary tumor in patients with neck nodal metastases from an

unknown primary, in the staging of primary head and neck cancer, and in the

detection of recurrent disease. In addition, FDG-PET provides independent

prognostic information in patients with newly diagnosed and recurrent head and

neck cancer. PET/CT improves lesion localization and accuracy of FDG-PET

and is strongly recommended in patients with head and neck cancer (Schoder

and Henry 2004).

Carcinoma of Unknown Primary of Squamous Cell Origin

Cervical nodal metastases from an unknown primary tumor constitute

2% of newly diagnosed head and neck cancers (Grau, et al 2000). Treatment of

these patients in most centers includes extensive fields of irradiation to include

the entire pharyngeal mucosa, larynx, and bilateral neck. The wide-field

irradiation reduces the risk of tumor recurrence; however it causes significant

morbidity, particularly in terms of xerostomia. Correct localization of the

primary tumor substantially reduces the complication risk of radiotherapy by

decreasing the size of the radiation portal (Mendenhall, et al 2001).

The available literature on the accuracy and usefulness of FDG-PET in

patients with carcinoma of unknown primary consists of many single-center

64

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition small studies with variable diagnostic workup before the PET scan. Rusthoven

and coworkers 2004 recently published a detailed review of FDG PET in

carcinoma of unknown primary. The overall detection rate, based on 20 studies

between 1992 and 2003, was 24.5% in a total of 302 patients. In a subset of

studies in which PET was performed after a negative endoscopy and negative

CT and/or MRI, the detection rate was similar, 27% in 150 patients (Wong,

Saunders 2003 and Fogarty, et al 2003 and Johansen, et al 2002).

PET probably should be performed as the initial test and biopsies

under endoscopy should be directed according to PET findings (Schöder and

Yeung 2004). FDG-PET also finds additional local and distant metastases in an

average of 27% of patients, which certainly changes the radiation field or the

objective of treatment from cure to palliation when distant disease is identified

(Rusthoven, et al 2004). One of the limitations of PET in this clinical setting is

the relatively high false-positive rate related to variable physiologic uptake of

FDG in head and neck structures. Since Gutzeit and coworkers 2005 have

reported their initial experience using PET-CT for detection of unknown

primary tumors that included 18 patients with cervical nodal metastases. The

sensitivity of CT, PET, side-by-side PET and CT evaluation, and co-registered

PET-CT were 25%, 25%, 29% and 36%, with no statistically significant

difference among the modalities in this small patient population.

PET for Primary Tumor Staging

At the time the patient is referred for staging (imaging) studies, the

primary tumor has already been diagnosed, and a clinical head and neck

examination has assessed the status of lymph nodes in the neck. The first goal of

imaging studies is therefore to determine the extent of the primary tumor, in

65

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition particular with regard to structures whose involvement may alter the surgical

approach (eg, bone invasion, orbital invasion, skull base invasion, tumor

“tracking” along nerves and blood vessels). This can be done by either CT or

MRI, and PET has little to contribute in this regard. In the few studies that have

addressed the ability of PET and CT/MRI to actually visualize a clinically

proven primary tumor, PET generally had a higher sensitivity than other

imaging studies. This is related to the fact that smaller or submucosal

malignancies may be difficult to distinguish from adjacent tissues with anatomic

imaging studies alone. For instance, in a recent study from Australia involving

40 patients with head and neck squamus cell carcinoma (HNSCC) (mostly

tumors of the oral cavity), FDG-PET detected 35/40 primaries (88%), compared

with CT, which only detected 18 of the 35 primaries imaged (51%). Of the 17

primaries not detected by CT, 11 were clearly visualized by FDG-PET

(Hannah, et al 2002).

Nodal Staging

The majority of patients with head and neck cancer present with

locally and regionally advanced disease with metastatic spread to cervical lymph

nodes. Correct staging of the cervical lymph nodes is critical to determine the

necessary extent of surgery (type of neck dissection, unilateral versus bilateral)

and for precise delineation of the radiotherapy field. Although the usefulness of

18F-fluorodeoxyglucose (FDG)-PET imaging is currently well established for

recurrent head and neck cancers, its role in the initial staging of these tumors is

less certain. FDG-PET appears to be at least as sensitive or slightly more

sensitive than conventional imaging for the detection of nodal metastases in the

initial staging of head and neck cancers. Schöder and Yeung 2004 reported an

average sensitivity and specificity range of 87%- 90% and 80%- 93% for FDG-

PET compared with 61%- 97% and 21%- 100% for CT/MRI in detection of

66

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition nodal metastases, respectively. However, the impact on outcome of improved

accuracy of PET in pre-therapy staging of cervical nodes is not well established.

The anatomic information with PET is markedly improved with the

use of combined PET-CT systems. PET-CT is almost certainly more accurate

than PET alone, although few studies have yet been published comparing PET-

CT with other modalities. In a recent pilot study, Syed and coworkers 2005

used PET-CT to study 24 patients with head and neck cancer before their

treatment. PET-CT down staged the disease and changed the management in

17% of patients, compared with PET alone, by correctly assigning areas of

increased uptake to fat or muscle tissue. PET-CT also significantly improved the

confidence in anatomic localization and the inter-observer agreement in

assigning lesions to specific anatomical territories. PET-CT, MRI, and multi-

slice CT are all changing rapidly and improving. It is not clear which is

currently the most accurate, although the combination of metabolic imaging

with PET combined with high-resolution CT is likely to be the most powerful

technique (Fig 22).

Patients with head and neck cancer and a clinically negative neck (N0

neck) pose another management dilemma to the treating surgeon.

Approximately 25% to 30% of these patients are found to have metastatic neck

nodes at surgery. This finding means that the majority of patients with N0 necks,

who undergo a neck dissection, are unlikely to have a therapeutic effect from

this procedure. Several studies have evaluated FDG-PET in this setting,

attempting to identify the patients who need radical neck dissection. In 3 studies

totaling 48 patients, in which a sentinel node biopsy with immunohisto-

chemistry was used as gold standard, the detection rate of PET was between 0%

and 30%, making PET an unreliable modality in this clinical setting (Hyde, et al

2003 and Stoeckli, et al 2003 and Civantos, et al 2002). This is not

67

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition unexpected, given that 40% of cervical nodal metastases are less than 1 cm in

size and PET detection rate for nodes less than 1 cm is reported at 71%. kovacs

and coworkers 2004 in a recent report, have proposed to use FDG-PET to

identify patients who should undergo sentinel node biopsy versus elective node

dissection. Given the high specificity of PET in the pre-therapy setting, they

suggest patients with a positive PET scan undergo a neck dissection whereas a

sentinel node biopsy should be performed in patients with a negative PET scan.

In their population of 62 patients with head and neck cancer, this algorithm

spared unnecessary neck dissections on 12 neck sides with false-positive CT

findings and a negative sentinel node biopsy.

68


Fig 22: Right tonsillar squamous cell carcinoma. It often is uncertain whether a tonsillar carcinoma arises in the lingual tonsil or palatine tonsil. In reality, these carcinomas frequently arise in the anterior tonsillar fold, which is probably where this carcinoma arose. Tonsillar carcinoma is the most common type of cancer in the neck. These tumors frequently metastasize to ipsi-lateral IIA lymph nodes. PET-CT imaging is worthwhile when there is clinical or CT evidence of metastatic disease. In this setting PET-CT often reveals additional disease, even occasionally contra-lateral, which changes management considerably. Currently, is does not seem to be worthwhile to do PET-CT imaging if there is no evidence of metastatic disease (i.e., the N0 neck) because microscopic disease is frequently present and will not be detected by FDG-PET imaging.

69


Assessment of Distant Metastases and Synchronous Second

Primary Malignancies

Distant metastases are rare in patients with head and neck cancers, but

the frequency increases with higher T-stage and size and number of tumor-

involved lymph nodes. Patients with nodal metastases in the lower neck or

supraclavicular region have a higher chance for distant metastases, too. In

general, patients with HNSCC have a higher propensity for synchronous second

primaries as compared with many other malignancies (Anzai, et al 2003). For

instance, in a smaller series evaluating the role of FDG imaging in head and

neck cancer, Stokkel and coworkers 1999 found a synchronous second primary

in 12 of 68 patients in their series, although a technically inferior dual-head

gamma camera was used. Five of these second primaries were also detected by

clinical examination, chest radiograph or CT, so that the PET detection rate was

really 7/68, or 10%.

In a recent prospective study of patients with stage II-IV carcinoma of

the oral cavity, oropharynx and larynx, FDG-PET detected distant metastases or

synchronous second primary tumors in the aerodigestive tract in almost 30% of

cases (7 distant metastases and 3 synchronous second primary tumors)

(Schwartz, et al 2003). Based on the experience a second primary or distant

metastases outside the neck will be detected in 3-8% of cases, depending on the

stage and location of the primary tumor. Indeed, this was also reported in a large

retrospective analysis, unrelated to PET imaging, where the risk for synchronous

second primary tumors also approached 8% (Schwartz, et al 1994).

70


FDG-PET has good sensitivity and specificity for the detection of

primary tumors in the upper aero-digestive tract and a higher accuracy for nodal

staging of the neck than any other imaging modality. Distant metastases or

synchronous second primary tumors are occasionally detected; therefore, the

imaged field of view should extend from the skull base to the floor of the pelvis

(Schoder and Yeung, 2004).

Role of PET in Treatment Planning

Depending on the stage and location of the disease, treatment options

in head and neck cancer include surgery, radiation therapy alone, or radiation

therapy in combination with (concurrent) chemotherapy, possibly followed by

surgery. If surgery is the primary treatment modality, this may be followed by

radiation therapy, depending on the stage and aggressiveness of the primary

tumor, status of surgical margins etc. CT and MRI rely on structural changes

and are notoriously unreliable in this setting. Because of treatment related edema

and inflammation, which may cause alteration of normal tissue planes and

nonspecific enhancement after administration of intravenous contrast, these

studies frequently can not assess the presence of residual disease with sufficient

accuracy. Metabolic PET imaging contributes valuable information in this

setting. It allows for the early detection of local and regional disease whose

treatment will improve local disease control with the extrapolation that this will

also improve survival or at least quality of life (Schoder and Yeung, 2004).

A number of studies have shown that PET can monitor the response to

chemo- or radiation therapy in patients with head and neck cancer and may

differentiate responders from non-responders; metabolic changes during therapy

appear to correlate with tumor growth rate (Reisser, et al 1995 and Kitagawa,

et al 2003).

71


Brun and coworkers 2002 studied 47 patients with head and neck

cancer undergoing radical radiation- or combined chemo-radiation therapy.

Almost two thirds of these patients had stage IV disease. FDG-PET was

performed before and 1 to 3 weeks after the initiation of therapy (i.e., during the

course of treatment). PET data were analyzed using SUV and quantitative

measurements (metabolic rate of glucose, MRGl). Patients with complete

response had, on average, lower post-treatment SUV and MRGl than those

without complete response, but there was considerable overlap. Interestingly, the

pretreatment SUV was lower in patients who showed a complete response to

therapy (median 8.0 versus 12.0). Post-treatment SUV was not different between

responders and non-responders (median 4.4 versus 7.7), but quantitative

measurements showed lower glucose metabolism in responders as compared

with non-responders (MRGl median 14 versus 27 umol/min/ 100 g).

Goerres and coworkers 2004 studied 26 patients with stage III-IV

HNSCC, and PET was performed at 6 weeks after the end of combined chemo-

and radiation therapy (median dose 70 Gy). PET correctly detected residual

disease in 10 patients (38%) and correctly excluded residual disease in 14

patients; one patient each had a false-positive and false-negative study. Hence,

the sensitivity and specificity were 91% and 93%, with an accuracy of 92% for

the detection of residual disease, metastases or second primaries. Interestingly,

in 2 patients the 6-week PET also revealed a second primary tumor or distant

metastases, which had not been detected at the time of initial staging.

In patients with locally advanced disease, chemotherapy or combined

chemo- and radiation therapy are also used in the neoadjuvant setting. PET

contributes valuable information in this setting. For instance, FDG-PET

appeared to distinguish accurately between responders and non-responders to

72

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition neoadjuvant chemotherapy in an organ-conservation protocol. All 27 patients

enrolled had tissue biopsies taken before and after therapy. At the end of

treatment 21 patients were found to be responders and 6 to be non-responders.

Using visual analysis and SUV, the study had a sensitivity of 90% and

specificity of 83% (Lowe, et al 1997).

In another study in 15 patients undergoing neoadjuvant chemo-

radiation therapy, lesions with higher pretreatment SUV (>7) showed residual

viable tumor cells after treatment in 3 of 8 cases, whereas all lesions with SUV

<7 were treated successfully (Kitagawa, et al 1999). All 7 tumors with post-

treatment SUV of <4 showed no viable cells on resection, whereas 3/7 tumors

with post-treatment SUV >4 did show residual viable tumor cells. In another

study in 23 patients the same authors separately analyzed the accuracy of

various imaging modalities for the assessment of residual disease after

neoadjuvant chemo-radiation therapy (Kitagawa, et al 2003). FDG-PET was

more accurate than MRI or CT in detecting residual disease (specificity 89%

versus 41%, 59%) in the primary tumor following treatment, although no such

difference was noted for nodal metastases.

Greven and coworkers 1994 have repeatedly investigated the role of

FDG-PET in the assessment of response to radiation therapy. The authors

concluded that imaging at 4 months after radiation therapy was more accurate

than at 1 month. However, it needs to be emphasized that no imaging studies

were acquired between 1 and 4 months. In our own experience a time interval of

6 to 8 weeks after treatment is usually sufficient to avoid most false positive and

false negative findings (Schoder and Yeung, 2004).

FDG-PET has the ability to detect patients with more aggressive

disease before therapy and to differentiate between responders and non-

73

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition responders to (chemo-) radiation therapy. However, most studies suffer from

limitations related to small sample size and the methods of data analysis (data

dichotomized based on median SUV in study population, use of arbitrary cut-off

values etc.). In addition, quantitative measurements of FDG utilization, as used

in some of these studies, are not practical in a clinical routine setting. Larger,

prospective studies in a well-defined setting are needed to determine the clinical

value of PET in these patients conclusively.

It is now clearly established that FDG-PET has a high sensitivity and

specificity for the detection of recurrent disease in patients with head and neck

cancer, regardless of the primary treatment modality used (surgery versus

radiation therapy) (Wong, et al 2002 and Kunkel, et al 2003). A patient

example is shown in (Fig 23). As a rule, clinically detectable recurrent disease is

extremely unlikely in the setting of an entirely negative PET scan. FDG uptake,

not related to tumor, can sometimes cause false positive (non tumor-related FDG

uptake considered to represent tumor; see (Fig 24) or false negative (tumor-

related FDG uptake misinterpreted as normal variant, inflammation)

interpretations. With adequate patient preparation, certain sources of non tumor-

related FDG uptake can be eliminated or at least correctly identified (e.g.,

laryngeal muscle uptake, radioactive saliva in the throat or vallecula epiglottica,

nonspecific FDG uptake in brown fat tissue of the neck) but others cannot

(treatment-related inflammation). Nevertheless, some false positive findings

may be unavoidable. Accordingly, the sensitivity for the detection of recurrent

head and neck cancer is consistently high, but specificity in the treated post-

surgical area is lower than elsewhere in the neck or at remote sites, such as lung

or bone. Across all studies the negative predictive value is consistently high.

Therefore, one can conclude that patients with suspected recurrence but negative

PET scan do not require any further evaluation. In contrast, positive predictive

value and specificity are somewhat lower for local recurrence at or near the site

74

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition of the primary tumor, related to a number of false-positive findings.

Nevertheless, if used in a clinical algorithm, a positive PET scan requires a

biopsy; if this biopsy is negative for recurrent cancer and does not provide

reasons for a false-positive PET scan (inflammation, infection, radiation

necrosis etc.), close clinical follow-up and potential repeat biopsy may be

required. If the biopsy is negative, a follow-up PET scan is suggested 2 to 3

months later. If the SUV decreases, malignancy is unlikely and no further

intervention is needed. If the SUV is unchanged or increases, repeat biopsy is

suggested, unless there is another obvious explanation, such as infection, fistula

or radio-necrosis (Kunkel, et al 2003).

The first year of follow up notably, 5/16 recurrences were detected by

PET only, while the other recurrences were also identified by CT/MR or clinical

examination. Early detection of recurrent disease is likely to improve the success

rate for any secondary therapy, but it is nevertheless difficult to justify such a

surveillance strategy without further supporting data. Moreover, PET studies for

the sole purpose of surveillance are currently not reimbursed (Wong and

Saunders, 2002).

75


Fig 23: recurrent disease in a 72-year-old male status post-esophagectomy with gastric pull-up, now presenting with dysphagia and hoarseness. Coronal (A) and Sagittal (B) positron emission tomography images show abnormal fluoro-deoxy-glucose (FDG) uptake in the anterior–superior mediastinum, consistent with malignancy with central necrosis. Additional coronal image (C), in a more anterior position and trans-axial image (D) show FDG uptake in the left hemilarynx. This represents normal tracer uptake in the left vocal cord; the abnormal finding in this study is the lack of FDG uptake in the right hemilarynx due to paralysis of the right recurrent laryngeal nerve, caused by the mediastinal mass (computed tomography image, E).

Fig 24: False-positive study of a 65-year-old male, status post chemo- and radiation therapy, for carcinoma at the base of tongue, now presenting with pain and trismus. Positron emission tomography images show abnormal fluoro-deoxy-glucose uptake in the left mandible (A, coronal; B, Sagittal; C, trans-axial). Physical examination revealed exposed, necrotic appearing bone of the mandible. Debridement and curettage were performed; the specimen showed acute and chronic osteomyelitis.

76


Radiotherapy Planning

PET-CT with FDG is highly accurate in pre-radiotherapy staging of

head and neck cancer, with a reported sensitivity of 96% and specificity of

98.5% in nodal level staging (Schwartz, et al 2005). FDG uptake in tumors is

also a prognostic indicator, with tumors with high FDG uptake reported to have

a high recurrence rate and poor prognosis (Allal, 2004). These tumors may

therefore require multimodality treatment and may benefit from high-dose

radiation such as obtained with intensity-modulated radiotherapy (IMRT). FDG-

PET data can be used in radiation treatment planning by importing the PET data

into the treatment planning computer and co-registering with the treatment

planning CT scan. For precise co-registration, the same immobilization head

mask should be used for the planning CT and the PET or PET-CT scan (Fig 25).

In a pilot study by Ciernik and coworkers 2003 the co registration of PET-CT

with the planning CT images was highly successful with average deviations of

1.2 +/- 0.8 mm in the x axis, 1.5 +/- 1.2 mm in the y axis and 2.1 +/- 1.1 mm in

the z axis. In the clinical setting, Paulino and coworkers 2005 have been able

to consistently obtain a co registration error of less than 5 mm. The target

volumes (gross tumor volume [GTV]) may be significantly modified when

FDG-PET data are incorporated into radiation treatment planning. The target

volume may be increased because metabolically active tumor can be detected in

normal sized nodes. On the other hand, the PET-based GTV is smaller than CT-

based GTV in some patients, because the tumor may be partially necrotic. The

radiation dose and volume are modified dramatically, from a curative intent to

palliation, if distant metastases are detected on the PET scan. The results of

several studies on the use of PET in radiation treatment planning are

summarized in (Table 4).

.

77


A recent study of 20 patients with mostly locally advanced disease

demonstrated an increase in sensitivity with hybrid PET/CT compared with CT

alone (Schwartz et al, 2005). The authors showed that PET/CT-based radiation

treatment would have significantly changed the dose distribution. These findings

need to be confirmed prospectively with larger study populations before this

technique can be implemented in routine use.

A number of other studies have compared radiotherapy volumes based

on PET-CT vs. CT alone. These studies showed both an increase and a decrease

in GTV planned using PET-CT over CT alone (van Baardwijk et al, 2006).

In head and neck cancers, the functional data of the hybrid PET-CT

may augment the delivering of radiotherapy. Undoubtedly, the greatest

advantage of PET in radiation planning will be in the definition of tumor-

bearing tissues. Dwight et al, 2004 demonstrated that PET and CT volumes

were different, which resulted in inclusion of additional tumor-bearing areas to

the planning target volume. Instead of resulting in the expansion of the PTV, the

additional PET information would actually result in a smaller PTV by improving

location of the CTV. Furthermore, the PET data are unlikely to change the initial

PTV, but, as occurred in our experience, may influence the size and

configuration of boost PTV by identifying suspicious areas for inclusion (Fig

26).

Some authors also have demonstrated fused FDG-PET with CT and

MRI can be useful in determining radiation target volumes for 3-D conformal

radiation therapy (Fig 27) for head and neck (Nowak et al, 1999 and Lenz et

al, 2000). These data suggests that PET can be used effectively to select targets

for treatment without compromising local control in FDG-negative areas.

78

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition Prospective studies are needed to define whether contours for treatment volumes

can be based on PET-CT imaging. This application may offer real opportunities

for dose escalation schemas and treatment algorithms aimed at improving loco-

regional control in advanced cases. Other authors who compared PET with the

current diagnostic methods had similar observations (Hannah et al 2002, and

Goerres et al, 2003).

Fig 25: Hybrid positron emission tomography-computed tomography (PET-CT) simulation setup. PET-CT table is modified by the addition of a radiation-planning couch planchet. Note head holder secured to planchet. Patient in treatment-planning position in hybrid scanner (inset).

79


Table 4: FDG-PET in Radiation Therapy Planning

AUTHER YEAR Number

of Patients

PET or PET/CT

for PET

imaging

Change in GTV With PET Comments

Nishioka et al 2002 21 PET increased in 1/21;

decreased in 1/21

Sparing of the parotid in 71% of pts with negative PET

Ciernik et al

2003 12 PET/CT increased in 2/12; decreased in 4/12

Heron et al

2004 21 PET/CT In primary tumor increased in 3/21, Decreased in 14/21. In nodal stations increased in 7/21 and decreased in 3/21

Primary only positive with PET in 3/21; distantmetastases detected with PET in 3/21.

Scarfone et al

2004 6 PET Increased in 5/6

Paulino et al

2005 40 PET/CT Decreased in 30/40 and increased in 7/40

PET/CT based GTV not included in the high dose IMRT area in 25% patients with CT-only based GTV.

Schwartz et al 2005 20 PET

Not reported for individual patients; mean PET/CT based GTV not significantly different from CT only based GTV.

Mean contralateral parotid and laryngeal cartilage dose significantly smaller with PET/CT based GTV.

80


Fig 26: Squamous cell carcinoma involving the right lateral oral tongue. The 3 orthogonal views clearly show the focus of increased uptake is in the lateral tongue. This lesion is a T1 tumor (< 2 cm).

81


Fig 27: A right posterior nasopharyngeal squamous cell carcinoma. The nasopharynx is the upper part of the pharynx, above the soft palate. Early stage nasopharyngeal cancer, such as the one shown, usually is treated with radiotherapy. PET-CT imaging is used to identify any metastases and to define extent of disease to guide radiotherapy treatment planning.

82


2- Thyroid Carcinomas

After thyroidectomy, FDG-PET has proven useful in patients with

clinical or serological evidence of recurrent or metastatic thyroid carcinoma but

negative whole body iodine scan. PET shows metastatic disease in up to 90% of

these patients, thereby providing a rational basis for further studies and therapy.

In patients with medullary thyroid cancer with elevated calcitonin levels

following thyroidectomy, FDG-PET has a sensitivity of 70-75% for localizing

metastatic disease. Occasionally incidental intense FDG uptake is observed in

the thyroid gland on whole body PET studies performed for other indications.

Although diffuse FDG uptake usually indicates thyroiditis, focal uptake has

been related to thyroid cancer in 25- 50% of cases and should therefore be

evaluated further if a proven malignancy would cause a change in patient

management (Schoder and Yeung, 2004).

• Differentiated Thyroid Cancer (DTC)

Early studies found a low sensitivity of FDG-PET in the detection of

metastases (Joensuu et al, 1988). However, others reported a sensitivity of 50%

in 58 unselected patients with DTC, thyroidectomy and prior radioactive iodine

(RAI) ablation, (Dietlein et al, 1997) and in a large multi-center study with un-

selected patients, the sensitivity of FDG-PET for localizing metastatic disease in

patients with DTC was 75 % (Grunwald et al, 1999).

Helal and coworkers 2001 prospectively looked at 37 patients with

DTC who had undergone resection, RAI ablation and presented with elevated

thyroglobulin levels but negative whole body scan (WBS). FDG-PET scan was

83

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition positive in 28 patients (76%); including 19 of 27 patients with no previously

detected metastases by conventional imaging. In a prospective study of 24

patients with DTC, negative WBS and elevated thyroglobulin levels, Frillings

and coworkers 2001 reported a sensitivity of 94.6% in the detection of

metastases, with specificity of 25%. PET results changed surgical tactics in 9/24

patients.

Schluter et al 2001 studied 118 PET scans in 64 thyroid cancer

patients with elevated serum thyroglobulin (n= 48) or clinical suspicion of

metastases (n = 16) and negative WBS. The positive predictive value of FDG-

PET scan was 83% (34/41) whereas the negative predictive value was 25%

(5/20). Treatment was directly changed in 19/24 patients with true positive PET

studies (30% of the entire cohort). They also pointed out that true positive FDG-

PET findings were correlated positively with increasing serum thyroglobulin

levels.

In addition to lesion detectability, there is also evidence that FDG-PET

is an independent prognostic indicator in thyroid cancer. In a study by Wang

and coworkers 2000, which included 125 patients with negative WBS, positive

FDG-PET, elevated thyroglobulin with a clinical follow-up of up to 41 months,

multivariate analysis demonstrated that the single strongest predictor of survival

was the volume of FDG-avid disease. More recently the same group showed

strong inverse correlation between the SUV for FDG uptake in metastatic

lesions and survival in thyroid cancer patients.

• Hurthle Cell Carcinoma

Hurthle cell cancer is a histologic subtype of DTC that is clinically

more aggressive. The tumor frequently shows little or no iodine uptake, but can

84

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition be identified with FDG-PET: a meta-analysis of two studies and 35 patients

showed a sensitivity of 92% and specificity of 82% (Plotkin et al, 2002). A

sensitivity of 92% (12/13 patients) was also reported in another recent study

(Lowe, et al 2003). More importantly, in 7 of these 13 patients PET showed

disease not identified by other imaging methods.

• Anaplastic Thyroid Cancer

This is an extremely aggressive tumor and imaging is not required for

staging, since all patients are classified as stage IV at diagnosis. As a result

FDG-PET scan in anaplastic thyroid cancer has not been studied systemically.

However, in some case reports (Joensuu et al, 1988) this malignancy usually

shows intense FDG uptake, and in selected cases FDG-PET may be helpful in

directing treatment and evaluating the efficacy of therapy (Fig 28).

• Medullary Thyroid Cancer

Medullary thyroid cancer is a rare calcitonin secreting tumor

originating from the para-follicular C cells. The primary treatment modality is

surgical resection. A PET study may be requested in patients with high serum

calcitonin level after surgery. The number of patients studied for this purpose is

limited, but it appears that FDG-PET can identify metastatic disease more

frequently than other imaging studies. A study of 20 patients reported a

sensitivity of 76 %,( Brandt-Mainz et al, 2000) and in a large multi-center

study the sensitivity of 78% among 55 patients in whom histologic confirmation

was obtained (Diehl et al, 2001). Interestingly, there was no correlation between

the calcitonin level and the probability of lesion detection. Indeed it has been

suggested that more undifferentiated cancer, which secretes less calcitonin, may

show higher FDG uptake, analogous to the situation in DTC. Novel, more

85

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition specific PET tracers, such as 6-18F-fluorodopamine or 18F-DOPA may be more

appropriate for the detection of recurrent or metastatic medullary thyroid cancer.

Fig 28: Anaplastic thyroid carcinoma. This 52-year-old male patient had local tumor recurrence after a complete thyroidectomy for anaplastic thyroid cancer. Positron emission tomography for staging of recurrent disease (A). showed intense fluorodeoxyglucose uptake in the right thyroid bed and a right supraclavicular lymph node. He was treated with external beam radiation and chemotherapy with good response, both clinically and on follow-up positron emission tomography (B). Three years later he was still alive and disease free.

86


6- PET/CT&

Breast cancer and female

genital system

87


1-Breast cancer

Breast cancer is the most common non-skin cancer and the second

leading cause of cancer death in women (Greenlee et al, 2000). The ability to

define the extent of disease, to monitor response, and to predict tumor behavior

in patients with breast cancer are therefore important public health problems

where positron emission tomography (PET) imaging may play a significant role

(Hortobagyi, 2000).

Weaker correlation has been reported with micro-vessel density, a

surrogate of angiogenesis and tumor cell density (Avril et al, 2001). Established

breast cancer prognostic factors that generally do not correlate with primary

tumor FDG uptake are steroid receptor status, axillary node status, and tumor

size (Crippa et al, 1998).

Detection of primary breast cancer

FDG-PET has been evaluated for diagnosis, staging, restaging and

monitoring therapy response in patients with breast cancer. Although the current

data suggest that FDG-PET may have limited diagnostic utility in the detection

of small primary tumors, in staging the axilla ,and in detecting blastic osseous

metastatic lesions ,but PET has superiority over conventional imaging in

detecting distant metastasis and recurrent disease and in monitoring therapy

response. FDG localization is significantly higher in ductal carcinoma than in

lobular (median SUV 5.6 for infiltrating ductal carcinoma vs. 3.8 for lobular

carcinomas). Breast density and hormonal status affect the FGD uptake in breast

tissue .dense breasts demonstrate higher FDG uptake than non dense breasts

88

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition however the highest SUV observed in dense breasts is relatively low at about 1.4

(Bos et al, 2002).

PET is also useful in the evaluation of patients with augmented breasts

in whom the other traditional diagnostic imaging techniques may be

inconclusive. For the diagnosis of breast cancer, lesion detectability appears

more with delayed scan time of 3 hours more than the usual time of 1-1.5 hours

(93% vs. 83% respectively) after intravenous injection of FDG.

Many studies have shown that the level of FDG uptake in primary

breast tumors carries clinical and biological information (Buck et al, 2002 and

Mankoff et al, 2002). The reason for variable FDG uptake among primary

breast tumors is unknown. FDG uptake reflects the culmination of complex and

incompletely understood biologic characteristics that affect glycolysis in a

specific tumor. Most studies suggest that higher FDG uptake is correlated with

more clinically aggressive behavior. This information may help to non-

invasively (1) stratify patients according to risk for recurrence or treatment

failure and (2) target the aggressiveness of therapy for an individual patient to

the aggressiveness of her tumor (Bos et al, 2002).

Most of the large prospective studies using FDG-PET on patients with

unconfirmed, suspicious breast abnormalities by clinical or mammographic

examinations have shown some of the limitations of FDG-PET in detecting

(1) Smaller (<1 cm) tumors,

(2) More well-differentiated histologic grade and

(3) Tumor histologic subtypes (tubular carcinoma, insitu carcinoma and lobular

carcinoma).

89


Avril et al, 2000, found that the sensitivity for detecting tumors less

than 1 cm using sensitive imaging reading criteria (sensitive image reading

(SIR) was achieved by including probable (grade 2) and definite (grade 3)

malignant lesions.)(PET scans with regional FDG uptake within the background

activity of normal breast tissue were considered grade 1 (unlikely), PET scans

with diffuse or moderate focally increased FDG uptake were considered grade 2

(probable), and cases with focally marked increased FDG uptake were

considered grade 3 (definite) to represent malignant tissue) was 57% (13/22),

compared with 91% (155/170) for tumors larger than 1 cm. The sensitivity for

detecting carcinoma in situ was even lower at 25% (3/12), and there was a

significantly higher false-negative rate with infiltrating lobular carcinoma (65%

[15/23]) than infiltrating duct carcinoma (24% [23/97]). The specificity of FDG-

PET in differentiating benign from malignant lesions was near 90% in most of

these studies with inflammatory conditions accounting for most of the false

positive results. Using SUV (STANDERIZED UPTAKE VALUES) threshold

values of 2.0 to 2.5) discrimination of benign from malignant lesions can be

obtained with about 90% accuracy (Avril et al, 1996 and Hoh et al, 1993). A

larger percentage of invasive lobular carcinomas are not detected (65% in one

study), possibly due to low tumor cell density, its infiltrative nature, and low

metabolic activity (Vranjesevic et al, 2002).

In general, correlative studies have suggested that FDG-PET provides

information on tumor behavior that is fairly independent of established breast

cancer markers and prognostic factors and may therefore contribute additional

information that can be used to infer tumor behavior and help tailor therapy

(Eubank and Mankoff, 2004).

Additional insights into tumor biology brought on by the development

of newer PET tracers such as 11C-thymidine (marker for cellular proliferation)

90

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition and 18F-fluoromisonidazole (marker for tumor hypoxia) will further refine in

vivo characterization of individual tumors (Mankoff et al, 2000).

Fig 29: left breast cancer the right photo is FDG-PET image which show intense accumulation of FDG, while the left image is a correlated CT to the same area.

91


Fig: 30 a multi-focal left breast cancer, the upper image show the CT slides of the lesions, but FDG-PET confirms the nature of these lesions.

92


Fig 31: IDC in the breast due to better lesion localization. On PET alone, the intense focus of FDG uptake in the right anterior lateral portion of the thorax (black arrow) was difficult to differentiate from axillary lesions, which were observed in the same slice. The FDG uptake was confirmed to be a breast lesion with the help of the CT mapping image (white arrow on CT and fusion images).

Fig 32: in the chest wall due to better lesion characterization. The focus of moderate FDG uptake in the left anterior medial portion of the thorax (black arrow) was considered as equivocal on PET alone. The anatomical and morphological information provided by CT (white arrow on CT and fusion images) allowed characterization of the FDG uptake as a malignant lesion in the chest wall.

93


Axillary Node Staging

FDG PET has limited sensitivity in staging the axilla in patient with

early breast cancer ,with false-negative rate that ,ay reach 20%.a recent

prospective multi-centre study of axillary nodal staging with FDG PET

demonstrated mean sensitivity, specificity, positive and negative predictive

values of 61%,80%,62% and 79%,respectively. FGD PET appears to be a

specific method for staging the axilla such that sentinel lymph node biopsy may

be avoided in patients with positive axilla on the PET study. The overall

sensitivity and specificity for detection of the axillary metastasis on FDG PET

does not appear to be related to the SUV of the primary carcinoma. The

differences among studies in the reported diagnostic performances of PET in

relation to axillary nodal staging are likely because of several factors, including

differences in tumor type, the prevalence of disease in the study population, the

imaging methodology, and the image interpretation criteria. however detection

of micro-metastases and small tumor infiltrated lymph nodes is limited to the

spatial resolution of the current PET imaging systems The larger series using

FDG-PET for axillary staging in breast cancer patients showed sensitivity in

57% to 100% and specificity in 66 to 100% ranges, (Wahl et al, 2004) shown in

Table (5) emphasize the trade-off between sensitivity and specificity in the

interpretation of FDG-PET findings.

Lovrics et al, 2004 and Wahl et al, 2004 FDG-PET consistently

underestimated the number of tumor-involved nodes compared with pathologic

evaluation from conventional axillary dissection. Both of these studies showed

that the sensitivity of FDG-PET in detecting axillary metastases is significantly

less when only one node is positive versus several positive nodes and when the

primary tumor has infiltrating lobular versus ductal histology.

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Table 5: Large Prospective Series Comparing Axillary Nodal Staging

Using FDG-PET with Pathologic Results of Axillary Lymph Node

Dissection in Patients with Breast Cancer

Number of Patients

Sensitivity Specificity Series

52 95 (19/20) 66 (21/32) Adler, 1997

122 100 (44/44) 75 (60/80) Utech, 1996

51 79 (19/24) 96 (26/27) Avril overall, 1996 18

23

33 (2/6)

94 (17/18)

100 (12/12)

100 (5/5)

T1 tumors >T1 tumors

72 85 (23/27) 91 (41/45) Crippa, 1998

50 90 (19/21) 97 (28/29) Smith, 1998

167 94 (68/72) 86 (82/95) Greco, 2001

113 79 (27/34) 92 (73/79) Schirrmeister, 2001

308 61 80 Wahl, 2004

90 40 97 Lovrics, 2004

Recent studies comparing preoperative FDG-PET with pathologic

results from sentinel L.N. (SLN) biopsy in patients with early-stage breast

cancer show sensitivity in range of 20% to 50% (Table 6) with false-negative

FDG-PET results occurring predominantly in small-sized (10 mm or less)

metastatic sentinel nodes (Barranger et al, 2003).

95


Table 6: Large Series Comparing Axillary Nodal Staging Using FDG-

PET with Pathologic Results of Sentinel Node Lymph Node Biopsy in

Breast Cancer

N Sensitivity Specificity Series

18 50% 100% Yang, 2001

15 20% 90% Kelemen, 2002

31 43% 94% Guller, 2002

70 25% 97% Van der Hoeven, 2002

24 20% 93% Fehr, 2004

72 27% 96% Lovrics, 2004

Although recent data do not support the routine use of FDG-PET for

axillary staging of early breast cancer, FDG-PET may be complementary to

SLN mapping and other standard axillary procedures in patients with more

advanced tumors and/or equivocally palpable axillary nodes (Schirrmeister et

al, 2001).

96


Detection of Loco regional recurrences and Distant

Metastases

FDG-PET can contribute in significant ways to the clinical

management of patients with suspected locoregional or distant recurrences.

Because it provides functional information, FDG-PET often is complementary

to conventional staging methods such as physical examination, cross-sectional

imaging (CT or MR) and bone scintigraphy, which rely more on changes in

morphology to detect disease recurrence. This is particularly true in the

evaluation of anatomic regions that have been previously treated by surgery or

radiation where the discrimination between post-treatment scar and recurrent

tumor can be problematic. Because of its high sensitivity in the detection of

metabolically active tissue, FDG-PET can help define the extent of disease when

conventional imaging (CI) is equivocal or negative and recurrence is suspected.

Earlier recognition of recurrent disease will hopefully provide more effective

treatment options and improve survival in this group of patients (Fig. 34)

(Eubank et al, 1998).

Lymphatic spread of tumor to the internal mammary (IM) nodes

occurs in up to 25% of patients at the time of initial diagnosis and possibly more

commonly in recurrent cancer. Metastases to IM and axillary nodes are usually

synchronous and prognosis is significantly worse when IM nodes are involved

(Cody et al, 1995). However, IM nodes are not routinely sampled or evaluated

in any systematic fashion in current practice because (1) compared with axillary

nodes, they are not as accessible and (2) in older studies, radiotherapy of IM

nodal disease failed to show improvements in survival and remains controversial

in current practice (Sugg et al, 2000). FDG uptake in the IM nodal chain has

97

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition been anecdotally reported in some of the studies that have focused on detection

of primary tumor or axillary staging. In one study of 85 patients who underwent

FDG-PET before axillary node dissection, (14%) had uptake in the IM region

but there was no histologic confirmation of these nodes (Bellon et al, 2004).

Experience with imaging patients with LABC shows that the prevalence of IM

FDG uptake can be as high as 25% and that the presence of IM FDG uptake

predicts treatment failure patterns of disease consistent with IM nodal

involvement and progression (Fig.33).

Fig 33: IDC in the internal mammary node due to better lesion localization. Positive PET/CT and equivocal CT findings. The smaller focus of intense FDG uptake in the right anterior medial portion of the thorax (black arrow) was difficult to definitely localize on PET alone. CT and fused PET/CT images confirmed that the FDG uptake was localized in the small internal mammary lymph node (white arrow on CT and fusion images), which was diagnosed as equivocal on CT owing to its small size of less than 1 cm

98


Fig 34: The patient shown in the case below had a history of breast cancer and had developed left chest pain. She presented for the evaluation of possible metastatic disease. The CT scan revealed extensive soft tissue thickening in the left breast which was felt possibly related to scar from prior surgery and radiation therapy. There was a 2 cm lymph node in the left axilla (not shown) which was concerning for metastatic disease. Axial (center) and coronal (right) images from the patients FDG PET exam demonstrated marked increased FDG accumulation within the left breast corresponding to the soft tissue abnormality on CT. There were also multiple foci of increased uptake within the left axilla. Biopsy revealed recurrent breast cancer.

The skeleton is the most common site of distant metastasis in breast

cancer. Bone scintigraphy is considered the most sensitive method of detecting

and determining the extent of skeletal metastases. However, purely lytic lesions

or metastases confined to the marrow cavity may be difficult to detect on bone

scan because of a lack of sufficient osteoblastic response (Nielsen et al, 1991).

In a study of 23 breast cancer patients with known skeletal metastases

who underwent both bone scintigraphy and FDG-PET, Cook and coworkers,

1998 showed that FDG-PET detected more lesions than bone scintigraphy

99

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition except in a subgroup of patients with osteoblastic metastases. Moreover, the

level of FDG uptake in lytic lesions was significantly greater compared with

osteoblastic lesions and the prognosis of patients with lytic-predominant disease

was significantly worse. These data clearly show a complementary nature of

bone scintigraphy and FDG PET in the evaluation of skeletal metastases in

breast cancer patients (Fig 35, 36).

Fig 35: IDC in the rib due to better lesion characterization. The focus of intense FDG uptake in the right lateral portion of the thorax (black arrow) was difficult to characterize as axillary, rib, or other lesions on PET alone. CT and fused PET/CT images confirmed this FDG focus to be due to a metastatic rib lesion (white arrow on CT and fusion images)

100


Fig 36: IDC in the bone due to better lesion localization. The focus of intense FDG uptake located slightly right of the midline (black arrow) was misdiagnosed as a focus of excretory radioactivity on PET alone because of the presence of similar FDG foci in the right kidney. CT and fused PET/CT images clarified this FDG focus to be a metastatic bone lesion (white arrow on CT and fusion images)

In a prospective study of 50 women undergoing staging studies for

suspected recurrent breast cancer, FDG-PET had a significant impact on

defining the extent of disease by changing the clinical stage in 36% of patients

and on management by inducing changes in therapy in 58% of the patients.

In retrospective study of 125 patients with advanced breast cancer

undergoing conventional imaging and FDG-PET for staging, the extent of

disease was changed in 67% (increased in 43% and decreased in 24%) of

patients and the therapeutic plan was altered in 32% of patients based on FDG-

PET findings. Among different referral categories, FDG-PET altered therapy

most frequently in patients suspected of locoregional recurrence, under

consideration for aggressive local therapy (44%) and patients with known

101

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition metastases being evaluated for response to therapy (33%) (Fig. 37)

(Eubank et al, 2004).

The need for a more sensitive staging tool in patients with first-episode

locoregional recurrence was recently corroborated by van Oost and coworkers,

2004 their study of 175 patients showed that 16% had distant metastases at the

time of locoregional recurrence and 24% developed distant metastases within 18

months of confirmation of recurrence. They estimated that FDG-PET would

upstage and likely change the therapeutic plan, in up to 29% of patients with

negative conventional staging studies.

102


Fig 37: Patient treated for breast cancer with recurrence in the left mammary region (arrow in the PET/CT fused image)

103


PET/CT and radiotherapy

Other than the localization per se, the pixel by pixel correspondence of

PET and CT may significantly modify our evaluation of tumor extension. So far,

the role of PET in oncology has mainly been to assess lymph node (N) and

distant metastases (M), rather than to determine tumor extension and its

relationship with surrounding tissues (T). PET/CT is changing this role by

integrating the information on tumor morphology provided by CT with that on

its metabolism and, particularly, on the number of neoplastic viable cells

(Ciernik et al, 2003).

During the follow-up of breast cancer, as already reported, the

frequency of recurrence or metastatic lesions is high, particularly for large

primary tumors (>2 cm) or a tumor stage of >N1. One possible treatment when

recurrent/metastatic lesions are limited in number and extension is high-dose

radiotherapy, such as stereo-tactic radiotherapy or radio-surgery. We believe

that PET/CT can play a major role in these cases by (a) correctly staging the

disease and (b) providing an accurate estimate of tumor volumes to be

selectively irradiated, characterized for their biological activity (biological target

volume). Although PET with co-registered CT via software algorithms can

provide similar information on biological target volume, the availability of a

dual PET/CT tomography certainly facilitates such application, and will thus

hopefully improve the therapeutic effects of radiotherapy procedures

(Dizendorf, 2003).

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2-Uterine cancers

Although FDG PET may significantly improve the management of

patients with gynecological cancers, inherent technical and biological limitations

have been shown to impair both the sensitivity and specificity of metabolic

imaging. Causes of inaccuracies with FDG PET in uterine cancers are

summarized in (Table 7) (Nakamoto et al, 2002).

Table 7: Causes of Inaccuracies with FDG PET in Uterine Cancers:

Literature Data

Causes of False Positive Results Causes of False Negative Results

- Ureteral stasis

- Bowel retention

- Post-radiation changes

- Post-surgery changes

- Recent traumas

- Inflammation / Infection: reactive nodes,

granulation tissue, anthracosis,

endometriosis, tuberculosis

- Functional ovarian cysts.

- Ovulatory and menstruating phases.

-Small (< 1cm) or microscopic

disease: cervix, nodes.

- Stromal invasion

- Parametrial involvement

- Indolent malignant disease

- Previous radiotherapy

- Low glucose transporter-1

(GLUT-1) expression

- Lack of anatomic landmarks

In cervical and endometrial cancers, initial results highlighted the

incremental clinical value of anato-metabolic imaging, especially in terms of

diagnostic accuracy. Pilot studies also suggest the potential expected from FDG

105

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition PET plus CT in treatment planning and survival prediction (Sugawara et al,

1999).

A. PET/CT software image fusion

1. Diagnosis

A recent study assessed the added-value of side-by-side interpretation

of FDG-PET and CT/MRI in gynecological cancers. Their analysis was focused

on the imaging discrepancies, which were correlated to pathology results in 32

patients (22 cervical cancers, 7 ovarian cancer, 2 endometrial cancers, and 1

leiomyosarcoma). Among the 24 women with uterine cancers, the software

fusion contribution was found significant for localization of biopsy sites (12

patients), treatment planning (5 patients), accurate diagnosis (9 patients: change

of FDG PET results in 5 and MRI/CT results in 4), differentiation between

pathological and physiological uptake (11 patients). As a conclusion, the authors

showed the clinical benefit derived from software image fusion in gynecological

cancers based on amore confident and more precise interpretation of FDG-PET

findings and MRI/CT results as well (Tsai et al, 2003).

2. Treatment planning and patients’ outcomes

The aspect of intensity modulated irradiation therapy (IMRT) and

treatment planning is most evident in patients with cervical cancer with positive

para-aortic lymph nodes (Fig. 38). Fused PET/CT images can be imported into

current radiation therapy treatment planning systems. Increased doses to positive

lymph nodes can be administered while decreasing the doses to normal tissue

(Belhocine and Grigsby, 2005).

106


An interesting area of development has been the use of FDG PET as a

guide to the evaluation and planning of intra-cavitary brachy-therapy for patients

with cervical cancer. Mutic et al, 2001 have developed a process whereby the

brachy-therapy irradiation applicators can be visualized within the metabolic

tumor volume isodose distributions can then be generated to demonstrate the

irradiation dose distributions to the metabolic tumor volumes. This process has

great potential to increase the irradiation dose to the primary cervical tumor

while decreasing the dose to normal structures.

In another pilot study, the metabolic volume as determined by FDG

PET and CT software image fusion allowed to selecting the patients who may

best benefit from radiation therapy; these patients had a tumor volume < 60cm3

and no lymph node disease. Alternatively, patients with other combinations

suggestive of poor prognosis (tumor volume >60cm3 and/or nodal involvement)

may be treated by more aggressive therapies (Miller and Grigsby, 2002).

B. Hardware PET/CT image fusion

With the advent of combined PET/CT devices, a single multimodality

imaging is nowadays feasible in clinical routine. In gynecological cancers, this

allows to avoiding many artifacts due to internal organs motion (i.e. abdominal

peristalsis, urine stasis) and patients' repositioning between PET and MRI/CT

(Wahl, 2004). In a reference study including 285 consecutive female patients,

Lerman et al, 2004 also showed the usefulness of PET/CT for differentiating

normal from abnormal FDG uptakes within the gynecological sphere; otherwise,

benign and physiological endometrial and ovarian patterns may have been

falsely interpreted as tumor uptake by using FDG PET alone. Hence, FDG PET

may benefit from the anatomic details provided by a concomitant CT; a "one-

stop-shop" imaging aimed at increasing the diagnostic accuracy of both

107

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition techniques, especially in treatment planning. Additionally, whole-body PET/CT

may reduce the number, and then the cost and irradiation, of separated CT and

PET studies.

Fig. 38: Treatment planning in a patient with FDG-avid para-aortic involvement. Fused PET-CT images can be imported into current radiation therapy treatment planning systems. Increased doses to positive lymph nodes can be administered, while decreasing doses to normal tissues.

In a study, Israel et al 2003 compared the performances of PET/CT

versus PET and/or CT alone in 57 patients with gynecological cancers, including

38 cervical cancers, 6 endometrial cancers, and 13 ovarian cancers. As a main

conclusion, PET/CT improved image interpretation over PET and/or CT in 51%

of patients. Combined imaging technique led to a change in management of 11

108

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition patients with uterine cancers (25%) including 10/38 patients with cervical cancer

and 1/6 patients with endometrial cancer. These results are in line with those

obtained by Cohade et al 2003, who directly compared PET and PET/CT in a

series of 15 patients with endometrial cancer. In this later study, 12 of out 49

tumor sites (24.5%) detected by PET/CT and PET were mis-localized or

misdiagnosed by PET alone. In particular, PET/CT helped to correctly reclassify

5 equivocal FDG-avid foci by PET alone as either benign or malignant lesions.

The same group also evaluated the added-value of PET/CT over PET in 13

patients with cervical cancer. Similarly, combined imaging was found

particularly contributive for a better anatomic localization (physiological versus

pathological) and characterization (benign versus malignant) of foci with

increased FDG uptake, which were difficult either to localize (>1/3 foci) or to

diagnose (~ 1/5 foci) on PET alone (Tatsumi et al, 2003).

Based on the current data, the clinical added-value of PET/CT

primarily relies upon its ability to accurately localize FDG-avid sites compared

to either PET alone or CT alone. So far, the role of PET/CT remains limited for

the detection of non FDG-avid sites, especially normal sized metastatic nodes

(i.e. microscopic tumors). Although the size/volume is a key-factor in the lesion

detectability by PET and PET/CT, the metabolic activity of tumor is another

important parameter to be considered. For instance, < 1cm nodes that are

metabolically active may be detected by PET and PET/CT, while > 1cm (nodes)

with a low FDG uptake (i.e. metastases with a low metabolic activity, benign

nodes, and irradiated nodes) may be missed by metabolic imaging (Belhocine

and Grigsby, 2005).

109


7- PET/CT&

Gastrointestinal malignancies

110


18F-fluorodeoxyglucose positron emission tomography (FDG-PET)

imaging is highly accurate in restaging colorectal cancer, esophageal cancer, and

gastrointestinal Stromal tumors (GIST). Overall, it compares favorably with

anatomical imaging in the evaluation of tumor recurrence because metabolic

abnormalities usually precede a structural change. Initial staging of these

malignancies with PET is best used in patients with locally advanced disease

who may benefit from curative resection if distant metastases are not found. It

also appears to have great potential in predicting histopathologic response to

neoadjuvant therapy and in monitoring the success of radiofrequency ablation

and 90Y micro spheres radio-embolization soon after intervention. FDG-PET

can be used in other gastrointestinal malignancies as a prognostic tool and to

detect distant disease but its role has not yet been well defined (Fabio, et al

2006).

The interpretation of PET abdominal images often is challenging

because of the bio-distribution of FDG. Although background FDG activity in

the chest usually is negligible, physiologic uptake in a variety of

abdominal/pelvic organs can make it difficult to distinguish benign from

malignant uptake. FDG is filtered but not reabsorbed in the kidneys, so activity

is expected in the urinary system. Stomach wall uptake is common and colonic

uptake may be intense, especially in the caecum and recto-sigmoid. The liver

has a typical mottled appearance and moderate uptake. The spleen has a more

homogeneous pattern, and the degree of uptake is less than the liver. Intense

focal ovarian uptake may be physiological in premenopausal women. Para-

spinal and peri-nephric fat uptake can be observed. Lymphoid tissue and skeletal

muscle often demonstrate increased uptake (Fabio, et al 2006).

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1-Colorectal Cancer

Several studies have shown the ability of FDG-PET imaging in the

detection of primary carcinomas and pre-malignant lesions of the large bowel

(Friedland et al, 2005 and Gutman et al, 2005). Sensitivity is highly

dependent on both the size of the lesion, reaching 72% if the tumor is larger than

1 cm, and grade of dysplasia, ranging from 33% in low-grade lesions up to 76%

in high-grade lesions and 89% in carcinomas. There is a wide range of

nonmalignant conditions in which increased FDG uptake is observed in the

colon, such as inflammatory bowel disease, diverticulitis, and physiologic

uptake in colonic mucosa, lymphoid tissue, and smooth muscle. Differentiation

between benign and malignant uptake is predominantly based on the focal

nature of hyper-metabolism. Inflammatory bowel disease and physiologic

uptake tend to be diffuse or segmental, whereas the accumulation of FDG in pre-

malignant and malignant lesions is focal. Despite a low positive predictive value

for malignancy, focally increased uptake of FDG in the large bowel should not

be ignored, particularly in light of the high incidence of pre-malignant adenomas

and colorectal cancer in the age group that typically undergoes FDG-PET

imaging. Focally increased uptake in the colon should lead to further

investigation with colonoscopy and, when necessary, biopsy or polypectomy

(Van Kouwen et al, 2005).

Few studies have focused on the usefulness of FDG-PET scanning in

the initial staging of colorectal carcinomas. Overall, the sensitivity for detection

of nodal metastasis is poor and is not significantly different from CT imaging.

These results are not surprising because of the inability of FDG-PET to identify

micro-metastases and the resolution capabilities of the scanners currently used.

112

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition The use of FDG-PET imaging in the preoperative staging of colorectal cancers

has been advocated, but a substantial impact on clinical management has not

been demonstrated. It is unlikely that initial treatment decision making will be

significantly altered on the basis of PET imaging (Kantorova et al, 2003).

Several studies have described the additional value of FDG-PET

imaging over anatomical imaging in recurrent colorectal cancer (Bipat et al,

2005). Metabolically active tumors can be detected before a morphologic

change is noted on anatomical imaging. A meta-analysis of 11 studies with 577

patients (Huebner et al, 2000) showed an overall sensitivity of 97% and

specificity of 76% for FDG-PET detecting recurrent colorectal cancer. A more

recent meta-analysis of 61 studies evaluating colorectal liver metastases (Bipat

et al, 2005) Showed that FDGPET had a sensitivity of 95% on a per-patient

basis, significantly better than CT (65%) and magnetic resonance imaging

(MRI) (76%) (Fig 39) (Kantorova et al, 2003).

Few studies have demonstrated the value of FDG-PET in patients with

rising CEA levels and no identifiable lesions on conventional imaging.

Flanagan and coworkers 1998 reported a positive predictive value of 89%

(15/17) and a negative predictive value of 100% (5/5) in patients with CEA

measurements of 10 to 45 ng/mL. Valk and coworkers 1999 showed a positive

predictive value of 95% (18/19) and a negative predictive value of 85% (11/13).

The positive impact of PET on management decision in this clinical scenario is

evident. Curative therapy may be attempted for patients with localized disease,

whereas unnecessary surgery may be prevented in patients with advanced stage

disease.

FDG-PET imaging has been shown to significantly alter patient

management when compared with conventional imaging modalities. A

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition prospective study by Ruers and coworkers 2002 demonstrated a change in

clinical management in 20% of patients being evaluated for resection of

colorectal liver metastasis. A change in patient management based on FDGPET

findings was determined to be 29% in a meta-analysis of 11 articles with 577

patients (Huebner et al, 2000). In a prospective study of 102 patients with

suspected or confirmed regional recurrence of colorectal cancer, FDG-PET

influenced management decision in 59% of cases. The high impact on treatment

planning in this particular study was predominantly due to avoiding surgery in

patients with widespread disease. In a subset of 20 patients with rising CEA

levels but no obvious site of recurrence on conventional imaging, FDG-PET

localized recurrence in 13 (65%) (Kalff et al, 2002).

Combined PET/CT imaging is particularly beneficial when

interpreting abdominal/pelvic images because focally increased uptake of FDG

may be observed in a variety of benign conditions. These include incisions,

ostomies, abscesses, fistulas, granulomas, diverticulitis, as well as physiologic

uptake in colonic mucosa, lymphoid tissue, and muscle. The anatomic detail

provided by CT helps differentiate benign from malignant uptake, increasing the

confidence of the reader and yielding a better and more specific report

(Rosenbaum et al, 2006).

Lesion characterization on CT also can increase the suspicion for

malignancy even in the setting of mild FDG uptake. For example, the sensitivity

of FDG-PET to detect mucinous adenocarcinoma is low, presumably because of

the hypocellularity of these tumors. The ability to identify cystic changes and

calcifications that are characteristic of mucinous lesions on CT scan should

increase the index of suspicion of the reader even if the degree of FDG uptake is

low (Whiteford et al, 2000).

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Precise measurement of small structures is yet another advantage of

combined PET/CT imaging. The identification of small lesions (typically less

than 1 cm) on CT may help us to prevent excluding malignancy on the basis of

low FDG uptake, since the metabolic rate in sub-centimeter lesions is often

underestimated because of resolution limitations of the PET scanners

(Kantorova et al, 2003).

Finally, the use of integrated PET/CT imaging also improves intensity

modulated radiation therapy planning in patients with rectal carcinoma. These

patients can be imaged prone on a flat bed to exactly match the position of

planned intensity-modulated radiation therapy sessions. Better delineation of

target volumes can be accomplished, limiting higher tumoricidal doses to areas

of increased FDG uptake and sparing normal adjacent structures (Brunetti et al,

2004).

Because the bowel and other gastrointestinal structures tend to move

during a distinctive period, the more or less simultaneous PET and CT

investigation by using PET/CT is especially valuable. However, for optimal

results, even in PET/CT, the examination should be carried out under optimized

preconditions, as many studies on CT colonography have shown. Therefore,

tailored PET/CT protocols may be able to enhance the diagnostic accuracy in

primary and recurrence staging and in patients with incomplete optical

colonoscopy and suspicion of synchronous tumor sites (Fig 38) (Nakamoto et

al, 2004).

Cohade et al, 2003 reported that the accuracy of staging in patients

with colorectal carcinoma increased from 78% with PET alone to 89% with

PET/CT. The number of lesions having an uncertain location was decreased by

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition 55% with PET/CT and the number of equivocal and probable lesion

characterization was decreased by 50%.

116


Fig 38: A, B Patient with incomplete optical colonoscopy and suspicion of synchronous tumor sites received PET/CT, which proved the existence of two tumor sites (arrows).

Fig 39: Whole-body PET MIP (left), trans-axial CT (top left), attenuation-corrected PET (top right), fused image (bottom left), and non-attenuation-corrected PET (bottom right) in a 56-year-old man with recto-sigmoid adenocarcinoma (arrows) and extensive liver metastases (arrowheads)

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2-Esophageal carcinoma

In recent years FDG-PET has been demonstrated to have a higher

sensitivity for the detection of primary esophageal tumors than CT (Flamen et

al, 2000). Himeno et al, 2002 found that PET can detect primary esophageal

cancer with a depth of invasion of T1b or greater and PET to be more accurate

than CT or EUS (endoscopic ultrasound) for diagnosing lymph node metastases.

Kato et al 2005 found an incremental effect of PET on diagnostic accuracy in

the initial staging of esophageal carcinoma including the M stage. Luketich et

al 1997 confirmed that PET has a greater sensitivity in detecting distant

metastases. In contrast to morphologic imaging methods Jones et al, 1999,

FDG-PET has been shown to be a good predictor of response to therapy,

because of its ability to differentiate between vital residual tumor tissue and

post-therapeutic changes. It is therefore able to distinguish responders from non-

responders to neoadjuvant chemotherapy shortly after beginning induction

therapy. PET does not depend on structural tissue changes and has been

demonstrated to be at least as good as CT in detecting recurrent disease (Fig 41)

(Kato et al, 2004).

FDG PET can be used in the planning of esophageal tumors by

improving the ability to define cranial and caudal extent, which can be difficult

using CT alone. A study of the effect of FDG PET on the CT planning of

esophageal tumors showed that FDG PET upstaged eight of 21 patients by

revealing metastatic or nodal disease. Radiotherapy planning based on CT alone

would have resulted in the exclusion of FDG-avid disease in 11 of the 16

patients eligible, which was mainly due to discordance in the cranial and caudal

extent of disease (Leong et al, 2006).

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PET/CT can improve the accuracy of PET imaging in distinguishing

recurrent disease from benign post-therapy changes, delineating the anatomic

location of metastatic disease, and monitoring therapy response by solving a

myriad of problems inherent in the post-therapy assessment of cancer. With the

use of the pattern of enhanced metabolic activity to facilitate field definition

(Fig 40), PET/CT also promises to improve the accuracy of radiation treatment

planning (Koshy et al, 2004).

Fig: 40 Utilization of positron emission tomography (PET)/computed tomography (CT) fused images for radiation treatment planning in a patient with moderately differentiated lower esophageal adenocarcinoma. (A) Sagittal view. The blue and orange lines show antero-posterior (AP) and postero-anterior (PA) beams, respectively. The red contour delineates gross target volume (GTV). The green contour encloses region of the esophagus superior to the metabolically active GTV to account for possible microscopic disease. (B) Coronal view. The blue and orange contours represent radiating field by AP and PA beams, respectively. Once again, the red contour represents GTV and the green contour is planned to encompass microscopic disease.

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120


Fig 41: Coronal CT (top left), attenuation-corrected PET (top right), fused image (bottom left), and non attenuation corrected PET (bottom right) in a 57-year-old man with a large lower esophageal cancer (arrows) and a malignant right para-tracheal lymph node (arrowheads). Uptake resolved in both regions after neoadjuvant chemotherapy and only minimal residual microscopic disease was present in the esophagus after resection.

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3-Gastric Carcinomas

The diagnosis of gastric carcinomas is made by endoscopy and tumor

biopsies. Local extension of the tumor is typically assessed by endoscopic

ultrasound, whereas abdominal ultrasound and CT are used for metastatic

workup. The sensitivity of FDG-PET to detect locally advanced gastric

carcinomas is dependent on the microscopic growth type of the tumor. Stahl

and coworkers 2003 showed that distinct increased uptake of FDG is more

commonly seen in the intestinal growth type (15/18, 83% sensitivity) than in

non-intestinal type carcinomas (9/22, 41% sensitivity), probably because of the

abundance of intra and extra-cellular mucous content and lack of expression of

the glucose transporter Glut-1 on the cell membrane of the latter. Both FDG-

PET and CT appear insensitive to detect regional lymph node metastasis from

gastric carcinomas.

In a retrospective study of 81 patients, Yun and coworkers 2005

showed a sensitivity of 34% for N1 and N2 disease and 50% for N3 disease

using FDG-PET. The sensitivity of CT for detection of N1 disease (58%) was

significantly better than that of FDG-PET.

A retrospective analysis of 33 patients with suspected recurrence of

gastric carcinoma showed a sensitivity of only 70% (14/20) and a specificity of

69% (9/13) for FDG-PET. However, the mean survival for the PET negative

group (18.5 months) was significantly higher than the PET positive group (6.9

months), suggesting that PET may serve as a prognostic rather than diagnostic

tool in gastric carcinomas (De Potter et al, 2002).

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Ott and coworkers 2003 prospectively evaluated patients with locally

advanced gastric carcinomas with FDG-PET at baseline and at 2 weeks after

initiation of cisplatin-based chemotherapy. Thirty-five of 44 primary tumors

(80%) were PET positive. By using a cutoff SUV reduction of 35%, FDG-PET

correctly predicted histopathologic response after 3 months of therapy in 10 of

13 responders and in 19/22 non-responders. The identification of non-responders

early in the course of chemotherapy will allow optimization of neoadjuvant

strategies in locally advanced gastric carcinomas potentially minimizing

progression of disease.

Despite the well-known moderately accentuated uptake of FDG in the

healthy stomach, FDG-PET is surely helpful in the management of patients with

gastric carcinoma. Studies addressing PET/CT in gastric carcinoma are lacking.

Therefore it is not known whether the additional information of CT in a

combined PET/CT device would further improve diagnostic performance, but it

would probably improve local lymph node staging. Further, we assume an

improvement in diagnostic accuracy in T and M staging (Rosenbaum et al,

2006).

4-Hepatic Tumors

FDG-PET has a poor sensitivity to detect primary hepatocellular

carcinoma because well-differentiated tumors may retain the capacity

gluconeogenesis (to convert FDG-6-phosphate to FDG). Lee and coworkers

2005 showed that GLUT1 (glucose transporter 1) concentration is low and HKII

(Hexokinase II) is high in hepatocellular carcinoma. In a small series of 12

patients (4 untreated and 8 treated) Lin and coworkers 2005 showed

improvement in sensitivity from 56% to 62.5% between images obtained at 1

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition hour and 2- to 3-hour delay. Ho and coworkers used 2003 C11 acetate PET in

32 patients and showed a sensitivity of 87% compared with that of 47% with

FDG-PET. Hence the importance of FDG-PET in the management of

hepatocellular carcinoma is mainly in detecting extra-hepatic spread. In 18

patients Sugiyama and coworkers 2004 showed that FDG-PET contributed to

the management of patients by detecting extra hepatic metastases. In a study by

Khan et al 2000 found that the sensitivity of PET in diagnosis of HCC was

55% compared with 90% for CT scanning, although some tumors were detected

by PET only (including distant metastases).

In conclusion, on the basis of the CT finding, the PET signal is suitable

to differentiate biological aggressiveness of primary tumors, which stresses the

need for combined film reading and therefore the use of PET/CT. It is also

reported clinical experience that PET and PET/CT have a high sensitivity to

detect extra-hepatic metastases of HCC (Khan et al, 2000).

Bohm et al 2004 investigated the effect of PET in histologically

proven intrahepatic lesions and found a sensitivity of 82% for FDG for the

detection of primary and secondary liver lesions, with PET being superior to

ultrasound (63%) and CT (71%). The sensitivity and specificity of PET and

MRI were comparable at approximately 82% and 96%, respectively, for intra-

hepatic lesions but PET was superior to MRI for detection of extra-hepatic

metastases of hepatic primary lesions, with the sensitivity and specificity

being63 % and 60% for PET and 40% and 50% for MRI, respectively. In this

study the PET results had a direct effect on operative management. Hepatic

metastases are quite frequent and the value of PET largely depends on the kind

of primary lesion. Liver metastases are likely to be detected only if the PET

tracer is frequently accumulated in the respective tumor entity. Further, the

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition tracer might physiologically accumulate in the liver, which decreased the

detection sensitivity in this organ.

This problem may be overcome, at least in part, by employing PET/CT

because tracer turnover in the lesion (as depicted by CT) can be analyzed. Thus

PET/CT improves sensitivity to detect liver metastases, but only in PET-positive

lesions. Moreover, clear discrimination between a superficial but intra-hepatic

lesion and a lesion adjacent to the liver requires precise image fusion as

available using PET/CT (Fig. 42, 43, 44) (Rosenbaum et al, 2006).

Fig 42: Patient with poorly differentiated HCC and previous hemi-hepatectomy. A) Contrast-enhanced CT shows a new hypodense nodule in the venous phase. B) PET reveals a large area of increased FDG uptake in the remaining right liver lobe. C) PET/CT fusion indicates a tumor beyond the nodule that is visible on CT, thus influencing planned radiofrequency ablation.

125


Fig 43: Patient with colorectal metastases and previous left hemihepatectomy. A) CT shows two hypodense nodules with contrast enhancement. B) PET/ CT fusion indicates a metastatic recurrent tumor beside a scar after operation. C) CT after radiofrequency ablation shows a large area without contrast enhancement (arrow). D) PET/ CT fusion after radiofrequency ablation indicates complete ablation of the recurrent metastasis with a photopenic lesion.

Fig 44: A) CT 3 month after radiofrequency ablation shows no sign of local recurrence. B) PET/CT 3 month after radiofrequency ablation demonstrates a local recurrent tumor.

126


5-Gallbladder carcinoma and

Cholangiocarcinoma

The sensitivity of FDG-PET in detecting carcinoma of the gallbladder

(GBC) and cholangiocarcinoma (CC) is quite high but seems to be dependant on

tumor subtype. Anderson et al. found a sensitivity of 78% for GBC. Sensitivity

was 85% for nodular CC but only 18% for infiltrating CC. Sensitivities for

extra-hepatic metastases were 50% for GBC and 65% for CC. In the cited study,

PET was falsely negative in all three patients with carcinomatosis; 58% of

patients had FDG uptake along the tract of a biliary stent (Anderson et al,

2004). Kim et al 2003 showed that peripheral hepatic CCs generally have

greater FDG uptake than hilar ones. FDG-PET identified distant metastases of

peripheral CC that were not detected with MRI and CT. Similar to gastric

mucin-containing carcinomas, Fritscher et al 2001 observed false-negative PET

scans in mucinous hilar adenocarcinoma. Kluge et al 2001 demonstrated a high

sensitivity for PET in detecting primary CC and its metastases, but regional

lymph node metastases were diagnosed with a sensitivity of only 13%. The

reason for this poor result is assumed to arise from the difficulty of

discriminating between extra-hepatic parts of the tumor itself and FDG-

accumulating lymph nodes in the perihilar region.

There have been no previous studies available addressing PET/CT and

GBC or CC, but certainly PET/CT is the optimal tool to overcome the

limitations of PET and CT alone (Rosenbaum et al, 2006).

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6-Pancreatic carcinoma

FDG-PET plays an important role in the differentiation of pancreatic

tumors when it is certain that patients have no hyperglycemia or serologic

evidence of active inflammation. The sensitivity of PET in detecting pancreatic

cancer is similar to that of CT, but PET seems to be more specific. Sperti et al,

2005 found a sensitivity of 94% for both modalities, but PET was significantly

more accurate in identifying malignancy. PET can also be helpful in identifying

unsuspected distant metastases and suspected recurrent carcinoma when

abdominal CT is non-diagnostic (Jadvar et al, 2001). Delbeke et al, 1999

showed that FDG-PET is more accurate than CT in the detection of primary

tumors and in the clarification and identification of hepatic and distant

metastases. In this study additional FDG-PET investigations altered the

management in up to 43% of patients compared with the management of CT

alone. Mertz et al 2000 found that EUS and PET improved diagnostic

capability in pancreatic adenocarcinoma. Nevertheless, Diederichs et al, 2000

found that PET had sensitivities and specificities of 49% and 63% for lymph

node staging and 70% and 95% for detecting hepatic metastases, respectively.

The combination of PET and CT in a single scanner overcomes these

limitations. The exactly fused anato-metabolic image provides better

differentiation of pathologic processes especially in surgically pretreated

patients and allows the detection of small metastases, which might be missed by

PET alone because they are close to background variations. As Lemke et al,

2004 recently reported, even retrospective image fusion improves the sensitivity

of malignancy detection in pancreatic lesions from 77% for CT and 84% for

PET to 89%. Because there are greater differences in patient positioning in

standalone CT and PET compared with PET/CT, these results are expected to be

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition even better for the combined device. Further, if optimized breath-holding

protocols are used, the frequency of severe artifacts in the area of the diaphragm

can be decreased by half (Beyer et al, 2003). Optimization of these factors and

the possibility to stage patients in a single examination will increase the use of

PET/CT as the main imaging tool in pancreatic cancer in the forthcoming years.

129


8- PET/CT&

Brain tumors

130


A high sensitivity is reported for primary brain tumor detection with

PET. Initial FDG-PET studies can identify elevated FDG uptake in primary

brain tumors (Derlon et al, 1989) with good correlation of the grade of

malignancy .Thus, low-grade astrocytomas are not easily identified or appear as

hypometabolic areas surrounded by normal high FDG uptake within the cerebral

cortex hindering a clear definition of exact tumor extension. Many clinical

studies have demonstrated that 11C-methionine- PET imaging is highly accurate

in defining of tumor boundaries both in primary or recurrent brain tumors,

regardless of their histological grading (Patronas et al, 1985).

Ogawa et al, 1993 demonstrated an excellent 97% sensitivity for 11C-

methionine-PET in 32 patients with high-grade astrocytomas, but only 61%

sensitivity in low-grade astrocytomas. A Large study was performed by Herholz

et al, 1992 finding 79% accuracy in distinguishing astrocytomas from non-

neoplastic lesions in 196 patients with a suspected primary brain tumor.

Mosskin et al, 1986 presented a patient-based sensitivity of 84%

using stereotactic biopsies from primary brain tumors and normal brain tissue

areas, indicating that tumor specificity of 11C-methionine contains a certain rate

of false-positive results. In a large series of astrocytomas, 95% of 37 lesions are

clearly visualized in 11C-methionine- PET studies, whereas FDG shows 41% as

hyper-metabolic, most of which are high-grade astrocytomas; and 49% as

hypometabolic lesions, whereas 10% are difficult to distinguish from

surrounding normal brain tissue (Kaschten et al, 1998). The reported advantage

of 11C-methionine over FDG in delineating astrocytomas is probably not

relevant in CNS lymphoma, where FDG uptake is much higher in tumor than

normal brain tissue (Roelcke et al, 1999).

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Experience with 18F-tyrosine as radio-labeled ligand for PET studies

in primary brain tumors is more limited. Pruim et al, 1995, using 18F-tyrosine

PET imaging for both primary and recurrent brain tumors (including metastases

and cerebral lymphomas), find 91% of 22 tumors positive for uptake. Wienhard

et al, 1991 could demonstrate increased uptake and transport rates of 18F-

tyrosine in primary brain tumors (n=15). Such an uptake appears more related to

amino acid transport than to protein synthesis.

Nearly all PET studies on tumor detection also addressed the

feasibility of tumor characterization and grading, comparing uptake between

both benign and malignant processes and between various grades of malignancy.

This clinically useful aspect is supported by in vitro proliferation markers (Kole

et al, 1999 and Wienhard et al, 1991). Sato et al, 1999 demonstrated a clear

positive correlation between proliferation cell nuclear antigen index and 11C-

methionine uptake, indicating that 11C-methionine is taken up more rapidly and

accumulated in highly proliferative tissue. Somewhat surprising is that this

relationship is not confirmed for 18F-tyrosine uptake (n=20) (DeWolde et al,

1997). Different 11C-methionione accumulations in vivo have shown an uptake

in low-grade astrocytomas being near background uptake but a high uptake in

oligodendrogliomas (Kracht et al, 2003).

FDG-PET, such a better tumor delineation is reported both for 11C-

methionine and 18F-tyrosine-PET (Kaschten et al, 1998)11C-Methionine of

FDG scanning is combined with activation studies using radio-labeled water (H2

15O) to depict tumor extension in relation to functional brain areas (Duncan et

al, 1997), with the aim to achieve a subsequent more aggressive surgical

resection with a reduced risk of neurological impairment. 18F-thymide PET is

useful for evaluating the histological grade and cellular proliferation of brain

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition tumors, as well as for the detection and delineation of brain tumors that show

decreased or similar uptake compared with normal gray matter on FDG-PET

(Choi et al, 2006). 18F-thymidine PET, however, does not appear sufficiently

useful for differentiating tumors from non-tumorous lesions.

Stereotactic biopsies of localizations that are based on either

methionine or FDG-PET seem to be more successful to find accurate brain

tumor tissue than are biopsy based on CT only .Especially, strong uptake

reduction of 11C-methionine in necrotic parts or high uptake in anaplastic parts

of the tumor tissue may influence the surgical planning and subsequent results of

brain tumor biopsies. In comparison with FDG, methionine is advantageous in

offering better detection of non-anaplastic tumor zones and brain tissue with

infiltrating neoplastic cells (Goldman et al, 1997). Planning of biopsy

trajectories is suggested to be improved by tyrosine, particularly in low-grade

astrocytomas (Go et al, 1994).

FDG-PET has been used to differentiate between toxoplasmosis and

lymphoma (Costa et al, 1995): high grade uptake of FDG is strongly suggestive

of a malignant lymphoma presenting as an extremely metabolically active

tumor, whereas a relatively hypometabolic lesion can be demonstrated in

toxoplasmosis. The problem of specificity, however, may limit the usefulness of

FDG-PET as a routine method, as inflammatory lesions can also accumulate

FDG (Wurker et al, 1996).

Luciganini et al, 1997 comprised 16 patients with the diagnosis of

primary tumor of the sellar/ para-sellar region; the results demonstrated that PET

with 18F-FESP is a very specific method for differentiating adenomas from

craniopharyngiomas and meningiomas at approximately 70 minutes after tracer

injection.

133


In the early postoperative period, FDG-PET can be used to

differentiate residual tumor tissue from postoperative surgical effects (Hanson

et al, 1990 and Kim et al, 1992). It seems clear that a decline in tumor tissue

uptake of FDG weeks or months after therapy is suggestive of a good response

to treatment, indicating either a reduced number of viable cells or reduced

metabolism of damaged cells (Haberkorn et al, 1993). After intensive

irradiation or chemotherapy for malignant brain tumors, MRI is not able to

distinguish tumor progression form radiation damage or necrosis. Some PET

methods appear promising as relatively specific indices of therapeutic response.

FDG uptake suggest the presence of viable brain tumor tissue (at least when

high tumor uptake of FDG was noted before therapy), whereas absence of FDG

uptake suggests that necrosis may be present (Fig. 46) (DiChiro et al, 1988 and

Ishikawa et al, 1993)

Detection of recurrent or residual viable brain tumor tissue can be

troublesome in brain tumors treated by surgery or irradiation. 11C-methionine

PET had a sensitivity of 77.8% and specificity of 100% for differentiating

recurrence of metastatic brain tumors from post-radiotherapy changes

(Tsugyuguchi et al, 2003). However, 11C-methionine uptake may also be

elevated in other conditions where there is a disruption of the blood brain

barrier, such as cerebral hematoma or even necrotic areas caused by

radiotherapy (Dethy et al, 1994), whereas glucose metabolism may be normal

or low in lower grade tumors compared with surrounding cortex. Combined use

of 11C-methionine and FDG-PET enhances the accuracy of discrimination

between recurrent tumor and post radiotherapy changes. Remarkably, the

protein synthesis rate, determined by using 18Ftyrosine- PET, remains

unchanged in 80% of patients after radiotherapy (Heesters et al, 1998). Four

hours after irradiation, the increase in tumor FDG uptake compared to the pre-

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition irradiation study is significantly assessed with MRI. For malignant

astrocytomas, this relationship has not been assessed yet. Voges et al, 1997

report on a series of 46 patients who underwent serial 11C-methionine and

FDG-PET studies after interstitial brachytherapy: 11C-methionine is superior to

FDG in delineating residual of recurrent tumor tissue (Fig.47). This finding

confirms earlier data on the comparison of FDG and amino acid in visualization

of untreated low- and high-grade astrocytomas.

Several PET studies try to establish a relationship between metabolic

response and prognosis after initiation of chemotherapy in patients with

glioblastoma multiform. The change of FDG uptake induced by chemotherapy

can be correlated with survival. Both positive and inverse correlations can be

found between metabolic responses and survival, making these data

inconclusive so far. In a more recent study, methionine is found to be superior to

FDG in monitoring the treatment effects in low-grade astrocytomas (Woesler et

al, 1997).

135


Fig. 46: CNS recurrent glioma: The patient below had a history of a right temporal lobe glioma. The lesion had been treated with surgery and radiation. A follow-up MR exam demonstrated areas of enhancement in the right temporal lobe on post-gadolinium images (black arrows). MR spectroscopy was inconclusive. The FDG PET exam demonstrated a hyper-metabolic focus in the area of MR signal abnormality consistent with recurrent glioma (white arrows).

136


Fig. 47: Recurrent glioblastoma multiforme. 11C-methionine positron emission tomography shows tumor infiltration in areas (arrows) located outside of the contrast enhancement on computed tomography and T1-magnetic resonance imaging.

137


9- PET/CT & male genital and bladder

cancer

138


1- Male Genital System

a) Prostate cancer (PC)

Imaging of the prostate is important because of its involvement in

many diseases of men. However, a number of problems have prevented success

in this area. The size and location of the prostate contribute significantly to this

problem.

X-ray computed tomography (CT) lacks soft tissue contrast resolution

for the detection of cancer within the prostate and offers no advantages over

TRUS (trans-rectal ultrasound) in biopsy guidance (Yu and Hricak, 2000).

Among the currently available nuclear medicine studies only positron

emission tomography (PET) has some potential (if any) to detect primary tumor

in prostate cancer. The PET tracers used for clinical studies of prostate cancer

are 18F-FDG (fluoro-deoxy-glucose), 11C-acetate, 18F-acetate, 11C-

methionine, 11C-choline, 18F-choline, and 18F-FDHT (16 beta-18F- fluoro-

5alpha-dihydrotestosterone) (Suman and Blaufox, 2006).

Several studies have been conducted using FDG-PET in localized

prostate cancer. Most of the results were disappointing (Hoffer et al, 1999 and

Schöder and Larson, 2004). Effert and coworkers 1996 studied 48 prostate

cancer patients and 16 patients with benign prostatic hyperplasia. They reported

a low grade FDG uptake in 81% of these tumors and there was a significant

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition overlap between benign prostatic hyperplasia and prostate cancer in uptake

values. Hoffer and coworkers 1999 reported similar findings.

In a study of 24 patients Liu and coworkers 2001 found a sensitivity

of 4% for FDG-PET in the diagnosis of primary PC. Melchior and coworkers

1999 reported higher FDG accumulation in poorly differentiated PC than in low

grade PC. Oyama and coworkers 1999 examined 44 consecutive patients with

histologically proven adenocarcinoma of the prostate. In visual analysis, 5

patients with BPH (control group) showed low FDG uptake. On the other hand,

28 of 44 (sensitivity 64%) patients with cancer were visually positive, showing

intermediate and high FDG uptake. There was a trend for FDG uptake in PC to

correlate Gleason scores. The possible explanations for disappointing results as

suggested by Schöder and Larson 2004 include: (1) a relatively lower

metabolic rate in the majority of prostate cancers with lower FDG uptake, (2)

older image reconstruction techniques (i.e., use of filtered back projection

instead of iterative reconstruction), (3) location of the prostate adjacent to the

urinary bladder, and (4) the lack of appropriate patient selection (FDG may be

more useful in patients with clinical suspicion of a high-grade cancer).

An in vitro study by Yoshimoto and coworkers 2001 showed that

tumor cell to non-tumor cell ratios were higher for acetate than deoxy-glucose.

During the last several years this tracer has been used in prostate cancer. Oyama

and coworkers 2002 studied 22 patients, among who 18 also had an FDG scan.

They reported 11C-acetate uptake in all primary tumors with standard uptake

values (SUVs) from 3.27 to 9.8, whereas FDG was positive only in 15/18 with

SUVs from 1.97 to 6.34.

In another study Kato and coworkers 2002 found that there was an

overlap of SUVs for patients with benign prostatic hyperplasia and those with

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PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition cancer. They also noted that SUVs in normal subjects of below 50 years of age

were significantly higher than that of above 50. Except for case reports of

Matthies et al, 2004 no significant data are available to evaluate the role of

18F-acetate in prostate cancer.

Similar to FDG, methionine, acetate, and choline are not specific

agents. Benign prostatic hyperplasia shows tracer uptake higher than normal but

lower than that found in cancer; however, there are no discriminating SUVs to

differentiate cancer from hyperplasia (Sutinen et al, 2004). At this time, PET

does not play a significant role in the primary diagnosis of prostate cancer. The

reasons include a lack of appropriate image acquisition techniques such as zoom

mode acquisition (the prostate is a small organ, therefore, zoom mode

acquisition may provide better visualization of a small lesion), image fusion

(combined PET/CT may provide more confidence to identify a hot area as

abnormal in the prostate gland rather than in the prostatic urethra), longer

acquisition time to increase sensitivity and possible dual time imaging (proven

to be useful in lung lesions to discriminate cancer from an inflammatory lesion;

this may help differentiate cancer from benign prostatic hyperplasia) (Fig. 48).

Currently, PET does not play a significant role in directing biopsy.

Acetate and choline seem to be better tracers than FDG; however, further studies

are needed to decide whether PET can have a significant role in the diagnosis of

primary prostate cancer. During routine whole body PET imaging, occasionally,

focal intense uptake of tracer in the prostate has been reported during FDG (Fig.

49) and 11C- choline imaging. Further evaluation of these lesions in terms of

PSA measurement and TRUS guided biopsy is important. Particularly, intense

FDG uptake may indicate presence of a high-grade cancer (Schöder and

Larson, 2004).

141


142


Fig 48: A 60-year-old African–American man underwent prostate biopsy in September 2001 due to a nodular prostate on rectal examination and an elevated PSA of 11.6. The biopsy showed focal glandular hyperplasia, basal cell hyperplasia, focal inflammation, and no evidence of cancer. In May 2004 the PSA increased to 14.2. Before repeat biopsy the patient underwent FDG-PET scan. A normally acquired PET scan displayed with magnification (A) showed mild asymmetric uptake (arrows) in the prostate, which was thought to be abnormal. The scan of the prostate was also acquired in zoomed mode at 60 min (B) and 120 min (C) after the FDG injection. There were discrete areas of FDG uptake in both images (B and C), which were clearly abnormal. These scans were performed on a PET/CT scanner. The SUV max of the prostate lesion was 1.9 from 60-min images (B) and was 2.2 from 120-min images (C). When PET images (D) were displayed with CT images (E) the focal uptakes were found to be located adjacent to the prostatic calcifications. The prostate biopsy was performed in the next week and the biopsy specimens were obtained from the calcified regions as suggested by PET/CT scan. The pathology was positive for adenocarcinoma (Gleason score 6/10 with minor foci of grade 5 adenocarcinoma).

143


Fig 49: A 75-year-old man with history of metastatic lung cancer found to have intense uptake of FDG (arrow) in the prostate in the PET/CT scan (A and B). Prostate biopsy revealed adenocarcinoma of the prostate; Gleason score 8/10 (5 +3).

144


FDG was found to have a low accuracy in primary staging of prostate

cancer. FDG is slightly better in detecting metastatic PC than that in primary

lymph nodes (Shvart et al, 2002). Heicappell and coworkers 1999 used FDG-

PET for preoperative imaging of pelvic lymph nodes in 17 newly diagnosed

prostate cancer patients and then compared the findings with postoperative

histopathology. FDG was able to diagnose metastatic lymph nodes accurately in

4 of 6 affected patients. The 2 false-negative results were attributed to the small

size of the lesions (less than 5mm). There was no false-positive result in this

study. Other small studies (Sanz et al, 1999 and Kotzerke et al, 2000) report

sensitivities ranging from 0 to 50% and specificities ranging from 72 to 90% for

detection of nodal metastases. FDG uptake was noted in pelvic lymph nodes in

patients with PET negative primary.

FDG-PET is variable in the detection of bone marrow metastases;

however, the general belief is that it is more sensitive for the detection of bone

metastases than local disease (Kumar et al, 2004). Shreve and coworkers,

1995 reported a sensitivity of 65% and PPV (positive predictive value) of 98%

in 202 bone metastases. Yeh and coworkers, 1996 found that only 18% of bone

lesions on the bone scan showed FDG uptake. Kao and coworkers, 2000

reported a high specificity of FDG-PET in detection of bone marrow metastases.

Nunez and coworkers, 2002 found better detection of cervical spine metastases

by FDG-PET than by bone scan. In another study Morris and coworkers, 2002

evaluated 154 bone lesions in 17 patients. Both FDG and the bone scan were

positive in 71% lesions, 23% were seen only on bone scan, and 6% were seen

only on PET scan. Schöder and Larson, 2004 suggested that FDG may

selectively detect more aggressive tumors, which depend on higher glucose

metabolism. In vitro studies in prostate cancer xenografts showed higher FDG

uptake in tumors with higher Gleason scores, (Agus et al, 1998) and in clinical

145

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition studies FDG uptake correlates with PSA level and PSA velocity as measure of

tumor size and progression (Herrmann et al, 2004). It seems that high FDG

uptake most likely suggests a relatively high-grade tumor.

18F-Fluoride PET The bone scan with 18F is reported to be more

sensitive and specific than the conventional bone scan to detect bony metastases,

particularly if used in conjunction with CT in a PET/CT scanner. The

indications to use this scan are the same as for a conventional bone scan. The

major limitation of this test at this time seems to be the cost. A cost-effective

study in comparison with conventional bone is needed before this study can be

used routinely for detection of bone metastases in prostate cancer (Schöder and

Larson 2004).

PET/CT This modality is slowly but steadily gaining popularity in

oncology. Any of the above-mentioned tracers can be imaged in this device.

This can increase the confidence of the interpreter in identifying a hot spot as

physiological versus pathological compared with any of the above PET tracers

used alone. Preliminary data suggest that this modality may be helpful in the

detection of recurrence in the local soft tissue, nodal, or even bone metastases

(Even-Sapir et al, 2004 and Schmid et al, 2005).

146


b) Testicular cancer

Initial Staging

Albers and coworkers, 1999 reported that FDG-PET in 37 patients

with stage I and II found FDG-PET had a sensitivity of 70% and specificity

100%, whereas similar values for CT were 40 and 78%, respectively. In this

study the 3 false-negative PET results were in 2 small (< 0.5 cm) nodal

metastases and a mature teratoma. High sensitivity, specificity, PPV, and NPV

of 87%, 94%, 94%, and 94% were reported by Cremerius and coworkers 1999

Hain and coworkers 2000 found similar results in the initial staging of

seminoma and non-seminoma. PET also identified additional unsuspected

visceral and bone metastases. Most of the studies suggested that PET is superior

to CT. However, in a small number (12 patients) of patients with stage I and II

non-seminoma, Spermon and coworkers, 2002 reported equivalent results for

PET and CT.

Residual/Recurrent Disease

Most patients with bulky nodal disease have residual mass after

treatment. In this situation viable tumor cells inside the mass require further

treatment, whereas fibrosis or necrosis requires watchful follow-up.

Unnecessary radiotherapy or chemotherapy can potentially increase the short-

term as well as long-term toxicities. Considering the fact that these individuals

are young and most of them will live more than 15 to 20 years when cured, they

are more likely to experience the long-term toxicities. Although tumor markers

are very useful in this regard, occasionally they may be misleading and not

147

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition helpful to locate the site of recurrence/residual (Sant et al, 2001). Imaging plays

a significant role in locating the residual/recurrent disease non-invasively.

Conventional imaging modalities including CT cannot confirm the presence of

viable tumor cells in a residual mass. FDG being a metabolic imaging modality

has better results. Stephen and coworkers, 1996 and Sugawara and

coworkers, 1999 reported that FDG-PET was able to differentiate viable tumor

from fibrosis in the post-treatment residual masses. However, the major

limitation of PET is mature teratoma, which is usually negative in the FDG-PET

scan but can cause a false-positive result if there are any inflammatory changes

associated with it. Hain and coworkers, 2000 reported sensitivity, specificity,

PPV, and NPV of 88%, 95%, 96%, and 90%, respectively, for FDG in

differentiating viable tumor from fibrosis or necrosis or mature teratoma.

Sanchez and coworkers 2002 found that FDG-PET can detect relapse earlier

than CT. Several other studies conducted in patients with seminomas or non-

seminomas have shown that FDG-PET is superior to CT in this regard

(Cremerius et al, 1998 and De Santis et al, 2001).

Monitoring Treatment Response

FDG-PET has been shown to predict response to chemotherapy,

similar to high-grade lymphomas (Fig. 50). Bokemeyer and coworkers, 2002

reported that FDG-PET accurately predicts the outcome of high-dose

chemotherapy in 91%; in comparison CT accurately predicted outcome in 59%

cases and tumor markers predicted the correct response in only 48% of cases.

148


Fig. 50: A 24-year-old man with a history of testicular cancer [mixture of teratoma (80%) and germ cell tumor], status post-surgical resection and chemotherapy. PET/CT was performed 4 weeks after chemotherapy; CT continues to show a large para-aortic mass; however, FDG-PET showed a photopenic lesion with very mild uptake at the periphery of the lesion. Subsequent excision biopsy of the lesion showed only necrotic tissue with surrounding inflammation; no tumor cells were found in the specimen.

149


2-Bladder cancer

The role of FDG-PET in the detection of localized bladder cancer is

limited because of the difficulty in differentiating radiotracer activity excreted

into the urine from tumor activity in the bladder or adjacent lymph nodes

(Suman and Blaufox, 2006).

However, FDG-PET has demonstrated some utility in identifying

distant lymph node involvement and distant disease. Kosuda and coworkers

1997 reported that PET imaging identified 17 of 17 patients with metastatic

disease (lung, bone, and remote lymph nodes) as well as 2 of 3 patients (67%)

with localized lymph node involvement. Similarly, Heicappell and coworkers

reported a 67% detection rate for local nodal disease. Investigators have

attempted to improve the sensitivity of PET by using tracers that are not

excreted in the urine. Ahlstrom and coworkers, 1996 found 11C-methionine is

superior to FDG; however, tumor was identified with a sensitivity of 78%

(18/23) only with methionine PET. They also reported that tracer uptake was

proportional to tumor stage. 11CCholine, another tracer minimally excreted in

the urine, was studied by de Jong and coworkers, 2002 in 18 patients with

bladder cancer before cystectomy and 5 volunteers. Normal bladder showed

little uptake. The primary tumor was visualized in 10 patients with residual

invasive diseases in the cystectomy specimen (mean SUV, 4.7 +/- 3.6, range,

1.5-13.0). Utility of FDG-PET in the evaluation of bladder cancer seems to be

limited to the evolution of distant metastases.

150


10- Summery and conclusion

151


In the rapidly changing world of health technology, PET/CT has now

gained a place of prominence. The clarity of the data achieved, the routine

implementation of image fusion in a multimodality setting, and the apparent

ease with which labeled fluoro-2- deoxy-D-glucose (FDG) can be used to depict

and follow up cancer are clearly the causes of the rapid acceptance of this

technological development within the community of cancer caregivers.

The Holy Grail of oncologic imaging would be a device that is able to

see both the anatomic and physiologic details of tissue. We are getting closer to

define the combined PET/CT scanners. With precision, functional images of

PET can be superimposed on the corresponding anatomic images and essentially

the PET tracer can be considered a metabolic contrast agent.

After performing many oncology studies using an integrated PET/CT

system, the investigators concluded that combined PET/CT images offer

significant advantages, including 1) more accurate localization of foci of uptake,

2) distinction of pathologic from physiologic uptake, and 3) improvement in

guiding and evaluating therapy.

PET/CT is possibly the superior imaging modality for the initial

staging and diagnosis of primary and recurrent head and neck cancers, NSCLC,

lymphomas, colorectal, hepatic and pancreatic carcinomas. PET/CT is best at N

staging and M staging in these patients, and it is clearly superior to CT and MR

in this context.

For brain tumors PET/CT is not a first tool for the investigation of a

patient suspected to have it. Most of the time, referrals arise from a series of

152

PET/CT in Radiotherapy Treatment Planning Review of Literature & Target Definition failed initial investigations. Perhaps the most direct referral for a suspected brain

tumor arises from those patients suspected to have para-neoplastic syndrome

where PET/CT is used to localize a tumor.

This was as regard to disease assessment and staging and restaging of

these cancers and others which can affect the treatment strategies. Recently

PET/CT is used as a powerful tool for better localization of the tumor for

radiotherapy target volumes and so better dose escalation for these targets.

The use of PET/CT for determining radiation target volumes for 3-D

conformal radiation therapy made GTV significantly modified than CT-based

GTV in some patients may be smaller because the tumor may be partially

necrotic, or larger because of the extend of biological tumor margin which can't

be seen by the anatomical imaging alone.

Many studies confirmed the efficacy of the use of PET/CT

radiotherapy treatment planning especially with HNSCC, NSCLC, brain tumors,

bulky lymphomas, melanomas. Other tumors are still investigational.

In general terms PET/CT is still not a first-line investigation for the

diagnosis of cancer. In most institutions, PET/CT is being used after the patient

has presented to a hospital and been submitted to a whole battery of clinical,

laboratory-based and conventional imaging-based studies. But in radiotherapy it

is going to be the first choice for precise treatment planning and good target

definition.

153


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لقد أصبح جهاز التصوير المقطعى . إن هناك تطورا مستمرا في تقنيات التصوير الطبي

لإلنبعاث البوزيترونى المدمج مع جهاز التصوير باألشعه المقطعية من أهم األجهزة التى تحتل مكانا

. مميزا

إن وضوح المعلومات و البيانات من ذلك الجهاز و سهولة دمج الصور كإحدى تقنياتـه

لهى من اهم االسـباب لـسرعة 18سهولة توفير و إستخدام الجلوكوز المعنون بمادة الفلورين مع

.قبول هذه التكنولوجيا الجديده في مجتمع رعاية مرضى االورام

ان من اهم شروط التصوير الجيد لالورام هو وجود جهاز يجمع بين امكانيـه رؤيـة و

و هذا الشرط غير متوفر سـوى فـي جهـاز .نسجةتصوير التفاصيل التشريحية و الفسيولوجية لال

.التصوير المقطعى لإلنبعاث البوزيترونى المدمج مع جهاز التصوير باألشعه المقطعية

استخلص الباحثون بعد العديد من الدراسات على مرضي االورام باستخدام هذا الجهـاز

:العديد من المميزات الهامة و تتلخص في

من خالل تصوير بؤر نـشاط االورام التـي تمـتص الجلوكـوز تحديد الورام بدقة متناهيه -1

.بصورة اكثر من االنسجة الطبيعية18المعنون بمادة الفلورين

.التفرقة بين االورام الخبيثة و الحميدة دون التدخل الجراحى -2

.تحسين توجيه و تقييم العالج الخاص باالورام -3

ونى المدمج مع جهـاز التـصوير لقد اصبح جهاز التصوير المقطعى لإلنبعاث البوزيتر

باألشعه المقطعية له دورا فعاال فى تحديد مراحل الورم عند بداية التشخيص و إعادة تقييمه عنـد

حدوث ارتجاع او انتشار و خاصة فى اورام الراس و الرقبة واورام الرئة والقولون و المستقيم و

فعالية جهازي االشعة المقطعية و الـرنين حيث انه تخطي . الكبد و البنكرياس و االورام اليمفاويه

.المغناطيسى

201


أما بالنسبة الورام المخ فلم يصبح بعد هذا الجهاز هو الخيار االول للتشخيص المبـدئى

.ولكنه االفضل في تحديد مكان الورم بدقه

مؤخرا اصبح جهاز التصوير المقطعى لإلنبعاث البوزيترونى المدمج مع جهاز التـصوير

قطعية من أقوى الوسائل فى تحديد الحقول االشعاعية و كذلك تحديد الجرعات االشعاعية باألشعه الم

.بصورة افضل من جهاز االشعة المقطعية بصورة منفصلة

إن إستخدام هذا الجهاز فى تحديد الحقول الشعاعية للعالج الشعاعي ثالثى االبعاد غيـر

ين وجود موت فى جزء من الـورم او انـه بصورة واضحة حدود تلك الحقول اما انه صغرها ألنه ب

.كبرها ألنه استطاع تصوير حدود بيولوجيه نشطه للورم لم يستطع اي جهاز اخر اكتشافها

العديد من الدراسات اكدت كفاءة استخدام هذا الجهاز تحديد الحقـول االشـعاعية الورام

اما بقية االورام فهى . و الميالنوما الرأس و الرقبة و الرئه والمخ و االورام الليمفاوية كبيرة الحجم

.مازالت تحت الدراسات لتحديد مدى فعالية الجهاز لترسيم حقولها االشعاعية

لم يصبح جهاز التصوير المقطعى لإلنبعاث البوزيترونى المدمج مـع جهـاز التـصوير

د يـتم اسـتنفاذ حيث انه في معظم المعاه -باألشعه المقطعية هو الخط التشخيصي االول لالورام بعد

، و لكنه يعد االن احد اهم -جميع كل وسائل التشخيص الطبى من اشعات عادية و فحوصات معملية

.االجهزة المساعده في التخطيط للعالج االشعاعي

202


الملخص العربي

203


204

الماجستيربروتوآول توطئة للحصول على درجة )مقال(

:عنوان البحث نبعاث البوزيتروني المدمج مع التصويرقطعي لال التصوير المدور قطعية فى التخطيط وتحديد الحقل العالجي االشعاعياألشعة المب

:اسم الباحث أحمد عبد الهادي عبد الرحمن عبد الرحمن مصطفى /الطبيب طبيب مقيم عالج األورام و الطب النووي/ الوظيفة

مستشفي المنصورة الجامعي

: المشرفون اذ مساعدأست

هاله محمد أحمد الشنشاوى/ الدآتورة أستاذ مساعد عالج األورام و الطب النووي

جامعة المنصورة–آلية الطب

محمد عبد الرحمن موسي داوود / الدآتور عالج األورام و الطب النووي مدرس

جامعة المنصورة–آلية الطب

:المشرف الرئيسي

أستاذ مساعد أحمد الشنشاوىهاله محمد / الدآتورة

أستاذ مساعد عالج األورام و الطب النووي جامعة المنصورة–آلية الطب

:بروتوآول رقم

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