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FDG PET-CT in metastatic prostate cancer

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FDG PET-CT in metastatic prostate cancer

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FDG PET-CT IN METASTATIC PROSTATE CANCER

by

Bhushan Desai

_______________________________________________________________________

A Thesis Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements of the Degree
MASTER OF SCIENCE
(CLINICAL AND BIOMEDICAL INVESTIGATIONS)

August 2010

Copyright 2010 Bhushan Desai
EPIGRAPH

Now here is a message for you guys out there.
A short word of warning - take care and beware.
If you have trouble peeing with all of your might
or have to get up more than once in the night
If all you can do is dribble and strain
zip yourself up - and then do it again,
then the prick you should look for is called a Blood
Test and the doctors and scientists do all the rest.
Your little prostate may be starting to grow
and squeeze on your organs - and you will not know.
But your pipe called Urethra goes right through the middle
which is why, when it grows, it gets harder to piddle.
It will only get worse - it will not just improve So make early
arrangements to ease or remove this walnut size organ that causes
such grief before it's too late - sort it out - get relief!
It may NOT be cancer - it could just have
grown so a quick exploration and all will be
known. But if it is cancer you have to be quick
to catch it and treat it before you get sick.

- Nigel Lewis-Baker (The Prostate Poem- A Word of Warning)
ii
DEDICATION

To my parents, mentor and patients

iii
ACKNOWLEDGEMENTS

The work in this thesis has been made possible by the efforts of many people to whom I
am most grateful; but there are some who deserve special thanks. Dr. Hossein Jadvar,
my Mentor, Supervisor and Study Chair, for providing me the opportunity to work on this
project and sharing his vast knowledge and wisdom in both science and life. I owe you
immensely for every-day tutoring, inspiration and generosity throughout the entire work.
It has been a privilege. Dr. Jacek Pinski, the Oncologist and committee member, for
always entertaining questions and stimulating talk and discussions. Dr. Susan Groshen,
chief statistician and committee member, for providing valuable counseling in statistical
matters. Ye Wei, statistician, for doing complex statistical analysis and helping me
understand statistical concepts. Dr. Stanley Azen, co-director and advisor of my course,
for providing me excellent guidance and for understanding and inspiring support,
encouragements when I was trapped in dilemmas. Dr. Tanya Dorff, Dr. David Quinn,
the oncologists at clinics, for maintaining a welcoming atmosphere and entertaining
questions. Dr. Robert Henderson, Dr. John Seto, Dr. Peter Conti, the Nuclear
medicine physicians at the PET center, for helping me out with interpretations of scans
and stimulating talks and discussions. Residents and Fellows, Dr. Aarti Kaushik, Dr.

Sindu Sheth, Dr. David Chang, at the PET center, for maintaining a welcoming
atmosphere and helping me with my research when I was trapped in a corner.

Julia Quillen, Research Nurse, for constructive discussions and kind assistance at the
PET center. Pranjali Bakeri, Programmer Analyst, for her kind and generous help with
setting up the database as per my requirements. My Friends and colleagues, for

iv

inspiring and motivating me in tough times. Staff, at the PET center, for all your help and
support throughout my study process. My family, for their love, support, endless patience
and solid belief in me. Finally I would like to thank all the patients who participated in
this study and made this research possible. Financial support was generously granted by

NIH-NCI R01-CA111613 and Cancer center core grant NIH-NCI-P30-CA14089.

v
TABLE OF CONTENTS
Epigraph ii
Dedication iii
Acknowledgements iv
List of Tables viii
List of Figures ix
Abbreviations xii
Abstract xiv
Preface xvi
Chapter 1: Introduction
1.1 Prostate Cancer – Scope of the Problem 1
1.2 Treatment of metastatic prostate cancer 7
1.3 Diagnostic imaging evaluation of prostate cancer 9
1.4 FDG-PET and Tumor metabolism 10
Chapter 2: Materials and Methods
2.1 The Clinical Protocol 19
2.2 PET imaging and Interpretation 22
2.3 Data collection, Monitoring and Quality control 23
Chapter 3: A pictorial review of various sites of metastasis from prostate
cancer as seen on FDG PET-CT scan. 24
Chapter 4: Detection of lymphadenopathy in metastatic prostate cancer:
18F-FDG PET vs. CT 37
Chapter 5: Imaging evaluation of osseous metastasis in prostate cancer:
A comparison of FDG PET, CT and Bone scan. 52

vi
Chapter 6: Case Reports: Diagnostic utility of 18F-FDG PET-CT for
evaluation of treatment response.
6.1 Castrate – Sensitive patients 64
6.2 Castrate – Resistant patients 73
Chapter 7: Clinical determinants of node vs. bone dominant metastatic
disease on FDG PET-CT – Preliminary analysis and Results 82
Conclusion 88
Future Perspectives 90
Accepted / In Review / In preparation Abstracts, Papers and Presentations
on this Thesis 91
Bibliography 92

vii
LIST OF TABLES
Table 1: Thesis at a Glance

xvi
Table 2: Inclusion/Exclusion criteria for all groups. 21
Table 3: Patient Demographics. 39
Table 4: Kappa statistics & Concordance rates for Region based LN analysis
comparing PET and CT. 41
Table 5: Concordance for LN‟s between PET and CT for all patients using
Cut-point SUVmax=2.5 vs. Cut-point SUVmax=Average liver SUV. 42
Table 6: Concordance rates for individual LN lesions between PET and CT
using cut-off values SUVmax ≥ 2.5 and CTLD ≥ 1.0 cm 43
Table 7: Differences of SUVmax & CTLD between CS and CR 43
Table 8: Spearman Correlation Coefficients 43
Table 9: Mean ± S.D, range of SUVmax, CTLD between CS & CR patients and
between pre-therapy and during therapy 44
Table 10: Region based Kappa scores and Concordance rates between
PET & CT vs. Bone scan 57
Table 11: Region based Kappa scores and Concordance rates between
PET or CT vs. Bone scan 57
Table 12: Concordance rates for individual bone lesions between PET or CT
vs. Bone scan for castrate-sensitive and castrate-resistant patients. 59
Table 13: Concordance rates for individual bone lesions between PET and CT
vs. Bone scan for castrate-sensitive and castrate-resistant patients. 59
Table 14: Comparison in concordance rates for individual bone lesions between
visits and between groups 60
Table 15: Distribution and characteristics of group 1 & 2 patients. 84
Table 16: Univariate logistic regression for presence of bone disease when
SUV≥2.5 was used as cut point (pts with prostate bed lesions
included N=70). 85

viii
LIST OF FIGURES
Figure 1: HPS stain showing prostate adenocarcinoma, acinar type
which is the most common type of prostate cancer. 2
Figure 2: Diagram showing the location of prostate, in front of rectum
and just below the bladder. 2
Figure 3: Graphical presentation of incidence and mortality rates
of prostate cancer in U.S. 3
Figure 4A: FDG uptake and accumulation in plasma and in benign
and malignant tissue. 10
Figure 4B: FDG PET-CT scan image. 10
Figure 5: The principle of PET. 11
Figure 6: Schematic illustration of the metabolism of glucose and of FDG. 13
Figure 7: Recruitment status for the ongoing Imaging trial. 20
Figure 8: Normal Prostate Gland as seen on FDG PET-CT scan. 24
Figure 9: FDG PET-CT scan demonstrating a lesion in prostate bed. 25
Figure 10: Metastasis to lungs from primary prostate cancer as seen on
FDG PET-CT. 26
Figure 11: Osseous metastasis to Brain from advanced prostate cancer. 26
Figure 12: Metastasis to Liver from advanced prostate cancer. 28
Figure 13: Metastasis to Axillary LN (Supra-diaphragmatic region). 29
Figure 14: Metastasis to lymph nodes in the retro-peritoneum from prostate
cancer. 30
Figure 15: Metastatic spread to lymph nodes in the Pelvis. 30
Figure 16: Metastasis to lumbar spine as seen by FDG PET-CT and Bone scan. 32
Figure 17: Osseous metastasis to pelvic bones from prostate cancer. 33
Figure 18: Osseous metastasis to extremities from advanced prostate cancer. 34
ix
Figure 19: Osseous Metastasis to Ribs. 34
Figure 20: Pattern of osseous metastasis as demonstrated
by FDG PET and CT scan. 35
Figure 21: Serial FDG PET-CT scan images showing changes in the
metabolic activity (SUVmax), morphologic appearance (CTLD)
and PSA levels for a lymph node lesion detected in pelvic region. 47
Figure 22: Serial FDG PET-CT scan images demonstrating changes
in metabolic activity (SUVmax), morphologic appearance (CTLD)
and PSA levels for a lymph node lesion detected in retro-peritoneum. 48
Figure 23: Serial FDG PET-CT scan images demonstrating changes in
metabolic activity (SUVmax), morphologic appearance (CTLD) and
serum PSA levels, for lymph node lesion in supra-diaphragmatic region. 50
Figure 24: Serial FDG PET-CT and Bone scan images showing changes in the
metabolic activity (SUVmax), sclerosis (HU) and PSA levels, for
an osseous lesion detected in thoraco-lumbar spine. 60
Figure 25: Graph depicting the serial interval changes in the serum PSA levels
in relation with increase in the SUVmax values for some reference
nodular lesions in the retro-peritoneum and a new osseous lesion
that was noted on 4
th
scan. 67
Figure 26: Serial FDG PET-CT scan images showing changes in the metabolic
abnormality (SUVmax) and morphologic appearance (CTLD) for
lymph node lesion in retro-peritoneum, demonstrating response
to treatment captured by PET, CT scan and correlating it with serum
PSA levels. 68
Figure 27: Coronal CT (left), MIP (maximum intensity projection) of whole
body PET scan (middle) and bone scintigraphy (right) images at
baseline, 4, 8 and 12 month correlating the changes in the intensity
and activity of lesions with changes in the therapy of the patient. 69
Figure 28: Serial FDG PET-CT scan images in a castrate-resistant metastatic
prostate cancer patient, demonstrating changes in metabolic
activity (SUVmax) and morphologic appearance (CTLD) and serum
PSA levels in response to his various therapeutic regimens. 77

x
Figure 29: Graph depicting the serial interval changes in the serum PSA levels
in relation with increase in the SUV values for some reference
nodular lesions in the lungs and a new lesion that was noted in
brain on 8 month scan. 78
Figure 30: FDG PET-CT and Bone scan images demonstrating a case where
high serum PSA and Alkaline Phosphatase levels were associated
with a predominant osseous metastasis. 86
Figure 31: FDG PET-CT scan images demonstrating a case where low serum
PSA and Alkaline Phosphatase levels were associated with a
predominant lymph node metastasis. 87

xi
ABBREVIATIONS

ACR American cancer society

BGO bismuth germanate oxide

CR castrate- resistant

CRF case report form

CS castrate-sensitive

CT computed tomography

CTLD computed tomography longest diameter

CTSD computed tomography shortest diameter

DRE digital rectal exam

EORTC European organization for research and treatment of cancer

FBG fasting blood glucose

FDG 2-deoxy-2-[18F] fluoro-D-glucose

GLUT glucose transporter

HCC health consultation center

HIPAA health insurance portability and accountability act

HPS hematoxylin phloxine saffron

HU Hounsfield unit

IC informed consent

KSOM Keck School of Medicine

LAC Los Angeles County

LN lymph node

LSO lutetium oxyorthosilicate

MDP methylene diphosphate

xii
MIP maximum intensity projection

MRI magnetic resonance imaging

NCI national cancer institute

NIH national institute of health

NOPR national oncology PET registry

PET positron emission tomography

PSA prostate specific antigen

RECIST response evaluation criteria in solid tumors

ROC receiver operating characteristic

ROI region of interest

S.D. Standard deviation

SEER surveillance epidemiology and end results

SUV standardized uptake value

TNM tumor, nodes, metastasis

USC University of southern California

xiii
ABSTRACT

The aims of present thesis are:

1) To provide a pictorial view of the various sites of metastasis from prostate cancer
as detected by FDG PET-CT scan and to compare its diagnostic potential with the
conventional gold standard imaging modalities (CT and Tc 99m-MDP bone
scintigraphy).

2) To assess the diagnostic utility of 18F-Fluorodeoxyglucose (FDG) Positron
Emission Tomography (PET) compared to Computed Tomography (CT) in
detection of lymph node metastasis in men with metastatic prostate cancer.

3) To compare the diagnostic utility of FDG-PET, CT and Bone scans in evaluation of
osseous metastasis in men with malignant prostate cancer.

4) To determine the effects of clinical variables (PSA, calcium, Gleason score,
Alkaline Phosphatase) in predicting a bone vs. non-bone (LN+ soft tissue) dominant
disease on FDG PET/CT in men with metastatic prostate cancer.

5) To identify interesting cases depicting the role of 18F-FDG PET scan for evaluation

of response to treatment in metastatic prostate cancer.

- Castrate-sensitive patients

- Castrate- resistant patients

xiv

Our long-range objective is to investigate the ability of the new hybrid positron
emission tomography and computed tomography (PET-CT) imaging systems to assess
treatment response in patients with metastatic prostate cancer in comparison to
conventional imaging. We believe that the combined anatomic and in-vivo metabolic
imaging information provided by PET-CT allows accurate objective assessment of such
critical clinical issues as early prediction and evaluation of response or resistance to
various therapeutic interventions, involving the novel chemotherapy regimen, as well as
the prediction of key clinical outcomes such as time to hormone-refractoriness and
survival.

xv
PREFACE

Table 1: Thesis at a Glance

Aim Result FDG-PET-CT image Conclusion

Role of 18F-FDG Region based Kappa Integrated FDG PET-

PET compared to scores & lesion based CT seems a more

CT, in detection of concordance rates effective tool compared

1
lymphadenopathy in showed moderate to to PET & CT alone for

patients with substantial agreement

detection of LN

metastatic prostate between PET & CT metastasis in prostate

cancer. imaging modalities. cancer.

Comparing FDG Region based Kappa, 18F-FDG PET-CT scan

PET-CT and concordance rates & showed reasonably

Tc99m-MDP Bone individual bone high concordance with

2
scan for evaluation lesions concordance gold standard Tc99m-

of osseous rates showed

MDP bone scan for

metastasis in substantial agreement detection of osseous

malignant prostate between FDG PET-CT metastasis in advanced

cancer. & Bone scan. prostate cancer

patients.

Determining the PSA was significantly PSA is an important

effects of clinical associated (p<0.001) clinical variable in

variables in with predicting predicting osseous vs.

3
predicting a Bone osseous compared to nodal predominant

vs. Non-bone nodal metastasis on PSA = 180 ng/ml metastasis on FDG

(LN+soft tissue) FDG PET-CT scan. PET-CT scan, in men

dominant metastasis Odds being 7.33 & 9 with malignant cancer

on FDG PET-CT times higher with PSA of the prostate.

scan in metastatic levels of 4.1-20 & >20

prostate cancer. ng/ml respectively.
PSA = 0.51 ng/ml

Evaluating the role Assessing response to FDG PET is an

of serial FDG PET- treatment is crucial accurate descriptor of

CT scan as a both in routine clinical treatment effects,

4
diagnostic tool for care and clinical trials. reflecting in a single

assessing response

modality the effects

to treatment for
FDG PET scan
now captured by three

patients with
showed substantial
measures: PSA, bone

metastatic prostate
correlation with CT,
scintigraphy and soft

cancer treated with
Bone scan & PSA
tissue imaging.

levels in assessing

xvi
Table 1: Continued

The use of hybrid PET-

Various forms of
CT imaging systems will

androgen ablation response to treatment
afford synergistic

and/or

for both CS & CR

diagnostic information

chemotherapeutic

malignant prostate

and increased diagnostic

regimens.

cancer patients.

confidence by providing

-castrate-sensitive a precise localization of

-castrate-resistant metabolic abnormalities.

A pictorial view of

the various sites of

5
metastasis from

primary prostate

cancer, as seen on

FDG PET-CT scan. Prostate Gland Lungs Brain

Liver Axillary LN Retro-Peritoneal LN

Pelvic LN Lumbar Spine Pelvis

Extremities Ribs Common Pattern

xvii
CHAPTER 1: INTRODUCTION

1.1 Prostate cancer - Scope of the problem

Cancer of the prostate is a serious health problem worldwide. Incidence of prostate
cancer varies widely across the world, with South and East Asia detecting fewer cases per
capita than in Europe, and especially the United States. Fortunately, prostate cancer is
one of the most treatable malignancies if it is caught early. Routine screening has
improved the diagnosis of prostate cancer in recent years. In addition, new and innovative
technology helps to minimize the side effects of prostate cancer treatment, including
urinary incontinence and erectile dysfunction. When new knowledge emerges in
medicine, it needs to be evaluated both clinically and experimentally to establish if and
how it may be beneficial to the patients. We performed these studies to investigate the
potential value of positron emission tomography (PET) with 2-deoxy-2-[18F] fluoro-D-
glucose (FDG) in men with metastatic prostate cancer.

Natural history and prognosis of prostate cancer

Epidemiology

Prostate cancer is the most common cancer affecting men in the United States, after
skin cancer. The American Cancer Society (ACS) estimates that there was roughly
192,280 new cases of prostate cancer in the United States and 27,360 men will die from
prostate cancer in 2009. Nearly 1 in 6 men will develop prostate cancer in their lifetime;
however it is usually diagnosed after the age of 40. The age-adjusted incidence rate was

156.9 per 100,000 men per year and the prevalence as of Jan 1, 2007, in Unites States

1

was 2,276,112 (SEER 2003-2007). The overall 5-year relative survival for 1996-2006 from
17 SEER geographic areas was 99.1%. As life expectancy increases, so will the incidence of
this disease, creating what will become an epidemic male health problem. More than 2
million men in the United States who have been diagnosed with prostate cancer at some
point are still alive today. Prostate cancer is a heterogeneous disease characterized by an
overall long natural history in comparison to the other solid tumors, with a wide spectrum of
biological behavior that ranges between indolent and aggressive states (Frank 1991, Kessler
2003). Figure 1 shows the most histopatholigical type of prostate cancer while Figure 2
shows the normal anatomic location of the prostate gland.

Figure 1 Figure 2

Figure 1: HPS stain showing prostate adenocarcinoma, acinar type which is the
most common type of prostate cancer.

Figure 2: Diagram showing the location of prostate, in front of rectum and just
below the bladder.

2

Figure 3 Graphical presentation of incidence and mortality rates of prostate
cancer in U.S. Source for incidence and mortality data: Surveillance, Epidemiology,
and End Results (SEER) Program and the National Center for Health Statistics.

Risk Factors, prevention, diagnosis and staging

The specific causes of prostate cancer still remain unknown. A variety of factors like age,
genetics, race, diet, lifestyle and medications have been determined as possible risk
factors for prostate cancer. Prostate cancer is very uncommon in men younger than 45,
but becomes more common with advancing age. Screening for prostate cancer is done
using the prostate specific antigen (PSA) blood test and digital rectal examination to find
unsuspected cancers. Prostate cancer is usually slow growing and most cancers never
grow enough to cause symptoms. The gold standard test for diagnosing prostate cancer is
biopsy of the prostatic tissue for microscopic examination. Staging of prostate cancer is
one of the most important factors in choosing treatment option. TNM (Tumor, Nodes,
and Metastasis) system is used for staging of prostate cancer. From National Cancer
Institute (NCI) site:

3

Primary tumor (T)

TX: Primary tumor cannot be assessed

T0: No evidence of primary tumor

T1: Clinically inapparent tumor not palpable nor visible by imaging

T1a: Tumor incidental histologic finding in 5% or less of tissue resected

T1b: Tumor incidental histologic finding in > 5% of tissue resected

T1c: Tumor identified by needle biopsy (e.g., because of elevated PSA)

T2: Tumor confined within prostate

T2a: Tumor involves 50% or less of one lobe

T2b: Tumor involves more than 50% of one lobe but not both lobes

T2c: Tumor involves both lobes

T3: Tumor extends through the prostate capsule

T3a: Extracapsular extension (unilateral or bilateral)

T3b: Tumor invades seminal vesicle(s)

T4: Tumor is fixed or invades adjacent structures other than seminal vesicles:
bladder neck, external sphincter, rectum, levator muscles, and/or pelvic
wall

Regional lymph nodes (N)

NX: Regional lymph nodes were not assessed

N0: No regional lymph node metastasis

N1: Metastasis in regional lymph node(s)

Distant metastasis (M)

MX: Distant metastasis cannot be assessed (not evaluated by any modality)

M0: No distant metastasis

M1: Distant metastasis

4

Histopathologic grade (G)

GX: Grade cannot be assessed

G1: Well differentiated (slight anaplasia) (Gleason score of 2–4)

G2: Moderately differentiated (moderate anaplasia) (Gleason score of 5–6)

G3-4: Poorly differentiated or undifferentiated (marked anaplasia)
(Gleason score of 7–10)

AJCC Stage Groupings Stage I

T1a, N0, M0, G1

Stage II

T1a, N0, M0, G2–4

T1b, N0, M0, any G

T1c, N0, M0, any G

T1, N0, M0, any G

T2, N0, M0, any G

Stage III

T3, N0, M0, any G

Stage IV

T4, N0, M0, any G

Any T, N1, M0, any G

Any T, any N, M1, any G

5
Prognosis and prognostic factors

According to the American Cancer Society, 5-year survival rates for all types of prostate
cancer have increased during the past 20 years from 67% to nearly 100%. Prediction of
prognosis is an important objective in the clinical decision making process, patient
counseling, and assessing treatment outcomes (Smaltez 2002a). To this end, Partin tables
and nomograms have been developed. Partin tables use the clinical stage, Gleason score,
age, and nuclear morphometry to predict disease-free survival among patients with
clinically localized prostate cancer after surgery (Partin 1992). However, such clinically
derived models cannot directly guide a specific therapy or provide accurate objective
means for early prediction of treatment response and comparison of clinical trials for
either the current conventional therapies or the potentially new treatments.

The role of PSA changes in predicting prognosis in patients with metastatic prostate
cancer who are treated with androgen withdrawal therapy has also been investigated. It
appears that patients with high initial PSA level have a worse cause-specific survival and
that serial PSA measurements can distinguish non-favorable responders early in the
course of treatment and assist in monitoring for disease progression (Miller 1992, Kelly
1993, Matzkin 1993, Spencer 1998, Furuya 2001). This is in fact what is done nowadays
clinically. PSA doubling time has been found to be useful in predicting systemic
progression free survival (defined as time to evidence of metastatic disease on bone
scintigraphy) in patients with biochemical failure (defined as PSA level > 0.4 ng/mL)
following radical prostatectomy (Roberts 2001). There are various definitions in use for
defining biochemical recurrence (PSA relapse) either post-radical prostatectomy or post-
6

radiation therapy. In patients with metastatic cancer who are treated with androgen
ablation therapy, PSA changes may be useful in determining the time to androgen-
independent progression in combination with the initial Gleason grade (Oosterlinck 1997,
Benaim 2002). In patients with hormone-refractory metastatic cancer who are treated
with chemotherapy and/or other therapies for hormone refractory disease, PSA can
predict pain end points as well as progression-free survival and overall survival (Small
2001). However, despite the utility of PSA as an “organ-specific marker”, it is not ideal
due to its non- specificity and low sensitivity. PSA should not be considered as a direct
measure of tumor growth since the serum level is influenced by the volume of the benign
epithelium, grade of carcinoma, inflammation, androgen levels, growth factors, and the
extracellular matrix (Crawford 1996). PSA may be undetectable or low in view of
disseminated prostate cancer (Sandhu 1992, Safa 1998, Sella 2000, Beardo 2001) and
there is emerging data to suggest that various therapies may affect the PSA expression in
a manner unrelated to the impact on tumor growth (Dreicer 1997, Bauer 1999, Horti
1999). Additionally, PSA is frequently a source of great anxiety and overstated diagnostic
expectations by the patient in a term coined as “PSA-itis” (Lofters 2002).

1.2 Treatment of metastatic prostate cancer

There is no absolute cure for metastatic prostate cancer. Treatment options for prostate
cancer may involve active surveillance (monitoring for tumor progress or symptoms),
surgery (i.e. radical prostatectomy), radiation therapy including brachytherapy and
external beam radiation, androgen deprivation therapy, chemotherapy, bisphosphonates,
bone targeted pharmaceuticals, immunomodulation (via granulocyte macrophage colony
7

stimulating factor), vaccines (Provenge), gene therapy or a combination of any of the
above treatments. However, there is lack of data on the outcome of the various treatment
modalities (Yao 2003). Which option is best depends on the stage of the disease, the

Gleason score, and the PSA level. Other important factors are the man‟s age, his general

health, and his feelings about potential treatments and their possible side-effects.
Because all treatments have significant side effects, such as loss of libido, impotence,
fatigue, osteoporosis, urinary incontinence, there have been controversies regarding the
best treatment option and hence treatment discussions often focus on balancing the goals
of therapy with the risks of lifestyle modifications.

If the cancer has metastasized to various sites, treatment options significantly change, so
most doctors use a variety of nomograms to predict the probability of spread. Androgen
deprivation (surgical or medical) is the cornerstone of treatment for patients that are
newly diagnosed with a metastatic prostate cancer. Hormone ablation therapy, although
initially highly effective, eventually results in a hormone refractory metastatic prostate
cancer over a relatively short period of 2-3 years and this is associated with a median
survival of around 8 months. Chemotherapy with or without hormonal therapy is offered
to such patients who present a failure with androgen deprivation therapy and continue to
show progression based on rise in PSA or imaging evidence of progression. All these
treatment modalities have met with variable success but large clinical trials are needed
to demonstrate the efficacy and safety of using these treatments either alone or in
combination at various stages of the prostate cancer.

8
1.3 Diagnostic imaging evaluation of prostate cancer

Imaging evaluation of prostate cancer remains challenging (Yu 2000). The optimal
method for imaging evaluation of men with PSA relapse (biochemical failure) is
unresolved, but the goal of imaging is to determine if recurrence has occurred in the
previously treated prostate bed or whether distant metastasis is present. The accurate
information on presence and extent of metastatic disease in combination with the
physiologic, histologic, antigenic, molecular, and genetic markers of the disease will
provide unprecedented opportunities for the new era of imaging-based cancer
diagnosis and therapy (Benaron 2002). Current imaging tests, including ultrasound,
CT, magnetic resonance imaging (MRI), bone scintigraphy, and In-111 capromab
pendetide (Prostascint, Cytogen, Princeton, NJ) are not sufficiently accurate to detect
local recurrence or metastatic disease in prostate cancer (Engelbrecht 2000, Haseman
1996, Haseman 2000).

Although bone scintigraphy can be useful in detecting osseous metastasis, the false
positive rate is high (Roudier 2003), and cannot detect soft tissue or lymph nodal
involvement, which is quite prevalent with the metastatic spread of this disease. Bone
scintigraphy has limited sensitivity in detecting metastasis when the serum PSA level is
below 2 ng/ml and only best correlates at high PSA levels of >16 ng/ml (Lee 1997,
Modoni 1997, Murphy 1997). Additionally, a flare phenomenon may be observed with
the initiation of hormonal ablation and even chemotherapy in the setting of clinical and
serologic improvement but worsening scan pattern (Coleman 1988). Newer imaging
methods using highly lymphotropic superparamagnetic nanoparticles in conjunction with

9

high-resolution MRI may also allow the detection of small and otherwise undetectable
lymph-node metastasis in patients with prostate cancer (Harisinghani 2003). However,
the exact utility of such diagnostic imaging approach in a diverse group of patients still
needs to be determined.

1.4 FDG-PET and Tumor metabolism

A B

Figure 4A: FDG uptake and accumulation in plasma and in benign and malignant
tissue. The yellow arrow indicates the relative difference in FDG accumulation
between benign and malignant tissue that forms the basis of the FDG PET image.
Modified from Ohlsson.

Figure 4B: FDG PET-CT scan image. By fusion of a PET image (top) and a CT
image (bottom), an anatomical location of the radiotracer uptake can be visualized
in a PET-CT image (middle). Maximum Intensity Projection (MIP) image showing
FDG uptake by numerous osseous metastatic lesions in axial and appendicular
skeleton.

10

Figure 5: The principle of PET. A positron from the administered radioisotope, in
this case 18F, was produced by cyclotron, annihilation occurred after injection

(A).This coincidence radiation is then detected in a PET camera (B), and thus the
position of the origin of the annihilation radiation can be located (C).

PET principle

PET, positron emission tomography, is an advanced molecular imaging modality
that enables non-invasive in vivo studies of the uptake and metabolism of radioactive
labeled substances. Acquired images are evaluated visually and additional quantitative
analysis can be done. Positron-emitting radionuclides are used to label biological
substances that are administered as tracers to the subject (Phelps 2004). A PET image
provides information on the relative distribution of the administered tracer.

11

The discovery of coincidence radiation led to the development of gamma cameras
in the 1960s and PET cameras in 1970s (Schaer et al. 1965; Ter-Pogossian et al. 1975).
The annihilation quanta are detected by the PET camera with crystals most commonly
composed of bismuth germanate oxide (BGO) and lutetium oxyorthosilicate (LSO). After
the radionuclide labeled molecular compound is injected into the body, the unstable
radionuclide decays by emitting a positron particle that collides with a nearby electron
and both are annihilated, releasing two positively directed 511kev γ photons. The
photons strike the detectors which surround the studied object in the field of view. The
coincidence events are recorded by the detector and stored in the workstation.
Subsequently, the collected data are reconstructed and stored in datasets that are
converted into three dimensional images with variable color scales, representing the
actual radioactivity concentration within the body (Figure 5). The spatial resolution of
PET is poorer than that of CT or MRI. For anatomical co-localization of the registered
activity a combination of PET and CT is often used in a sequential set-up. Recently,
combinations of PET and MRI have been presented. Software fusion solutions for PET
images and conventional images are available. A PET image, a CT image, and the fused
PET-CT image are seen in Figure 4B.

12

Blood Tissue

Glucose Glucose-6P Glycolysis

Glucose

hexokinase

K3

K1

FDG

FDG

FDG-6P

K2 K4

Figure 6: Schematic illustration of the metabolism of glucose and of FDG. It shows
a compartment model of FDG metabolism, in which k1-k4 is the transport rate
constants between the vascular FDG, the tissue-FDG and the tissue FDG-6P.
Modified from Phelps.

PET Radiotracers

The existence of a positively charged anti-particle to the electron, the positron, has been
known since 1930s (Anderson 1933). In the 1950s detection of the annihilation
radiation created when a positron and an electron meet, conjugate and annihilate was
made possible. Coincidence counting of the energy quanta from the positron decay was
found to be of use in the location of the source of annihilation along a straight line, the
coincidence line, between the detectors (Wrenn et al. 1951). Positron-emitting
radionuclides are produced in a cyclotron, a powerful accelerator. The half-life of the
radionuclide determines its use in clinical practice. Commonly used radionuclides are
fluorine (18F), nitrogen (13N), and carbon (11C) with half-lives of 110, 10 and 20
minutes, respectively (Oehr 2004).

13

Different PET radiotracers offer different advantages during various clinical states of
prostate cancer, depending on the most relevant biological markers of disease at each
stage (Oyama et al. 2002, Farsad et al. 2008). In oncology 2-deoxy-2-[18F] fluoro-D-
glucose (18F-FDG), as a marker for glucose metabolism, is by far the most used
radiotracer. Many other PET radiotracers are currently being explored, including 11C-
labelled or 18F-labelled acetate or choline, 11C-labelled methionine, androgen-
receptor-avid agents such as 18F-FDHT (16β-18F-fluoro-5α-dihydrotestosterone), anti-
FACBC (1-amino-3-18F-fluorocyclobutane-1-carboxylic acid) a synthetic L-leucine
analog, a radiolabelled PSMA inhibitor and 18F-fluoride (for bone metastasis) (Jadvar
2009). Prospective clinical imaging trials using various PET tracers in different clinical-
state-specific patient cohorts with well-defined end points will be needed to decipher
the optimal use of PET in prostate cancer.

Tumor metabolism and FDG

The uncontrolled proliferation of malignant cells requires sustained angiogenesis, tissue
invasion, metastatic potentiation, evasion of apoptosis, insensitivity to growth-inhibitory
signals, and an accelerated metabolism leading to a high glucose demand and an
increased glucose uptake compared with normal cells (Warburg 1956; Weber 1977a;
Weber 1977b; Jadvar 2009). Glucose is transported into cells by facilitative glucose
transporter (GLUT) proteins. At present, 13 isoforms of GLUTs have been identified,
each with a different affinity for glucose and a different distribution within the body
(Joost et al. 2002; Macheda et al. 2005). Over-expression of GLUTs, such as GLUT1 and
GLUT3, has a high affinity for glucose which has been demonstrated in many types of

14

cancer and at an early stage in the malignant transformation (Medina et al. 2002; Flier
et al. 1987).

FDG is the most common tracer of PET in oncologic imaging. It is an analog of glucose
with 18-Fluorine substituting a hydroxyl group in the second position of the glucose
molecule. As a result of this substitution, FDG only participates in initial enzymatic
reactions of glucose metabolism. After FDG is injected intravenously, it competes with
normal glucose and is transported from plasma to tissue by specific glucose transporters
in cell membranes and phosphorylated to 18F-FDG-6- phosphate by the enzyme
hexokinase, after which it is trapped in the cells without further metabolism. High
uptake of FDG is therefore due to the over-expression of glucose transporters and
hexokinase in the tumor cells (Jadvar et al. 2009) and only indirectly associated with
increased glycolysis. FDG PET has achieved a central role for evaluation of patients
with various tumor types. It has been used not only for staging, restaging, distinguishing
recurrence, but also for delineating biological target volumes for RT treatment planning
and monitoring tumor response to chemotherapy (Young et al. 1999; Gregiore et al.
2007). Malignant cells exhibit low levels of glucose-6-phosphatase compared with
normal tissues and benign inflammatory processes, leading to differences in FDG
accumulation between benign and malignant tissues (Yamada et al. 1995; Nakamoto et
al. 2000). This is visualized in Figure 5 and Figure 6.

15
Evaluating FDG-PET scans

Visual analysis of FDG-PET is often enough in routine clinical practice. For quantitative
analysis of tracer uptake, a Region of Interest (ROI), encompassing the tumor, is defined
on the PET image, and the amount of radioactivity within the ROI is evaluated. The most
commonly used method in clinical routine is the semi-quantitative analysis of the
standardized uptake value (SUV) (Strauss et al. 1991). The SUV is the ratio between the
tumor concentration of 18F-FDG in relation to injected activity and body mass of the
patient.

Decay-corrected Mean lesion ROI (cps/pixel) X Calibration
Factor (mCi/g/cps/pixel)

SUV = -----------------------------------------------------------------------------------------

Injected Dose (mCi) / Lean Body Weight (g)

The SUV is dimensionless and a tracer molecule that is evenly distributed within
the body will have an SUV of 1. The SUV method is denoted semi-quantitative
but it remains a popular method because it is simple to handle (Huang 2000;
Castell et al. 2008). The SUV is presented as either SUV mean which is the mean
FDG uptake in a ROI, a tumor, or as SUV max which is the highest SUV value
within a ROI. A strong correlation has been demonstrated between the SUV and
GLUT1 expression, reflecting the high influx of FDG in tumors (Yen et al 2004;
Riedl et al. 2007). For measuring osseous lesions on CT scan, Hounsfield units
(HU) are commonly used for determining the amount of sclerosis.

16
Role of FDG-PET in prostate cancer

As experience accumulate with FDG PET in prostate cancer, it has become evident that
FDG accumulation in high-grade, high Gleason primary tumors and in metastatic lesions
is elevated with a standardized uptake value (SUV) of up to 6 or more at a positive
predictive value of 98% (Effert 1996, Shreve 1996, Hofer 1999, Liu 2001, Patel 2002). In
a study on 24 patients with rising serum PSA level after treatment for localized prostate
cancer, FDG PET was found to be a valuable diagnostic imaging tool for detection of
metastatic disease with sensitivity of 75%, specificity of 100%, positive predictive value
of 100%, and negative predictive value of 68% in patients who had negative whole body
bone scans and equivocal CT findings (Chang 2003). Therefore, FDG PET had a
diagnostic advantage over the standard bone scan and CT for detection and localization
of metastatic sites in these men. Detection of metastatic disease at PSA relapse is
important since it prompts palliative androgen ablation therapy. In another study Morris
et al. evaluated FDG PET in 157 metastatic lesions in 17 patients with progressive
metastatic prostate cancer (Morris 2002). This study also noted that tumor SUV changed
in parallel with the PSA level. Additionally, 6% of metastatic lesions were seen only on
FDG PET and all these lesions proved to be active disease in the subsequent bone scans.
In a study in Germany that compared FDG and C-11 acetate, FDG PET was more
accurate in visualizing distant metastasis than acetate PET (median SUV 3.2 vs. 2.3,
respectively) (Fricke 2003). Additional evidence for the expected diagnostic utility of
FDG PET in metastatic prostate cancer was impacted by an important report published in
March 2004 (J Nucl Med) from the Memorial Sloan-Kettering Cancer Center (MSKCC)

17

in New York, which showed the tumor localization abilities using FDG in
progressive metastatic prostate cancer. FDG can also be used to monitor the response
to chemotherapy and hormonal therapy (Schoder 2004).

Limitations of FDG-PET

Before evaluation of radiotracer uptake, data must be corrected for large potential biases
like correction for attenuation, random effects and scatter which is usually done
mathematically. Motion artifacts also need to be taken into consideration when evaluating
small lesions. Since FDG accumulates in metabolically active tissue, as previously
mentioned, access to clinical data is vital to produce a valid visual evaluation. Among
possible pitfalls are hyperglycemias in diabetic or non-fasting patients, the physiological
FDG accumulation in the brain, the heart, active muscle tissue, the gastrointestinal tract,
and in brown fat (Engel et al. 1996; Hany et al. 2002). The FDG uptake of infectious
processes and of inflammatory cells may pose an important confounding factor (Ozer et
al. 2009; Sanli et al. 2009). This has also been verified in experimental studies where
inflammatory cells have shown an elevated FDG uptake (Kubota et al. 1992; Spaepen et
al. 2003). In addition, there is a physiological FDG uptake in ovaries and endometrium of
premenopausal women related to the menstrual cycle (Nishizawa et al. 2005). Finally,
FDG molecules that are not taken up into the cells are excreted via the urinary tract and
may complicate evaluation of adjacent structures (Oehr 2004).

18
CHAPTER 2: MATERIALS AND METHODS

2.1 The clinical protocol

The HIPAA- compliant prospective imaging trial is being performed with approval from
the University of Southern California Institutional Review Board; a written informed
consent was obtained from each patient after the nature of procedures had been fully
explained. To date, beginning in Oct 2005, we have screened over 1000 prostate cancer
patients at LAC+USC hospital, Norris Cancer Center and other referral centers; the
patients who met the inclusion criteria were offered inclusion in prospective clinical trial
of “FDG PET-CT in metastatic prostate cancer”. Eligible patients had stage IV prostate
cancer and tumor characteristics that could be fitted into one of the two categories.
Group 1 consists of men with hormone-responsive measurable metastatic prostate cancer
who will be treated with hormone ablation therapy. Group 2 consists of patients with
hormone refractory metastatic prostate cancer who will be treated with chemotherapy
and/or other therapies for hormone refractory disease. Figure 7 & Table 2 show the
recruitment calendar and a summary of inclusion/exclusion criteria respectively.

19

RECRUITMENT STATUS

Norris - 94

Total patients recruited

LAC+USC

N = 148 (10/05 – 04/10)

Other - 12

Signed IC, no show @ baseline scan

N = 6

Patients with at least 1 scan

N = 142

Group 2

Group 1

N = 80

N = 62

Off study On Study Off study On Study

N = 49 N = 13 N = 61 N = 19

Primary Primary

Outcome Outcome

Disease Progression

Death on study

N =? (Analysis underway)

N = 34

Figure 7: Recruitment status for the ongoing Imaging trial.

20
Table 2: Inclusion/Exclusion criteria for all groups.

Inclusion Criteria

Group-I (hormone-responsive) inclusion criteria

Histological diagnosis of adenocarcinoma of prostate currently
metastatic as evidenced by CT or bone scintigraphy, which is judged to
be hormone responsive despite possible prior hormonal therapy received
prior to development of objective evidence of metastasis or recurrent
disease.

Group-II (hormone-refractory) inclusion criteria

Histological diagnosis of adenocarcinoma of prostate which is currently
metastatic and is unresponsive to hormonal therapy. Evidence of
refractory disease should be documented by either a frank progression
on CT or Bone scan or clinical progression (bone pain) or 3 consecutive
rises in serum PSA level (>2 ng/ml).

Exclusion Criteria

History of cancer other than prostate.

History of poorly-controlled diabetes (with FBG ≥ 200 mg/dl)

Active infection or other inflammatory conditions (e.g.
rheumatoid arthritis, sarcoid).

Creatinine ≥ 2.5, prior surgery within 14 days and not competent
to consent.

21

For the purpose of this study, Group 1 & Group 2 patients underwent 4 FDG PET-CT
scans at an interval of 3 months each over a 1-year period. The PET predictor parameters
were obtained at 0, 4, 8, and 12 months after the initiation of androgen ablation therapy
(Group 1) or chemotherapy and/or other therapies for hormone refractory disease (Group
2). Each patient was followed-up for one year after the last scheduled FDG PET scan.
The predictor parameters included: serology (serum PSA. Alkaline Phosphatase,
calcium), number and location of metastatic lesions on chest, abdomen and pelvis CT and
bone scintigraphy.

2.2 PET Imaging Protocol & Interpretations

PET and CT were performed with a commercial hybrid PET/CT scanner (Siemens True
point Biograph, Knoxville, TN). The CT scanner is dual ring design, offering diagnostic
quality spiral CT imaging for image co-registration and/or attenuation correction. The
PET scanner design (HR+) incorporates LSO crystal detectors arranged in detector rings
spanning 15 cm axial field of view, provide high count rate, and high resolution imaging.
The system has an intrinsic resolution of 4.2mm and allows 3D acquisition of data.
PET/CT imaging was performed 1 hour after intravenous administration of 15.34 ± 1.08
(±S.D) mCi of FDG. Helical CT (120 kVp, 220 mAs at 15mm/rot) was obtained for
attenuation correction and image fusion and oral contrast was given for the opacification
of the bowel. The data was collected at each bed position for 3 minutes to cover the
anatomic area from top of the head to just below the knees. During the 4-6 hours prior to
imaging, patients had fasted, except for water. All patients had a blood glucose level of
less than 200 mg/dl (11.1 mmol/L) before FDG administration. All images were visually

22

interpreted at a workstation by using PET/CT fusion software (E-soft, Siemens) by
experienced nuclear medicine physicians at USC PET imaging center, in conjunction
with the clinical information and close correlation with other available imaging studies.
All scans were assessed for regional nodal involvement, for the presence of distant
metastasis (bone and soft tissue) and for the presence of recurrence in prostatic bed. A
maximum of up to 10 reference lesions were recorded on baseline scan which were then
followed up on future scans. The presence of abnormal FDG uptake was indicated when
accumulation of radiotracer was moderately to markedly increased relative to the uptake
in comparable normal structures (liver used as a reference), with the exclusion of
physiologic bowel, urinary, and inflammatory activity. For semi- quantitative analysis,
node size in longest diameter (CT) and SUVmax (PET) were determined using vendor
provided software (Siemens). Before analyzing data, a quality control was done (by H.J)
and when discrepancies were detected, interpretations were achieved via consensus.

2.3 Data collection

Data were collected using study-specific case report forms (CRF‟s) using study ID
numbers and coded letters. CRF‟s were completed by the study coordinator and all
research data was kept confidential in secure locked cabinets located in the USC PET
Imaging Science Center in HCC1, room 350. Additionally, all study-specific
information was recorded in the Norris Cancer Center database, CAFÉ, system.

23
CHAPTER 3: A PICTORIAL VIEW OF THE VARIOUS SITES OF
METASTASES FROM PROSTATE CANCER AS SEEN ON FDG
PET-CT SCAN

Metastasis is more likely to occur during advanced prostate cancer (Clinical stage
IV). Metastatic disease refers to prostate cancer that has left the prostate gland and its
neighboring organs, which occurs through a process called angiogenesis. Malignant
cells are capable of „hitching a ride‟ into another part of the body and commonly
become lodged in bones and lymph nodes. All the patients recruited in this study were
having stage IV disease. We showcase all different sites of metastasis from primary
prostate cancer that were observed among these patients.

A) Normal Prostate gland.

Max CT density = 96 Max SUV = 2.1 Mean SUV = 1.5 Size = 3.6 cm
HU

Figure 8: Normal Prostate Gland as seen on FDG PET-CT scan.

A study was conducted on 145 men (Jadvar et al. 2008) with indications unrelated to
prostate pathology for assessing the glucose metabolism and CT density of the normal
prostate gland in relation to age and prostate size using FDG-PET-CT. The average
prostate size was 4.3 ± 0.5 cm (mean ± S.D), with a range of 2.9-5.5 cm. Mean and
maximum CT densities were 36.0 ± 5.1 HU (range 23-57 HU) and 91.7 ± 20.1 HU

24

(Range 62-211 HU), respectively, whereas mean and maximum SUVs were 1.3 ± 0.4
(range 0.1-2.7) and 1.6 ± 0.4 (range 1.1-3.7), respectively. The mean SUV tended to
decrease as the prostate size increased (r = -0.16, p= 0.058), whereas the prostate
size tended to increase with increasing age (r=0.32, p<0.001).

B) Lesion in Prostate gland.

A) CT scan B) SUVmax = 7.7 C) PSA = 14.6 ng/ml
D)

Figure 9: FDG PET-CT scan demonstrating a lesion in prostate bed.

FDG-PET -CT scan images of a lesion in prostate bed in a 67-year-old male with a
biopsy confirmed prostatic adenocarcinoma & Gleason score 8. (A) Axial pelvis CT
image with no abnormal correlate of a lesion in prostate bed. (B)&(C) Axial PET image
and fused PET-CT image shows high accumulation of FDG in metabolically active
lesion in the right prostate bed. SUVmax corresponding to prostate bed (7.7) with
demonstation of elevated levels of PSA (14.6 ng/ml). (D) Sagittal view showing lesion in
the prostate bed with physiologic urinary activity above.

25
C) Metastasis to Lungs

CTLD = 2.7 cm SUVmax = 6.3
PSA = 0.03 ng/ml

Figure 10: Metastasis to lungs from primary prostate cancer as seen on FDG PET-

CT.

Multiple FDG-avid metastatic lesions are noted in the lungs and lymph nodes of the
mediastinum in a 67-year-old male with hormone refractory metastatic prostate cancer,
status post radical prostatectomy diagnosed originally with prostatic adenocarcinoma in
1984. Prostate cancer spreads to the lungs in about 50 percent of patients with metastatic
disease (Bubendorf et al. 2000). Data collected before the importance of PSA values was
recognized, indicate that the average time from the diagnosis of prostate cancer to the
occurrence of metastasis is 35 months for lung metastasis (Varkarakis et al. 1974).

D) Metastasis to Brain.

SUVmax = 6.6 PSA = 0.03 ng/ml

Figure 11: Osseous metastasis to Brain from advanced prostate cancer.

26

Case presenting metastasis to brain in a 67-year-old male with hormone refractory
metastatic prostate cancer, status post radical prostatectomy diagnosed originally with
prostatic adenocarcinoma in 1984. He had multiple sites of metastasis in the brain
(R.Occiput, R.Temporal & L.Parietal). Brain metastasis is rare in prostate cancer and
occurs late in the course of the disease. It usually represents the failure of hormone-
deprivation therapy and the presence of disseminated disease. This patient had
widespread metastasis to lungs and to lymph nodes in the mediastinum at the time of
entry into the study. He was then started on chemotherapy regimen with Taxotere,
Cisplatin and Gemcitabine. The patient continued to progress on this therapy after
showing a response initially. On his 8 month scan the patient was found to have multiple
FDG avid lesions in lungs, mediastinum and in axial and appendicular skeleton. At this
time, he was also diagnosed with metastasis to various regions in the brain. The patient
continued progressing and he died 2 months after his 8 month scan. Data collected before
the importance of PSA values was recognized, indicate that the average time from the
diagnosis of prostate cancer to the occurrence of metastasis is 60 months for brain
metastasis (Lynes et al. 1986). The long time between diagnosis and brain involvement
strongly favors the cascade theory of tumor spread. Metastasis to the brain can occur by
way of Batson's plexus or by direct extension from adjacent structures such as the
sphenoid bone or sinuses (Capito et al. 1991). The most common intracranial sites of
prostate cancer metastasis are the leptomeninges (67 percent), cerebrum (25 percent),
and cerebellum (8 percent).

27
E) Metastasis to Liver.

CTLD = 6.4 cm SUVmax = 8.2 PSA = 10.4 ng/ml

Figure 12: Metastasis to Liver from advanced prostate cancer.

Trans-axial FDG PET-CT images demonstrate multiple necrotic hepatic metastases in a
59-year-old male with hormone refractory metastatic prostate cancer, diagnosed
originally with a poorly differentiated prostatic adenocarcinoma, Gleason score 5+5, and
post radical prostatectomy. Liver metastasis from prostate cancer is not very rare but
appears to be a rather late event in the course of the disease. In chemotherapy-naïve
patients, the occurrence of liver metastasis does not alter the overall prognosis. In a
large autopsy programme including 1589 patients with hormone-refractory prostate
cancer, Bubendorf et al., reported 25% had liver metastasis and suggested that liver
locations were more frequent when the primary tumor was >8cm in diameter.

F) Metastasis to Lymph-Nodes.

There are two types of lymph node metastasis: local and distant. Local lymph
node metastasis is designated by clinical stage N1. Two lymph nodes lie on either side
of the bladder. Because these nodes are close to the prostate gland, metastasis is
considered local. If cancerous cells begin to grow in any other lymph node, the

28

metastasis is considered distant. Distant lymph node metastasis is denoted by
clinical stage M1a.

a. Supra-diaphragmatic Lymph node

A. CTLD = 1.1 cm B. SUVmax = 11.4 C. PSA = 284 ng/ml

Figure 13: Metastasis to Axillary LN (Supra-diaphragmatic region).

Axillary LN metastasis in a 63-year-old male with androgen-sensitive metastatic prostate
cancer, diagnosed initially with a biopsy proven adenocarcinoma of prostate, Gleason
score 4+3, in 2007.Metastasis to supra-diaphragmatic nodes is rare, seen more commonly
in patients with advanced stages, but 0.6% to 14% of patients with metastatic prostate
cancer may initially present with mediastinal adenopathy (Lindell et al. 1982).

A. Unenhanced CT scan shows lymph node of 1.1 cm in long axis diameter in axilla.

B. 18F-FDG PET scan shows area of intense FDG uptake in Axillary region
(arrow). Owing to absence of precise anatomic landmarks, high accumulation of
radiotracer depicted cannot be unequivocally attributed to lymph node metastasis.

C. Fused PET-CT image shows that abnormal FDG uptake corresponds to
Axillary lymph node (arrow) seen in A, suggesting presence of nodal cancer spread.

29
b. Retro-peritoneal Lymph node

A. CTLD = 1.2 cm B. SUVmax = 5.2 C. PSA = 73.7 ng/ml D.

Figure 14: Metastasis to lymph nodes in the retro-peritoneum from
prostate cancer.

Typical case of metastatic Para-aortic lymph node (PAN) in a 67-year-old male with
castrate-refractory metastatic prostate cancer who was initially diagnosed in 1997
with a biopsy proven adenocarcinoma of prostate and Gleason score of 3+4.

A. Transaxial CT scan shows enlarged (long-axis diameter was 1.2 cm) PAN
(arrow). B. Transaxial image on 18F-FDG PET scan shows area of intense uptake in
right paraaortic region (arrow) with SUV max of 5.2, with a PSA level 73.7 ng/ml.

C. Fused PET-CT image showing abnormal FDG uptake in paraaortic LN.

D. Coronal view of PET image shows positive FDG uptake in this PAN (arrow).

C. Pelvic Lymph node

A. CTLD = 1.6 cm B. SUVmax = 10.3
C. PSA = 75.2 ng/ml D.

Figure 15: Metastatic spread to lymph nodes in the Pelvis.

30
Metastasis to Right common iliac lymph nodes in a 67-year-old male with castrate-
refractory metastatic prostate cancer, who was originally diagnosed with
adenocarcinoma of prostate cancer, Gleason score 4+3, in 2007.

A. Unenhanced CT scan shows abnormal conglomerate lymph nodes in right common
iliac region (long-axis diameter 1.6cm).

B. Axial image on 18F-FDG PET scan shows an area of increased FDG uptake in
right common iliac region with a SUV max of 10.3

C. Fused FDG PET-CT scan images shows that abnormal FDG uptake corresponds to
right common iliac region suggesting presence of nodal cancer spread which is
also captured by coronal PET images as shown in D.

G) Metastasis to Bones.

The presence or absence of bone metastasis is a critical issue in the initial staging and
follow-up of cancer because it can directly alter the therapeutic strategy. In patients with
prostate cancer, the assessment for bone metastasis is considered essential not only in the
determination of therapeutic strategy but also in the determination of patient prognosis
(Yamashita et al. 1993). Standard imaging technique, Tc99 MDP Bone scan, has been
used for the detection of osseous metastasis (Davis et al. 1976). FDG PET-CT has
recently been investigated for detecting osseous metastasis in patients with varied type
of cancers. PET-CT scanners provide detailed anatomic information regarding the sites
of the abnormal PET findings. With PET-CT, we can assess the morphologic features of
lesions that are suspected of being bone metastasis at PET. Despite the high accuracy of

31

FDG PET in many cancers and the advantages of its ability to enable evaluation of the
entire body in a single examination, in clinical practice it is often necessary to correlate
PET results with findings obtained with other imaging modalities like CT, MRI and
conventional Tc99 MDP bone scan, to diagnose or confirm that the suspected lesions
truly represent metastatic lesions to the bone and not other glycolytic processes.

Below are examples of varying patterns of bone metastasis detected by PET and
correlated with corresponding findings on CT and conventional Tc99 MDP Bone scan.

a. Thoraco-lumbar spine

A. HU = 652 B. SUV = 5.5 C.PSA=51.1 D. E F.

Figure 16: Metastasis to lumbar spine as seen by FDG PET-CT and Bone scan.

FDG PET-CT and Bone scan images in a 63-year-old male with castrate-sensitive
metastatic prostate cancer, diagnosed initially in 2007 with biopsy proven
adenocarcinoma of prostate, Gleason score 4+3. B. PET scan image shows a FDG avid
lesion in Thoracic spine with SUV max = 5.5. Corresponding thoracic spine lesion on the
CT scan, A, shows no definite morphologic abnormality with HUmax = 652. Fused PET-
CT images, C, also show the same lesion and the patient had a PSA level of 51.1 ng/ml at
that time. D. is a coronal image of the Thoraco-lumbar spine on CT scan showing no
abnormal lytic, sclerotic or mixed lesion but corresponding coronal image on the PET
32

scan, E, and shows abnormal FDG uptake in multiple areas on the Thoraco-lumbar spine.
Image F. shows the conventional Tc99 MDP Bone scan with multiple lesions in thoracic
and lumbar spine. These images show that in this particular case both PET and Bone
scan were better than CT scan alone while fused PET-CT scan was equivalent to a Bone
scan in detecting osseous metastasis.

b. Pelvis

A. HUmax = 1117 B. SUVmax = 6.2
C. PSA = 714.9 ng/ml

Figure 17: Osseous metastasis to pelvic bones from prostate cancer.

FDG PET-CT scan images in a 59-year-old male with androgen-sensitive metastatic
prostate cancer, who was originally diagnosed in 2006, with a biopsy proven
adenocarcinoma of the prostate, Gleason score 4+4. This patient had widespread
metastasis in axial and appendicular skeleton. A. Transaxial CT images of the pelvic
skeleton demonstrating sclerotic changes in both right and left sacrum and iliac
bones with a HU max of 1117 in Right sacrum. B. corresponding Trans axial PET
images showed focal intense activity in the entire sacrum with a SUVmax = 6.2 in
right sacrum. C. Fused PET-CT images of the pelvis in this patient who had a PSA
level 714.9 ng/ml at this time.

33
c. Extremities

A. HU max = 988 B. SUV max = 5 C. PSA = 11.8 D.

Figure 18: Osseous metastasis to extremities from advanced prostate cancer.

FDG PET-CT and Bone scan images in a 69-year-old male with castrate-sensitive
metastatic prostate cancer, diagnosed primarily in 1994, with a biopsy proven
adenocarcinoma of prostate, Gleason score 3+3. Corresponding to the markedly
abnormal focus of increased tracer uptake in the left humerus on the Transaxial PET
image (B), slightly higher attenuation (compared with the attenuation correction in
the same location on the opposite side) is seen in the left humerus on the CT image
(A); this finding is consistent with bone metastasis. D. Tc99 MDP Bone scan also
demonstrated focus on uptake in the left humerus.

d. Ribs

A. HU = 1050 B. SUV = 2.7 C.PSA = 432 ng/ml

Figure 19: Osseous metastasis to ribs from advanced prostate cancer.

34

FDG PET-CT scan images in a 68-year-old male with castrate-resistant metastatic
prostate cancer, diagnosed primarily in 1996, with a biopsy proven adenocarcinoma of
the prostate, Gleason score 4+3. The focal intense uptake of FDG on axial PET image

(B) Corresponded to a lesion in the right rib (arrow), SUV max 2.7, that is seen
clearly on the axial CT (A) image with a dense sclerotic lesion having HU max 1050.

H. Most frequently observed Pattern of osseous metastasis demonstrated
by SUV-HU on PET-CT images.

L5 HU = 1099 L5 SUVmax = 5.1 PSA = 6.5 ng/ml

Figure 20: Pattern of osseous metastasis as demonstrated by FDG PET and CT scan.

FDG PET-CT scan images in a 69-year-old male with castrate-resistant metastatic
prostate cancer, diagnosed primarily in 1997 with a biopsy proven adenocarcinoma of
the prostate, Gleason score 4+4.

Three patterns of bone metastasis are possible:

1. FDG uptake without any corresponding morphological changes on CT; i.e.
the lesion is only detectable on PET

2. FDG uptake with concomitant morphological changes on CT as sclerotic, lytic
or mixed lesions.

3. Negative FDG-PET but highly suspicious sclerotic changes on CT.

35

All these 3 patterns can be observed in every patient depending upon the stage of his
treatment. Pattern 1 is mostly observed when the patient was diagnosed with a new
metastatic osseous lesion showing a metabolically active lesion on the PET scan but no
corresponding abnormal CT correlate. Once the patient was started on a new therapy
than the FDG uptake on the PET scan gradually decreased while there was a significant
morphologic progress in the sclerosis on CT scan, mostly representing pattern 2 as
mentioned above. As the treatment continued, the sclerosis on CT scan continued
progressing with the lesion showing almost complete resolution on PET scan. The above
images are from a patient at his 12 month scan (4
th
FDG PET-CT scan) which shows
that the previously metabolically active lesion on left side of L5 vertebral body has
become intensely sclerotic with a low activity on PET scan but the right side of L5
vertebral body shows development of a new metabolically active lesion with no
corresponding abnormally on the CT scan.

36

CHAPTER 4: DETECTION OF LYMPHADENOPATHY IN
METASTATIC PROSTATE CANCER:
18
F-FDG PET vs. CT

Objective:

The purpose of our study was to compare the diagnostic utility of 18F-
Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) and
Computerized Tomography (CT) in detection of nodal metastasis in patients with
malignant prostate cancer.

Introduction

Biologically and clinically, prostate cancer is a heterogeneous disease which is
characterized by states ranging from indolent to aggressive, making imaging a critical
modality for diagnosing the extent and metastasis of tumor cells. Current imaging
modalities, including computed tomography (CT), magnetic resonance imaging (MRI),
and ultrasound are not sufficiently accurate in detection of local recurrence or metastatic
disease. The limitation of this size-based imaging modalities are that metastasis in normal
sized lymph nodes can be missed, and reactive lymph node enlargement cannot be
reliably differentiated from tumor infiltration. In contrast to these morphologic imaging
techniques, Positron emission tomography and recently hybrid PET-CT with
Fluorodeoxyglucose (FDG) have become diagnostic imaging tools for the identification,
localization, and characterization of a diverse group of malignancies (including distant
metastasis) (Small et al. 1998, Dong et al. 1996). Scanning with fluorine-18-
fluorodeoxyglucose provides data on tumor metabolism, detecting increased cellular
uptake of glucose and the glucose analogue Fluorodeoxyglucose, one of the key

37

alterations associated with high glycolytic rate of cancer cells (Fletcher JW et al. 2008).
To our knowledge, however, there have been limited studies comparing CT with PET in
evaluating nodal metastasis form prostate cancer.

The purpose of our study is to compare the diagnostic utility of CT and FDG-PET
in detection of nodal metastasis in patients with malignant prostate cancer.

Patients

As a part of ancillary data analysis, 37 patients (20 castrate-sensitive (CS) and 17 castrate-
resistant (CR)) who completed the ongoing prospective imaging trial (i.e. a baseline scan
±14 days from the start of new therapy followed by 3 additional scans at 3 month interval)
were included in the current analysis. One patient had only 3 scans as he had missed his
scheduled 2
nd
scan. Table 3 shows the demographics on these patients.

Classification of LN’s

We detected a total of 47 LN lesions (in 37 patients) with their exact anatomical
location, longest axial diameter (CTLD) and maximum standardized uptake value
(SUVmax). These nodal sites were anatomically split into 3 regions: Pelvic (9), retro-
peritoneal (27), and supra-diaphragmatic (11). The CT criterion for defining an abnormal
metastatic LN lesion was CT longest diameter ≥ 1cm while PET criterion was an
increased radiotracer uptake by a lymph node with a SUV max cut-off point ≥ 2.5 or
average liver SUV. We classified a patient in 4 ways: (a) at least one involved pelvic
LN, (b) at least one involved retro-peritoneal LN, (c) at least one involved supra-
diaphragmatic LN, and (d) at least one involved in any of the 3 sites.

38
PET Imaging Protocol & Interpretations

As described in section 2.2 above

Table 3: Patient Demographics

Group1 Group 2

Total Patients (N = 37) 20 17

Age (years) 66 ± 8 67 ± 9
( 55-86 ) ( 50-87 )

PSA (ng/ml) *

- Baseline 11.9 26.7
(6.38 – 74.95) (9.62 - 52)

- 4 month 0.89 20.1
(0.15 – 13.65) (5.67 – 40.1)

- 8 month 0.805 12.7
(0.09 – 7.9) (2.12 – 75.2)

- 12 month 1.47 19.3
(0.1 – 7.7) (4.65 - 80)

FDG injected (mCi) 15.34 ± 1.08 15.17 ± 1.15
( 12.4-19.1 ) ( 12.5-17.8 )

Blood glucose (mg/dl) 112.04 ± 23.09 108.38 ± 18.09
( 72-188 ) ( 79-169 )

Gleason score 7.65 ± 1.26( 6-10 ) 7.88 ± 1.3( 5-10 )

Weight (lbs) 188.36 ± 28.53 172.64 ± 26.3
( 135-245 ) ( 130-232 )

Avg liver SUV 2.61 ± 0.19 3.02 ± 0.72
( 1.9-3.1 ) ( 1.3-4.9 )

LN lesions (N = 47) 22 25

- Pelvic 4 5

-Retro-peritoneal 12 15

-Supra-diaphragmatic 6 5

- Age, FDG injected, Blood glucose levels, Gleason score, Weight and Avg Liver SUV
are presented as Mean +/- S.D (Range).

* PSA levels are presented as Median (25
th
– 75
th
percentile)

39
Statistical Analysis

We performed node-based and region-based analysis separately for observing the
concordance and agreement between PET and CT. For region-based analysis, Cohen‟s
kappa statistics were calculated. Concordance rates were also calculated by dividing the
number of lesions seen with both modalities or not seen with either modality by the total
number of lesions. The effects of group, PSA and Gleason score on the Kappa statistics
was tested using Fleiss‟s method and on the concordance rates was tested using
population-averaged logistic regression model. For node-based analysis, McNemar‟s
test was used to compare CT and PET and test whether one modality is more likely to
detect a lesion than the other. The serial scans in the same patient were treated as
independent studies. Wilcoxon signed rank test and Mann-Whitney-Wilcoxon test were
used to test the difference in PET-CT concordance rates between baseline and follow-up
scans and between castrate-sensitive and castrate-resistant patients, respectively.

Region based analysis

Cohen‟s kappa statistics, after applying the cut-off points, revealed a moderate to
substantial agreement between PET and CT as evidenced by the high kappa scores.
Kappa scores between PET and CT appeared to be marginally higher for baseline than for
follow-up visits at all sites with overall score of 0.73 vs. 0.63, p =0.24. Kappa scores
were significantly higher in CS (castrate- sensitive) patients compared to CR (castrate -
resistant), with overall scores of 0.84 vs. 0.47 and a p-value of 0.004. Individual kappa
scores at pelvic, retro-peritoneal and supra-diaphragmatic sites for groups and visits are
presented in Table 4. Concordance rates, calculated by dividing the number of lesions

40
seen with both modalities or not seen with either modality by the total number of lesions
seen by at least one modality, showed high percentages of concordance between PET and
CT imaging modalities. Concordance rates were 89 % vs. 86% for baseline vs. follow-up
scans and 94% vs. 78% for CS vs. CR patients, with none reaching a statistically
significant difference (Table 4). Fleiss‟s and population-averaged logistic regression
methods did not show any significant effects of PSA and Gleason score on Kappa
statistics and Concordance rates respectively. (Table 4)

Sites Retro- Pelvic Supra Overall

N peritoneal diap-

hragmatic

Visit
Baseline 37 0.65 (89%) 0.89 (97%) 0.47 (94%) 0.73 (89%)

Follow-up 111 0.50 (86%) 0.57 (91%) 0.57 (90%) 0.63 (86%)

p-value 0.19 (0.61) 0.09 (0.13) 0.39 (0.29) 0.24 (0.44)

Group
Group 1 80 0.73 (94%) 0.70 (94%) 0.73 (94%) 0.84 (94%)

Group 2 68 0.40 (79%) 0.62 (91%) 0.30 (88%) 0.47 (78%)

p-value 0.045(0.18) 0.64 (0.75) 0.03 (0.46) 0.004(0.11)

PSA
0-4 60 0.58 (92%) 0.73 (97%) 0.64 (95%) 0.63 (88%)

(ng/ml)
>4-20 36 0.41 (83%) 0.64 (94%) 0.64 (94%) 0.55 (86%)

>20 52 0.58 (85%) 0.62 (87%) 0.46 (85%) 0.69 (85%)

p-value 0.44 (0.87) 0.60 (0.75) 0.42 (0.52) 0.45 (0.45)

Gleason
≤7 17 0.60 (88%) 0.77 (94%) 0.64 (94%) 0.72 (88%)

score
>7 20 0.69 (90%) 1.00 (100%) 1.00 (95%) 0.74 (90%)

p-value 0.78 (0.86) -- -- (0.91) 0.95 (0.86)

Table 4: Kappa statistics & Concordance rates for Region based LN
analysis comparing PET and CT.

Numbers presented as kappa scores (concordance rate %) P-value of <0.05 was regarded

as statistically significant. SUVmax ≥2.5 & CTLD ≥ 1 cm used as cut points.

41
Node based analysis

The mean of Avg liver SUV was 2.54 ± 0.23 (±S.D) and it was not significantly different
across scan dates controlling for patients (p=0.72). The concordance rate was 93%
between using 2.5 and average liver SUV as the cut-points for defining abnormal nodal
metastasis on PET. The results using the two criteria were always consistent with each
other in the comparisons between PET and CT (Table 5). The PET-CT concordance rate
was 42% for LN‟s for all patients and all visits combined. Concordance rates were
marginally significantly higher for patients with castrate-sensitive (CS) than for those
with castrate-resistant (CR) disease (54% vs. 29%, p-value =0.079). Similarly,
concordance rates were higher at baseline than follow-up studies although the difference
did not reach statistical significance (53% vs. 38%, p-value=0.13). (Table 6)

Table 5 Concordance for LN’s between PET and CT for all patients using:

Cut-point SUVmax = 2.5 vs. Cut-point SUVmax = Average liver SUV.

CT scan Conco CT scan Concor

PET scan Not
Seen

rdance
PET scan Not Seen dance

seen

Rate

seen Rate

All visits (137 lesions)
All visits (132 lesions)

Not seen
N/A
67

42%
Not seen N/A 68
42%

Seen 13 57

Seen 8 56

Baseline (32 lesions)
Baseline (31 lesions)

Not seen
N/A
12

53%
Not seen N/A 12
55%

Seen 3 17

Seen 2 17

Follow-up scans (105 lesions) Follow-up scans (101 lesions)

Not seen N/A 55

38%

Not seen
N/A
56
39%

Seen 10 40

Seen 6 39

42

Table 6 Concordance rates for individual LN lesions between PET and CT using
cut-off values SUVmax ≥ 2.5 and CTLD ≥ 1.0 cm

Castrate-sensitive patient‟s Castrate-resistant patient's

CT scan Concord

CT scan Concor

PET scan

dance

PET scan

Not

ance

Not
Seen

Seen

seen Rate

seen Rate

All visits (69 lesions)

All visits (68 lesions)

Not seen

N/A

44

Not seen N/A 23
54%

29%

Seen

5

20

Seen 8

37

Baseline (15 lesions)

Baseline (17 lesions)

Not seen

N/A

10

Not seen N/A 2
76%

27%

Seen

1

4

Seen 2

13

Follow-up scans (54 lesions)

Follow-up scans (51 lesions)

Not seen

N/A

34

Not seen N/A 21
47%

30%

Seen

4

16

Seen 6

24

Table 7: Differences of SUVmax & CTLD Table 8: Spearman Correlation

Between CS and CR Coefficients

All Scans (n’=147)

All Patients 0.23

SUVmax

CTLD

(n=37)

(p=0.09)

CS

3.53 ± 2.2

1.40 ± 0.57

CS

0.39

(n=20)

( 0.7 – 12.3 )

( 0.7 – 3.7)

(n”=68)

(n”=68)
(n=20) (p=0.02)

CR 2.6 ± 1.97 1.88 ± 1.19
CR

0.05

(n=17)

( 0.7 – 10.3 )

( 0.5 – 7.2 )

(n=17)

(p=0.84)

(n”=69)

(n”=69)

All 3.05 ± 2.13 1.65 ± 0.97

Patients ( 0.7 – 12.3 ) ( 0.5 – 7.2)

(n=37) (n”=137) (n”=137)

CS vs. CR P=0.006 P=0.002

(Values shown as Mean ± S.D and range),

n = number of patients and n” = number of lesions

43

Table 9: Mean ± S.D, range of SUVmax, CTLD between CS & CR patients and
between pre-therapy and during therapy

Pre-Therapy During Therapy
(n’=32) (n’=105)
SUVmax CTLD SUVmax CTLD

CS 4.00 ± 1.25 1.49 ± 0.46 3.39 ± 2.39 1.37 ± 0.59
(n=20; n’=68) ( 2.3 – 6.2 ) ( 0.7 – 2.5 ) ( 0.7 - 12.3 ) ( 0.6 – 3.5 )

CR 2.29 ± 1.62 1.86 ± 1.33 2.69 ± 2.08 1.89 ± 1.16
(n=17; n’=69) ( 0.9 – 8.2 ) ( 0.5- 6.4 ) ( 0.7 – 10.3 ) ( 0.6 – 7.2 )

All Patients 3.10 ± 1.68 1.69 ± 1.02 3.04 ± 2.26 1.63 ± 0.96
(n=37;n’=137) ( 0.9 – 8.2 ) ( 0.5 – 6.4 ) ( 0.7 – 12.3 ) ( 0.6 – 7.2 )

CS vs. CR P=0.001 P=0.268 P=0.089 P=0.003

Discussion:

A noninvasive technique which accurately identifies nodal metastasis in malignant
tumors can prove helpful in facilitating clinical management decisions and improve
patient outcomes. CT and MRI, cross sectional techniques, are currently in use for
discriminating between malignant and benign lymph nodes. Both these morphologic
techniques use node size measurement criterion which has proved to be of limited
accuracy for differentiating between metastatic and non-metastatic lymph nodes of
similar size. PET scanning with FDG, a functional method based on increased glucose
metabolism of cancer cells, may fill the vacuum that exists for the reliable and accurate
imaging evaluation of patients with metastatic prostate cancer.

Our current study evaluates the diagnostic accuracy of FDG PET compared to CT in
terms of detection of regional nodal metastasis in prostate cancer patients. Kappa
statistics (Table 4), for region based analysis, showed a moderate to substantial

44

agreement between PET and CT at all sites when we compared baseline to follow-up
scans, with a marginally higher agreement at baseline than follow-up scans(0.73 vs.
0.63). Similar high agreement was also observed when comparing CS to CR patients with
difference between them reaching a statistical significance (0.84 vs. 0.47, p=0.004). The
effects of visit, group, PSA and Gleason score on concordance rates for region based
analysis, using population averaged logistic regression model, showed high rates of
concordance between FDG PET and CT with concordance values ranging from 78% -
94%. Individual lesion based analysis also showed concordant results compared to region
based analysis, with concordance higher at baseline than follow-up (76 % vs. 47 %) and
higher concordance for CS than for CR patients at both baseline (76 % vs. 27 %) and
follow-up visits (47 % vs. 30 %). The images in Figure 21, 22, 23 below also depict
similar results, with high concordance between PET, CT and PSA values across 4 serial
FDG PET-CT scans.

The statistically significant differences seen between baseline and follow-up scans is
attributed mainly to the treatment effect. We observe that once the patient is put on some
kind of therapy either hormonal or chemotherapy, the findings on PET scan and CT scan
show some differences, with PET scan able to better capture the response to treatment
than the conventional CT scan. The differences observed between castrate-sensitive and
castrate-resistant patients may be attributed to the cut points we have used in the current
analysis. From Tables 7 and 9, we observe that the mean +/- S.D of SUVmax and CTLD
was significantly different between CS and CR patients (p value 0.006 between CS &
CR for SUVmax and p-value 0.002 between CS & CR for CTLD) with mean +/- S.D of

45

SUVmax higher in CS than CR (3.53 ± 2.2 vs. 2.6 ± 1.97). On the other hand, mean +/-
S.D of CTLD was higher in CR than in CS patients (1.88 ± 1.19 vs. 1.40 ± 0.57). Both
these factors collectively resulted in statistically significant differences between CS and
CR patients. We also observed a statistically significant difference of SUV max between
CS and CR patients for baseline scans (p-value 0.001) (4.00 ± 1.25 vs. 2.29 ± 1.62) and
a statistically significant difference of CTLD between CS and CR patients for follow-up
scans (p-value = 0.003) (1.37 ± 0.59 vs. 1.89 ± 1.16).

Our study had certain limitations. First, the number of patients involved was relatively
small. Our study is still recruiting new patients and in future we plan to analyze a much
larger patient number. By using cut-point SUV max ≥2.5, we might have lost a few
metabolically active metastatic LN lesions on PET scan which can be responsible for
slightly lower concordance numbers for individual node based analysis. Similarly, for
future analysis we will use separate CT cut points depending upon the region. For
example we will use 0.8 mm cut point for lymphadenopathy in pelvis and 1 cm cut point
in retroperitoneal LN‟s. We also plan to run similar analysis using short axis diameter
(RECIST 1.1). With more patients in future analyses, we will be able to draw ROC
curves and come up with a more accurate cut-points for SUVmax on PET and CTLD &
CTSD on CT scan. Our future analysis also will reflect the relational effect of FDG PET
and CT on prognosis. Our current findings reflect the accuracy of PET-CT in a selected
cohort of patients with metastatic prostate cancer.

46

BASELINE 4 MONTH 8 MONTH 12 MONTH

A
CTLD = 1.4 cm CTLD = 0.7 cm CTLD = 0.7 cm CTLD = 1.4 cm
B
SUV max = 4.1 SUV max = 1.5 SUV max = 1.3 SUV max = 4.1

C
PSA = 95.6 ng/ml PSA = 5.84 ng/ml PSA = 2.27 ng/ml PSA = 26.1 ng/ml
D

E
Docetaxel + Docetaxel + Docetaxel + Docetaxel re-started
Bortezomib Started Bortezomib Continues Bortezomib Stopped due to disease
(08/26/2008) (03/15/2009) progression
(09/18/2009)

Figure 21: Serial FDG PET-CT scan images showing changes in the metabolic
activity (SUVmax), morphologic appearance (CTLD) and PSA levels for a
lymph node lesion detected in pelvic region.

47

Figure 22: Serial FDG PET-CT scan images demonstrating changes in metabolic
activity (SUVmax), morphologic appearance (CTLD) and PSA levels for a lymph
node lesion detected in retro-peritoneum.

48
Baseline

CTLD = 1 cm

SUV max = 2.9

PSA = 67.1 ng/ml

4 month

CTLD = 1 cm

SUV max = 1.8

PSA = 20.1 ng/ml

8 month

CTLD = 1.6 cm

SUV max = 7.9

PSA = 75.2 ng/ml

12 month

CTLD = 1.1 cm

SUV max = 1.9

PSA = 93.4 ng/ml
New Bone mets
at 12 month

L2 CT HU = 646

SUV max = 4.4

PSA = 93.4 ng/ml

Case Presentations

Figure 21 (above): FDG PET-CT scan images at baseline, 4, 8, and 12 month in a 60-
year-old male with metastatic castrate-resistant prostate cancer, Gleason score 5+4, who
had undergone a radical prostatectomy. Metastatic lymph node in the retro-peritoneal
region is shown by the arrows. (A)Transaxial Computed Tomography (CT), (B) Positron
Emission Tomography (PET), (C) Fused PET/CT, (D) Coronal and (E) MIP images
from serial FDG PET-CT scans showing changes in the CTLD, SUVmax, PSA scores
and therapy.

Figure 22 (above): Images in a 68-year-old man with metastatic castrate-resistant
prostate cancer diagnosed in June 2000 with Gleason score 4 + 3. This patient had
multiple metabolically active nodular lesions in the retro-peritoneum and pelvic regions.
The reference lesion in the retro-peritoneum is shown by arrows here, with serial changes
in the metabolic and morphologic abnormalities on PET and CT scan (SUVmax and
CTLD) respectively. Serial changes in SUVmax and CTLD correlated with changes in
PSA levels and change in therapy. At 12 month scan the lymphadenopathy underwent a
partial response but some new osseous metastasis was noted in the Thoraco-lumbar spine
which is captured by PET scan better than CT scan.

49
LD=0.8 SD=0.5 SUV max = 3.7 PSA = 223.3 ng/ml

LD= 1.1 SD=0.5 SUV max = 11.4 PSA = 284 ng/ml

LD=1.1 SD=0.5 SUV max = 8.9
PSA = 119 ng/ml

LD= 1.1 SD=0.4 SUV max = 4.8 PSA = 52.5 ng/ml

Figure 23: Serial FDG PET-CT scan images demonstrating changes in metabolic
activity (SUVmax), morphologic appearance (CTLD) and serum PSA levels, for
lymph node lesion in supra-diaphragmatic region.

FDG PET-CT scan images in a 63-year-old male with castrate-resistant metastatic
prostate cancer, originally diagnosed with adenocarcinoma of the prostate (Sep 2007)
involving 95% of the prostate extending beyond the prostatic capsule and a Gleason
score of 4+5. Unenhanced serial transaxial CT scan images show the changes in the
morphologic appearance of Axillary LN with CTLD remaining stable throughout. 18F-

50

FDG PET scan images shows area of intense FDG uptake in Axillary region (arrow).
Owing to absence of precise anatomic landmarks, high accumulation of radiotracer
depicted cannot be unequivocally attributed to lymph node metastasis with SUVmax
changing from 3.7 – 11.4 – 8.9 – 4.8. Fused PET-CT image shows that abnormal FDG
uptake corresponds to Axillary lymph node (arrow) seen in A, suggesting presence of
nodal cancer spread. Changes in the SUV max were correlated with the serial changes
in PSA levels capturing the disease progression as well as response to therapy. I this
particular case, FDG PET proved better than conventional CT scan in diagnosing
metastasis to Axillary LN.

Conclusion:

18F-FDG-PET and CT scanning appears complementary for detecting regional lymph
node metastasis in men with metastatic prostate cancer. The use of hybrid PET-CT
imaging systems will afford enhanced diagnostic information and increased
diagnostic confidence by providing precise localization of metabolic abnormalities
and by characterizing the metabolism of morphologic abnormalities. In conclusion,
integrated FDG PET-CT is a more effective tool compared to PET and CT alone for
detection of lymph node metastasis in patients with malignant prostate cancer.

51
CHAPTER 5: IMAGING EVALUATION OF OSSEOUS
METASTATIS IN PROSTATE CANCER: A COMPARISON OF
FDG-PET, CT AND BONE SCAN.

Objective

The purpose of this study was to compare the detection of osseous metastasis by positron
emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) and
techintium-99m methylene diphosphonate (MDP) bone scintigraphy in patients with
metastatic prostate cancer.
Introduction

Prostate carcinoma represents the second most common malignancy in men, with more
than 670,000 new diagnoses annually worldwide. Clinical nomograms based on PSA
levels, Gleason score at biopsy, and clinical stage at presentation are used for
pretreatment risk stratification and for predicting the probability of local recurrence and
distant metastasis. About 30% of these patients show bony metastasis at the time of
diagnosis and over 80% at the time of death (Scher et al. 1994). The mechanism of bony
metastasis in prostate cancer has been extensively studied. The metastatic spread to the
vertebral bodies, ribs and pelvis through Batson‟s venous plexus supports the „Seed and
Soil‟ hypothesis described by Paget in 1889. The precise details of this mechanism have
not yet been completely explained. As the disease evolves, patients may experience
biochemical progression, local recurrence or metastatic spread. Skeletal metastasis occurs
in approximately 90% of patients presenting with advanced stage of prostate cancer. At
this stage, complete remissions are rare and a lot of effort is being put in to investigate the

52
therapeutic interventions which slow the progression of bone disease. This requires an
accurate assessment of the disease burden in the bones and response to the treatment.
PSA is usually used for assessing the response to treatment but PSA levels are
influenced by both soft tissue and bony disease and hence PSA levels do not always help
in accurately assessing the tumor burden in a patient.

Imaging bone metastasis from prostate cancer presents several challenges. Conventional
techniques like bone scan, magnetic resonance imaging (MRI), computed tomography
(CT) have been extensively used for determining the response to treatment in prostate
cancer. None of these techniques is able to measure the quantitative changes during
disease progression or to monitor accurately the response to treatment. In particular the
changes in bone scans are slow, poorly reflect the clinical condition of the patient, and do
not provide information regarding the metabolic activity of the lesion. Moreover, the
assessment of therapeutic response in clinical trials relies solely on qualitative assessment
of bone scintigraphy, as Response Evaluation Criteria in Solid Tumors (RECIST) criteria
classify osteoblastic bone metastasis as non measurable (Eisenhauer et al. 2009). Also,
the results of more recent reports have raised doubts whether bone scan is as effective as
was previously perceived.

The present study was undertaken to evaluate the usefulness of PET scan using FDG to
measure the glycolytic activity in patients with known bone metastasis from advanced
prostate cancer and to determine the concordance and discordance between FDG PET-CT
and Tc99m- MDP bone scintigraphy.

53
Patients

As a part of an interim data analysis, 37 patients (20 castrate-sensitive (CS) and 17
castrate-resistant (CR)) who completed the imaging protocol (i.e. a baseline scan ±14
days from the start of new therapy followed by 3 additional scans at 4 month interval)
were included in the current analysis. One patient had only 3 scans as he had missed his
scheduled 2
nd
scan

Classification of osseous metastatic lesions

For doing individual lesion based analysis, the findings on PET, CT and bone scans were
first dichotomized as “seen” and “not seen” and cross-tabulated. The lesions were
defined as “not seen” by PET if maximum SUV is less than 2.5 and “seen” by PET if
maximum SUV is 2.5 and above. The lesions were defined as “seen” by CT if HU is
positive (> 0) and “not seen” by CT otherwise. The comparison between PET and CT
were done for all patients and separately for patients with androgen sensitive disease and
those with androgen refractory disease. The comparison between PET/CT and bone scan
was done similarly.

For doing region based analysis, the bone lesions were divided into C-spine, T-spine, L-
spine, pelvis, ribs and extremity. “Seen” or “Not Seen” by each modality at each site was
recorded. If disease was observed in at least one of the sites, it was defined as “Seen”
overall. Otherwise, it was “Not Seen” overall.

54
Statistical analysis

For individual node based analysis, McNemar‟s test was used to test whether one
modality is more likely to detect a lesion than the other. The serial scans in the same
patient were treated as independent studies. The Spearman partial correlation
coefficients were also calculated between max SUV and HU for the lesions that were
seen by both PET and CT, adjusting for patient and scan date. The purpose of adjusting
for patient and scan date was to adjust for the fact that PET or CT measurements
performed on the different dates for the same patient were not independent from one
another. Wilcoxon signed rank test and Mann-Whitney-Wilcoxon test were used to test
the difference in PET-CT concordance rates between baseline scans and follow-up
scans and between androgen-sensitive patients and androgen-refractory patients,
respectively.

For analysis based on regions, Cohen‟s kappa statistics were calculated. The effects
of group, PSA and Gleason score on kappa statistics were tested using Fleiss‟s
method. The kappa statistics between baseline and follow up studies were compared
using the permutation test with 1000 permutations. The concordance rates were
calculated by dividing the number of patients seen with both modalities or not seen
with either modality by the total number of patients. The effects of visit, group, PSA
and Gleason score on concordance rates between two modalities were tested using
population-averaged logistic regression models.

55
Region based analysis

Cohen‟s Kappa statistics, after applying the cut-off point (SUVmax ≥2.5), revealed a
substantial agreement between PET & CT vs. Bone scan as well as PET or CT vs. Bone
scan as evidenced by high overall kappa and concordance rates. PET & CT vs. Bone scan
means a target lesion was seen on both PET & CT scan and compared to bone scan to see
if that abnormal lesion was captured by bone scan, while PET or CT vs. Bone scan
means a lesion was either captured by PET or CT imaging modality and compared with
bone scan to see if that lesion was captured by the bone scan. There were no statistically
significant differences for overall kappa scores between baseline vs. follow-up and group
1 vs. group 2. Region wise kappa and concordance rates also showed moderate to
substantial agreement at all sites, with scores reaching a statistically significant
difference for C-spine between group 1 vs. group 2 (p-value=0.001) which may be
mainly attributed to the cut-off points used for SUV max (≥2.5). Fleiss‟s and population-
averaged logistic regression models did not show any significant effects of PSA and
Gleason score on Kappa scores and concordance rates respectively, for both PET & CT
and Bone scan as well as PET or CT and Bone scan (Table 10 & 11).

56
Table 10: Region based Kappa scores and Concordance rates between PET & CT
vs. Bone scan. (Cut-point SUVmax >2.5), B= baseline, F=follow-up, p= p-value,
values presented as Kappa scores / concordance rates %.

Variable C-spine T-spine L-spine Pelvis Ribs Extremity Overall

B 0.60/89% 0.92/95% 0.91/94% 0.85/94% 0.36/69% 0.67/86% 1 /97%

Visit
F 0.34/71% 0.63/80% 0.81/87% 0.97/98% 0.47/72% 0.62/81% 0.89/95%

p 0.18 0.07 0.24 0.12 0.26 0.34 0.13

Group
G- 1 0.69/88% 0.68/86% 0.73/85% 0.95/98% 0.43/69% 0.68/84% 0.84/93%

G- 2 0.15/66% 0.74/85% 0.89/94% 0.93/96% 0.43/73% 0.58/81% 0.96/98%

p 0.001 0.64 0.17 0.70 0.97 0.53 0.22

0-4 0.19/81% 0.81/92% 0.73/90% 0.93/96% 0.51/76% 0.58/85% 0.86/93%

4-20 0.48/82% 0.64/79% 0.85/89% 0.93/96% 0.38/65% 0.53/83% 0.92/96%

PSA
20 0.40/69% 0.67/85% 0.81/91% 0.95/98% 0.89/71% 0.68/79% 0.94/98%

p 0.33 0.32 0.51 0.80 0.53 0.41 0.46

Gleason
≤7 0.63/93% 0.84/93% 0.84/93% 0.84/93% 0.55/80% 0.71/87% 0.86/93%

>7 0.48/84% 0.89/95% 0.89/95% 0.89/95% 0.24/63% 0.66/84% 1 /100%

p 0.71 0.78 0.79 0.78 0.28 0.85 --

Table 11: Region based Kappa scores and Concordance rates between PET or CT
vs. Bone scan. (Cut-point SUVmax >2.5), B= baseline, F=follow-up, p= p-value,
values presented as Kappa scores / concordance rates %.

Variable C-spine T-spine L-spine Pelvis Ribs Extremity Overall

B 0.58/87% 1/97% 0.92/94% 0.85/94% 0.77/85% 0.92/93% 1 /97%

Visit
F 0.71/84% 0.87/91% 0.94/97% 0.93/97% 0.74/85% 0.71/83% 0.92/97%

P 0.25 0.12 0.48 0.22 0.47 0.14 0.25

Group
G- 1 0.76/87% 0.86/92% 0.91/95% 1/100% 0.68/82% 0.67/83% 0.89/95%

G-2 0.65/85% 0.89/95% 0.93/96% 0.85/93% 0.79/90% 0.81/89% 0.96/98%

P 0.42 0.74 0.80 ----- 0.43 0.31 0.43

0-4 0.53/84% 0.92/97% 1/100% 1/100% 0.75/89% 0.58/83% 0.93/96%

4-20 0.71/82% 0.93/95% 0.92/96% 0.86/93% 0.65/81% 0.78/87% 0.84/93%

PSA
20 0.72/89% 0.80/91% 0.85/93% 0.89/95% 0.76/90% 0.81/89% 1/100%

P 0.37 0.26 ----- ------ 0.50 0.22 -----

Gleason
≤7 0.76/93% 0.84/93% 0.84/93% 0.84/93% 0.71/87% 0.86/93% 0.86/93%

>7 0.58/84% 1/100% 0.89/95% 0.89/95% 0.68/84% 0.89/95% 1 /100%

P 0.54 ----- 0.78 0.78 0.92 0.85 --

57

Individual bone lesion analysis

The mean of Avg liver SUV was 2.54 ± 0.23 (±S.D) and it was not significantly different
across scan dates controlling for patients (p=0.72). The concordance rate was 93%
between using 2.5 and average liver SUV as the cut-points for defining abnormal nodal
metastasis on PET. Table shown below are from a preliminary analysis for assessing the
concordance rates between PET-CT and Bone scan imaging modalities. We still need to
add some more features to this analysis to help us better understand and determine the
effects of PET, CT and Bone scan in determining osseous metastatic lesions from
prostate cancer. The preliminary results depict that there was a strong concordance for
assessing bony metastasis between PET or CT and Bone scan, with concordance rates in
the range of 89-99%. These high concordance rates are most likely attributable to seen,
not seen status on CT scans, which overshadow the actual role of PET scans in
determining osseous metastasis. When we use the condition PET & CT and Bone scan,
we observe that the concordance rates drop by 50% for both groups and for all baseline
and follow-up scans with concordance rates ranging from 45-62%. There were no
statistically significant differences between group 1 vs. group 2 and between baseline vs.
follow-up, when applied for both conditions separately (Table 12 & 13).

58
Table 12: Concordance rates for individual bone lesions between PET or CT vs.
Bone scan for castrate-sensitive and castrate-resistant patients.

PET or CT vs. Bone scan CS PET or CT vs. Bone scan CR

PET Scan CT Scan P- Conco
Not value rdance
Seen Seen rate
All visits (482 lesions)
Not seen N/A 9 0.022 98%
Seen 1 472
Baseline (154 lesions)
Not seen N/A 5 0.22 96%
Seen 1 148
Follow up studies (328 lesions)
Not seen N/A 4 -- 99%
Seen 0 324

PET Scan CT Scan P- Conco
Not seen value rdance
Seen rate
All visits (321 lesions)
Not seen N/A 11 0.057 96%
Seen 3 307
Baseline (93 lesions)
Not seen N/A 8 0.11 89%
Seen 2 83
Follow up studies (228 lesions)
Not seen N/A 3 0.63 98%
Seen 1 224

Table 13: Concordance rates for individual bone lesions between PET and CT
vs. Bone scan for castrate-sensitive and castrate-resistant patients.

PET and CT vs. Bone scan CS PET and CT vs. Bone scan CR

PET Scan

CT Scan P- Conco

PET Scan

CT Scan P- Conco

Not

value rdance
Not seen value rdance

seen Seen rate Seen rate

All visits (319 lesions)

All visits (482 lesions)

Not seen

N/A 164 <0.0 48%

Not seen N/A 218 <0.0 55%

1

Seen

1 154 1

Seen 1 263

Baseline (91 lesions)

Baseline (154 lesions)

Not seen

N/A 39 <0.0 57%

Not seen N/A 57 <0.0 62%

1

Seen

0 52 1

Seen 1 96

Follow up studies (228 lesions)

Follow up studies (328 lesions)

Not seen

N/A 125 <0.0 45%

Not seen N/A 161 <0.0 51%

Seen

0 167

Seen

1 102 1

1

59

Table 14: Comparison in concordance rates for individual bone lesions between
visits and between groups

Visit G-1 vs. G-2
PET vs. CT 0.21 0.93
PET vs. Bone scan 0.23 0.89
CT vs. bone scan 0.13 0.89
PET or CT vs. bone scan 0.13 0.91
PET & CT vs. bone scan 0.23 0.81

B. HU = 772 SUV = 24.5 PSA = 223.3

4. HU = 837 SUV = 21.7 PSA = 284
8. HU = 1084 SUV = 16.8 PSA = 119
12. HU = 1121 SUV = 8.1 PSA = 52.5

Figure 24: Serial FDG PET-CT and Bone scan images showing changes in the
metabolic activity (SUVmax), sclerosis (HU) and PSA levels, for an osseous lesion
detected in thoraco-lumbar spine.

60
Case Presentation

The case is of a 63-year-old male with castrate-resistant metastatic prostate cancer,
originally diagnosed with adenocarcinoma of the prostate (Sep 2007) involving 95% of
the prostate extending beyond the prostatic capsule and a Gleason score of 4+5. PSA
level at the time of diagnosis was 1401.4 ng/ml and hence he was started on a hormone
ablation therapy. Unfortunately, the patient failed on the hormone ablation therapy as
evidenced by PSA relapse in April 2008 and evidence of osseous metastasis on CT and
Bone scan. Patient was enrolled in our imaging trial as a hormone refractory patient. As a
part of the protocol he underwent serial FDG PET/CT scans at baseline, 4, 8, and 12
months along with his routine standard of care (i.e. bone scans, CT scans, PSA levels and
chemotherapy). Figure above show images of his serial (Baseline, 4, 8 & 12 months)
FDG PET, CT and Bone scan along with SUV (PET), HU (CT) and PSA levels. It is
noticed that the amount of FDG uptake by the reference lesion goes on decreasing on
follow-up scans as evidenced by the SUV‟s, while there is an increase in the area of
sclerosis on CT scan as evidenced by a rise in HU‟s. Drop in SUV‟s (24.5 to 8.1) was
correlated with a drop in PSA levels (223.3 to 52.5) which shows a good response to
chemotherapy. On the contrary all the lesions on the thoraco-lumbar spine got more
sclerotic on follow-up scans and even the intensity on bone scans did not differ much. We
observe similar trend in a large group of patients having osseous metastasis.

61
Discussion

The limitations of bone scintigraphy have spurred an interest in PET imaging in prostatic
bone metastasis. Early detection or exclusion of bone metastasis is of a high clinical
importance in management of patients with high-risk prostate cancer. We observed that
the sclerotic metastases show little FDG uptake compared with lytic and mixed lesions.
In other words, the lesions started as lytic metabolically active lesions on PET scan with
no abnormal CT correlate but after the start of therapy the metabolically active lesions
showed decrease in activity (a sign of response to treatment) while their corresponding
counterparts on CT scan became more sclerotic (in some cases interpreted as disease
progression). This is being captured by SUV max on the PET scan and HU on the CT
scan. We have gathered and are continuing to gather a rich data on SUVmax and HU,
which will soon be analyzed to show their correlation. The exact cause of this reduced
uptake is not known but speculation centers on lower volumes of tumor associated with
sclerotic metastasis, a difference in sclerotic tissue metabolism or attenuation of photons
by densely calcified tissue. FDG PET scan is therefore less sensitive than bone
scintigraphy in detecting sclerotic metastasis. The lesions that are not detected by FDG
PET scan are often those that are stable on follow-up bone scintigraphy. However, some
lesions detected by FDG PET scan alone become positive on bone scintigraphy after
some time. A new lesion or rise in SUV within a lesion is correlated with a rise in PSA
indicates disease progression, thus suggesting that FDG PET is very promising as an
outcome measure for prostate cancer. Even without CT correlation, FDG PET offers
superior resolution to conventional gamma camera imaging, and the acquisition of
62

tomographic images is routine. The combination with CT on hybrid PET/CT
scanners offers the advantage of fusing structural and functional data.

Conclusion

18F-FDG PET-CT is a reasonably sensitive and specific modality for detection of bone
metastasis in patients with high-risk prostate cancer in comparison to the conventional
Tc99m MDP bone scintigraphy. CT images obtained as a part of PET-CT were helpful in
yielding the precise location of bone lesions. Further validation of imaging biomarkers of
metastatic bone disease would benefit if guided by consensus groups with the purpose of
clearly defining objectives, prioritizing imaging modalities to be taken forward, unifying

„gold standards‟ for bone disease and coordinating multicenter prospective imaging trials.

63

CHAPTER 6: CASE REPORTS: DIAGNOSTIC ACCURACY OF
18F-FDG PET FOR EVALUATION OF TREATMENT RESPONSE.

We present here a case each for castrate-sensitive (CS) and castrate-resistant (CR) patient
to illustrate the diagnostic accuracy of F18-FDG PET-CT scan for evaluation of treatment
response to hormonal, chemo and/or other therapies used for treating metastatic prostate
cancer.

6.1 Castrate-sensitive patient

Objective

We are testing the hypothesis that serial fluorodeoxyglucose (FDG) positron
emission tomography (PET) scans can serve as a good diagnostic tool for assessing
response to treatment for patients with metastatic prostate cancer treated with various
forms of androgen ablation and/or chemotherapeutic regimens.

Introduction

Assessing response to treatment is crucial both in routine clinical care and clinical trials.
For patients with metastatic prostate cancer, such determinants are complicated by the
fact that the primary site of metastatic spread is bone. The dimensions of such osseous
lesions cannot be measured using standard radiographic imaging techniques. Response
evaluation criteria like RECIST 1.0 & 1.1 do not take into account osseous lesions and
for measurable lymph node and soft tissue lesions there are still debates going on.
Furthermore, bone scintigraphy is not an ideal modality for assessing treatment effects,
as a brisk antitumor response may manifest as a worsening bone scan, a flare
64

phenomenon known as “pseudo-progression.” Changes on bone scintigraphy are often
lagging behind the clinical events, such as increase in pain or biochemical changes
such as an increase in PSA. Due to shortcomings of standard imaging techniques, it has
long been recognized that prostate cancer clinical trials are poorly served by standard
response criteria, which focus on measurable visceral metastasis. Thus, prostate cancer
trials have required disease-specific methods of assessing and reporting outcomes. One
of the most important elements in assessing treatment effects in this disease is the post-
treatment PSA. Post-treatment PSA level declines of >50% are associated with a
survival benefit, as are post-treatment alterations in PSA velocity and/or doubling time.
Despite the apparent linkage between post-treatment PSA alterations and clinical
benefits, the PSA is not accepted as a surrogate for survival and as a basis for drug
approval.

Positron emission tomography (PET) is a non invasive technique that can image bone
and soft tissue in a single modality, evaluate high-grade tumors that may not produce
PSA, and provide a quantifiable expression of changes using the standardized uptake
value (SUV). In the present prospective imaging trial, we are exploring the potential
of PET as an outcome measure. We sought to determine whether treatment produced
changes in PET would parallel clinically judged treatment responses based on PSA,
bone scintigraphy, and soft tissue imaging.

65
PET Imaging Protocol & Interpretations

As described in section 2.2 above.

Case presentation

The patient is a 69-year-old male with castrate-sensitive metastatic prostate cancer,
originally diagnosed in 1997 with a biopsy proven adenocarcinoma of the prostate,
Gleason score 7, status post radical prostatectomy. The patient was doing well until
2004, when a slight elevation in serum PSA was noted rising to 2.5 ng/ml. He
underwent pelvic irradiation treatment which decreased his PSA to 1.1 ng/ml but then it
soon began to increase reaching 9.48 ng/ml in Nov 2004. The patient‟s PSA level
increased to 73.7 ng/ml in 7/2007, at which time he was consented for our ongoing
prospective imaging trial “FDG PET-CT in metastatic prostate cancer.” He was
commenced on androgen deprivation therapy with Casodex. On his first FDG PET scan,
multiple metastatic lymph nodes were noticed in the retro-peritoneum with a reference
LN lesion at the level of aortic bifurcation having SUVmax 3.6 on PET scan and long
axis diameter 1.8 cm on CT scan. The patient failed to benefit from Casodex therapy as
evidenced by the rising PSA levels thereafter (230 ng/ml) and it was also captured by
PET, CT scans. On his 4 month FDG PET scan, additional new lymphadenopathy was
noticed in hilar region while reference lesion in retro-peritoneum had increased in size to
2.5 cm with metabolic activity on PET scan (SUV max) rising to 7.4. The patient was
now started on prednisone and ketoconazole but he did not show favorable response to
that therapy as evidenced by his rising PSA levels at time of the 8 month scan reaching
level of 446 ng/ml. The 8 month FDG PET scan showed lower metabolic activity in
66

metastatic lesions while the CTLD remained stable, with the reference lesion SUVmax
decreasing to 5.4 and CTLD remaining stable at 2.4cm. Interestingly, at his 12 month
FDG PET scan, there was a progression of disease as evidenced by appearance of new
osseous lesions in T10 vertebral body and R humerus (SUVmax 7.7, HU 827) but the
nodal lesions showed partial response with the SUV max and CTLD of the reference
lesion in retro-peritoneum decreasing to 3.6 & 2.1 respectively and there was also a
decrease in the serum PSA level to 380 ng/ml. Since, the patient had a progressive
disease with the appearance of new osseous metastasis; he was started on SWOG-
S0421 clinical trial (5/08) with docetaxel +/- Atrasentan. The patient has been doing
well since the start of this therapy.

Figure 25 Graph depicting the serial interval changes in the serum PSA levels in
relation with increase in the SUVmax values for some reference nodular lesions
in the retro-peritoneum and a new osseous lesion that was noted on 4
th
scan.

Also plotted are the various chemotherapy and radiotherapy regimes given to
the patients which corresponds to his serum PSA and SUV values on FDG-PET.

67

Baseline

CTLD = 1.8 cm SUV = 3.6 PSA = 73.7 ng/ml

month

4

CTLD = 2.5 cm SUV = 7.4 PSA = 230 ng/ml

month

8

CTLD = 2.4 cm SUV = 5.4
PSA = 446 ng/ml

month

12

CTLD = 2.1 cm
SUV = 3.6
PSA = 380 ng/ml

New
Mets

HU = 827
SUV = 7.7 PSA = 380 mg/ml

Figure 26: Serial FDG PET-CT scan images showing changes in the metabolic
abnormality (SUVmax) and morphologic appearance (CTLD) for lymph node
lesion in retro-peritoneum, demonstrating response to treatment captured by PET,
CT scan and correlating it with serum PSA levels.

68
Baseline

Casodex start

4month

4

Casodex stop Ketoconazole started

8month

8

ketoconazole continues

12month
Ketoconazole Docetaxel +/-

stopped Atrasentan

start

Figure 27: Coronal CT (left), MIP (maximum intensity projection) of whole body
PET scan (middle) and bone scintigraphy (right) images at baseline, 4, 8 and 12
month correlating the changes in the intensity and activity of lesions with
changes in the therapy of the patient.

Case Presentation: Transaxial CT, FDG PET, and fused PET-CT images at baseline, 4,
8, and 12 month scans showing changes in metabolic activity and size of a metastatic
lymph node lesion in retro-peritoneum just above the aortic bifurcation (arrows) and
correlating it to the conventional clinical parameter (PSA) used for assessing response to
treatment. Last row shows the new osseous lesion in the R humerus (arrows) that was
captured on the 12 month scan. It is interesting to note that PSA levels raised between
69
4 and 8 month scan while both the metabolic activity on PET scan and CTLD stayed
stable. However, both imaging modalities detected new osseous metastasis at 12 month
scan while the PSA levels started dropping between 8 and 12 month scan.
Discussion

Prostate cancer is a disease with a paucity of good outcome measures. By consensus,
investigators now independently report PSA, bone scan findings and changes in soft
tissue imaging, in recognition that each of these outcome measures tells only part of the
story. As an imaging modality, PET has the potential to capture all of these data in a
single study. The SUV is quantitative like the PSA, and PET can assess both bone and
soft tissue disease simultaneously, including the ability to detect the appearance of new
lesions. All the PET-CT scans were performed using a CT Siemens Biograph PET-CT
imaging system. A non-enhanced CT transmission scan was obtained for attenuation
correction after administration of oral contrast media. PET emission images were
obtained 60 minutes after an intravenous administration of 15.3 (±0.6) mCi FDG in a
caudal-cranial direction from upper thighs to skull base after voiding. In this case, we
see that the activity of the metabolically active reference lesion in the retro-peritoneum
increased from baseline to the 4 month scan with SUVmax going from 3.6 to 7.4, while
CTLD changing from 1.8 to 2.5 cm and some new lymph node lesions were seen in the
retro-peritoneum and hilar region. PSA levels too showed a progression going from
73.7 to 230 ng/ml. All these factors correlated with the change in therapy from Casodex
at baseline to prednisone + ketoconazole at 4 month. Between 4 and 8 month scan,
there were diverse findings on PET, CT scans & clinical findings. Metabolic activity of

70
various LN lesions showed partial response with SUVmax of the reference lesion
reaching 5.4 from 7.4, while CTLD remained stable. The PSA levels continued to surge
reaching 446 ng/ml from 230 ng/ml. There was no change in therapy at this time since
both restaging CT and bone scintigraphy showed stable disease. On 12 month FDG
PET scan, the metabolic activity of the LN lesions continued to show partial response
(SUVmax of reference lesion coming down to 3.6 from 5.4) but some new osseous
metastatic lesions were noted with reference lesion in Right Humerus having SUVmax
7.7. CT scan also showed a partial response for LN lesions with CTLD decreasing to
2.1 from 2.4 and it also detected the osseous mets with HU measuring 827. However,
the PSA levels started going down and were measured at 380 ng/ml, which is explained
by the start of new therapy using Docetaxel +/- Atrasentan just before the 12 month
scan. This case shows a good correlation of FDG PET scan with the conventional
imaging modalities (CT scan and bone scintigraphy) and clinical parameters.
In future, we would perform response to treatment analysis on a larger set of patients
that are already recruited in our study by applying RECIST 1.1 criteria for measurable
LN and soft tissue lesions on CT scan and EORTC criteria to measurable LN, soft tissue
& bone lesions on PET scan. FDG PET may well complement standard methods of
assessing treatment effects in routine clinical practice. For example, clinicians may
obtain routine interval scans even if the PSA is declining to confirm that the PSA
decline is not masking early progression of resistant clones, or to verify the absence of
an emerging non-PSA producing phenotype. In these scenarios, FDG PET may have a
role in clarifying whether a patient is responding or progressing. In addition, clinicians
who do not routinely perform scans and primarily follow the PSA to guide therapy may

71
now have a reliable method of directly assessing skeletal tumor burden and of detecting
early progressive disease. Of course, further study is needed to establish whether PET
scanning can serve in these roles.

Conclusion

As a single modality, FDG PET is promising as an outcome measure in prostate
cancer as it can show treatment effects that are usually described by a combination of
PSA, bone scintigraphy and soft tissue imaging. FDG PET warrants further study as
an outcome measure for assessing response to treatment for prostate cancer.

72
6.2 Castrate- resistant patient

Objective:

To detect the role of FDG PET-CT in determining the response to various
chemotherapeutic agents by applying measurability criteria based on the Response
Evaluation Criteria in Solid Tumors (RECIST) to LN & soft tissue lesions detected by
CT scan and European Organization for Research and Treatment of Cancer (EORTC)
criteria to LN, soft tissue and osseous lesions detected by the PET scan.

Introduction

Prostate cancer is a major public health problem, as it constitutes the most common type
of malignancy among men, excluding nonmelanoma skin cancers and is the second
leading cause of cancer specific mortality affecting men in the US. Biologically and
clinically, prostate cancer is a heterogeneous disease which is characterized by states
ranging from indolent to aggressive. Current clinical practice uses PSA to monitor the
disease despite its limited sensitivity and specificity (PSA might remain undetectable or
low in some cases of disseminated diseases while high levels can sometimes be
associated with benign disease). Inspite of having good treatments for the localized
prostate cancer, around 40% of men experience a detectable rise in serum PSA level
within approximately 10 years of primary treatment (biochemical failure), which
suggests that prostate cancer can metastasize relatively early in the course of the disease.
Therefore imaging becomes a critical modality for diagnosing the extent and the
metastasis of tumor cells, owing to the inherent heterogeneity of the disease. The optimal
73

method for detecting biochemical failure remains unresolved and hence research is
currently focused on developing an imaging modality which can detect whether
recurrence has occurred in the previously treated prostate bed or whether distant
metastasis has occurred. This will help clinically in directing therapeutic management,
including consideration of use of salvage therapy for local recurrence and systemic
treatment for metastatic disease. Positron emission tomography (PET) and recently
hybrid PET-computed tomography (CT), with [F-18] fluorodeoxyglucose (FDG) have
become important diagnostic imaging tools for the identification, localization and
characterization of a diverse group of malignancies. Results from the National
Oncologic PET Registry (NOPR) have shown that FDG-PET influenced clinical
management in 35.1% of prostate cancer cases.

Chemotherapy has traditionally been considered ineffective at prolonging survival of
patients with castrate resistant prostate cancer (CRPC). However, two large clinical trials
(TAX 327 AND Southwest Oncology Group 99-16) recently demonstrated improved
survival in patients with progressive HRPC treated with docetaxel-based chemotherapy
(Petrylak DP et al. 2004, Tannock IF et al. 2004). There is continuing interest in new
chemotherapeutic agents or agents that can be combined with docetaxel to further
enhance survival in HRPC. Unfortunately, the task of quantifying disease progression in
patients with HRPC is difficult and continues to hinder the progress of clinical trials.
Morphologic criteria such as the RECIST 1.0, RECIST 1.1 and EORTC, used in clinical
trials to measure tumor response have proven difficult to apply to prostate cancer. Not
only is the prostate excluded as a measurable disease site by RECIST, but also the

skeletal system which often dictates morbidity and mortality in HRPC is also largely

74

ignored by these criteria. Taking these points into consideration a NIH/NCI funded
clinical trial “FDG PET-CT in Metastatic Prostate Cancer” is currently ongoing at Keck
School of Medicine (KSOM), USC. The below mentioned case happens to be one of the
interesting and clinically relevant case that we came across while looking at the PET-CT
images for patients with locally recurrent and metastatic prostate tumors.

PET Imaging Protocol & Interpretations

As described in section 2.2 above.

Case Presentation

The patient is a 67-year-old Caucasian male with a hormone refractory metastatic
prostate cancer involving the bladder, bones and lungs, originally diagnosed in 1984
with a biopsy proven adenocarcinoma of the prostate, Gleason score 4+4, status post
radical prostatectomy done in 1994. The patient was doing well until 1996 when he had
a prostatic bed recurrence and completed 35 days of radiation therapy. In February 2003,
he had an elevated PSA with adenopathy on CT scan for which he was subsequently
started on hormonal therapy with Casodex and Zoladex under SWOG-9346 clinical trial
from February 2003 to March 2006. In July of 2006, the patient had some major
obstructive issues despite of self catheterization. This had somewhat inquisitively
occurred with a major fall in PSA from 2.81 to 0.23 after withdrawal of Casodex. The
patient was enrolled in a prospective imaging clinical trial titled “FDG-PET in metastatic
prostate cancer” since he showed progression of metastasis on CT scan and was
scheduled to undergo 4 FDG PET-CT scans at the PET imaging center, USC, at an
interval of every 4 months for first year followed by one year of follow-up visits. The

75
patient underwent first FDG-PET scan in June 2006, at which time there were found
multiple nodular lesions in the lungs with highest SUVmax of 7.1, CTLD 1.9cm
corresponding to a lesion in the middle lobe of the R. lung and a lesion in the left ischial
tuberosity with a SUVmax 12.7 and PSA level at this time was 0.09 ng/ml. He received 4
cycles of Cisplatin/Gemcitabine chemotherapy (from August 2006 to October 2006) and
showed immediate improvement in terms of his performance status and decreased
complaint of pain, particularly in his penis and in his bones. The patient came in for the
second FDG-PET scan in October 2006, at which time all the lesions showed a partial
response (PR) based on EORTC (European Organization for Research and Treatment of
Cancer) and RECIST criteria. The SUVmax dropped from 7.1 to 0.8 and CTLD from 1.9
to 0.9 cm for the reference lesion in the lungs while the SUVmax for lesion in left ischial
tuberosity dropped from 12.7 to 3. There was shrinkage in all the nodular lesions in the
lungs and the PSA levels continued to stay low at 0.04 ng/ml. In February 2007, the
patient underwent his 3
rd
FDG-PET scan and a progression was noted for all the lesions
based on RECIST and EORTC criteria for determining response to treatment. There was
a marked progression for the reference lesion in the lungs (SUVmax 6.3 from 0.8, CTLD
2.7 from 0.9 cm) and in ischial tuberosity (SUVmax 9.3 from 3). At this time, he also
developed multiple new brain metastases (in R.Occiput, L.Parietal and R.Temporal) with
the hottest lesion having a SUVmax of 6.6, for which he received radiation therapy. The
PSA level continued to stay low and was 0.03 ng/ml at this time while both the FDG
PET and CT scan showed a marked progression in the activity of metastatic lesions. The
patient expired on 4/13/2007 before undergoing his last FDG-PET scan which was
scheduled in June 2007. Below are the images of the patient‟s FDG PET-CT scan which

76
explains the role of FDG PET in assessing the response to treatment in comparison with

CT scan and PSA levels.

Figure 28 Serial FDG PET-CT scan images in a castrate-resistant metastatic
prostate cancer patient, demonstrating changes in metabolic activity (SUVmax)
and morphologic appearance (CTLD) and serum PSA levels in response to his
various therapeutic regimens.

Transaxial CT (lung window), FDG PET, fused PET-CT, coronal CT and MIP
(maximum intensity projection) images at baseline, 4 & 8 months in a male with
hormone refractory metastatic prostate cancer, along with the serum PSA levels (ng/ml)
77
Baseline

CTLD = 1.9
cm

SUV = 7.1

PSA
=0.09ng/ml

Taxotere

6/06 – 7/06
4 month

CTLD = 0.9
cm

SUV = 0.8

PSA =0.04ng/ml

Cisplatin +
Gemcitabine

8/06- 10/06
8 month

CTLD = 2.7
cm

SUV = 6.3

PSA =
0.03ng/ml

XRT to
sacrum &
Penis

12/06 - 2/07
12 month

Death of the patient before the final scan due to disease progression (metastasis to bones,
and Brain in addition to the lungs).

and the treatment changes. Multiple FDG-avid metastatic lesions are noted in the lungs
and lymph nodes of the mediastnum. The intensity of metabolically active lesions in the
lungs dropped at 4 month scan as compared to baseline while on 8 month scan there was
a progression in the activity of the nodular lesions in the lungs and the mediastinum and
elsewhere (ex. Ischial tuberosity). The patient died before his scheduled 12 month scan
due to disease progression with extensive metastasis to lungs, bones and Brain.

Figure 29 Graph depicting the serial interval changes in the serum PSA levels in
relation with increase in the SUV values for some reference nodular lesions in
the lungs and a new lesion that was noted in brain on 8 month scan.

Also plotted are the various chemotherapy and radiotherapy regimes given to
the patients which corresponds to his serum PSA and SUV values on FDG-PET.

Discussion

The role of PET using FDG for the imaging evaluation of patients with various types of
cancers is undeniable, and current studies are exploring the clinical use of PET and PET-
CT using FDG as a tracer in prostate cancer. As experience accumulates with FDG PET
in prostate cancer, it has become evident that FDG accumulation in high grade, high
78

Gleason primary tumors and in metastatic lesions, is elevated with a standardized uptake
value (SUV) of up to 6 or more. All the PET-CT scans were performed using a CT
Siemens Biograph PET-CT imaging system. A non-enhanced CT transmission scan was
obtained for attenuation correction after administration of oral contrast media. PET
emission images were obtained 60 minutes after an intravenous administration of 15.3
(±0.6) mCi FDG in a caudal-cranial direction from upper thighs to skull base after
voiding. In this case we see that as compared to the baseline scan done in June 2006, the
PET scan done in October 2006 showed a decrease in metabolic activity in both nodular
and bone lesions. A reference nodular lesion in Right middle lobe lung had an SUVmax
of 7.1 on first scan which decreased to 0.8 on second scan. Same was the case for bone
lesion in left ischium whose SUV max dropped from 12.7 on the first scan to 3 on the
second scan. According to EORTC criteria for evaluating response to treatment for PET,
all the lesions showed a partial response. (i.e. the SUV max of the lesions dropped by ≥

25% compared to the baseline). On the third scan all the lesions were metabolically very
active suggesting a progression of the metastasis from prostate cancer. The reference
nodular lesion in right middle lobe of the lung showed an increase in the SUV max which
went up to 6.3(previously 0.8) and that of the left ischial tuberosity was 9.3(previously 3).

The CT scans were in concordance to the PET scans showing similar outcomes when
evaluated by RECIST criteria. This is presented well in the figures 28 & 29. Also, a new
metastatic lesion in the brain came up on 3
rd
scan. Figure 29 shows a graphical overview of
the reference nodular and bony lesions in relation to the serum PSA values and various
chemotherapy & radiotherapy regimes. However, the serum PSA values stayed low

during this time interval. The serum PSA values at baseline, 4 & 8 month scans were

79

0.09, 0.04 and 0.03 respectively, which are highly insignificant compared to the
widespread nodular and osseous metastasis. This goes along with our observation
mentioned in one of the study mentioned above that in case of a LN predominant disease
(as in this case) the serum PSA levels tend to keep low in comparison to a bone
predominant disease where the PSA levels are at higher levels. The observations in this
patient are in concordance with previous studies which have shown that the level and
extent of FDG accumulation in metastatic lesions might provide information even on the
prognosis. An increase of over 33% in the average max SUV measurement from up to 5
lesions, or the appearance of new lesions, was reported to be able to categorize castrate
sensitive metastatic prostate cancer patients treated with chemotherapy into progressors
or nonprogressors (Schoder et al. 2004). Since FDG uptake in prostate tumors depends on
presence and activity of androgens, FDG-PET can also be useful in predicting the length
of time to reach the androgen refractory state. This might facilitate earlier therapeutic
modification to avert or delay this clinical state to improve the overall outcome.

CONCLUSION

This case is in concordance with the hypothesis of usefulness of FDG PET in diagnosing
locally recurrent and distant metastatic prostatic tumors and in assessing the response to
treatment. It presents that FDG-PET might be useful in detecting disease in fraction of
the large population of men who present with local recurrence and distant metastasis to
lungs, liver, brain etc. In such a group of men, early detection by FDG-PET can direct
appropriate treatment, such as salvage radiation therapy for local recurrence in prostatic
bed and adjacent areas or systemic therapy for metastatic disease to nodes and bones. The

use of hybrid PET-CT imaging systems will afford synergistic diagnostic information and
80

increased diagnostic confidence by providing precise localization of metabolic
abnormalities and by characterizing the metabolism of morphologic abnormalities. It has
been clearly mentioned in the first NOPR data that FDG –PET modality can influence
and change the way prostate cancer patients are treated globally. Research is also focused
on different radiotracers likely to be suited to various clinical stages of prostate cancer.
Further studies in greater number of patients with varying PSA levels would be required
to accurately evaluate lesion detection at different PSA levels, as well as to determine
whether F18-FDG PET-CT can complement PSA for measuring tumor burden and
response. Subsequent studies would also benefit by including correlations with clinical
outcomes, because better tools for risk-stratification are needed for prostate cancer.

81

CHAPTER 7: CLINICAL DETERMINANTS OF NODE vs. BONE
DOMINANT METASTATIC DISEASE ON FDG PET-CT –
PRELIMINARY ANALYSIS & RESULTS.

Objective

The purpose of this study was to determine the effects of clinical variables in predicting a
Bone vs. Non-Bone (Lymph node + soft tissue) dominant metastasis in patients with
metastatic prostate cancer using FDG PET-CT imaging.

Introduction

Prostate cancer has been increasingly detected earlier, which is attributable to the
widespread use of PSA screening. Freeland et al. reported that patients with post-
operative PSA values greater than 0.2 ng/ml are at a very high risk of developing an
additional increase in PSA, whereas Stephenson et al. reported that biochemical failure
defined as PSA value of 0.4 ng/ml followed by another increase best predicts the
development of distant metastasis. As a part of interim analysis, we tried to determine the
effects of clinical variables (like PSA, calcium, Gleason score and Alkaline Phosphatase)
in predicting bone vs. non-bone metastasis by using results of the baseline FDG PET-CT
scans.

Patients

Baseline clinical data (PSA, Gleason score, Alkaline Phosphatase) on 70 metastatic
prostate cancer patients (35 castrate-sensitive (CS), 35 castrate-resistant (CR)) who
had completed the ongoing prospective imaging trial were included for doing some

preliminary analysis. As a part of this imaging trial, the patients were required to undergo
82

4 serial FDG-PET-CT scans in an interval of one year, with scans 3 months apart. These
70 patients were those who had completed the imaging trial and were off study with
having completed 4, 3, 2 scan (patients with 3, 2 scans were either lost to follow-up or
died while on the trial due to disease progression). Table 15 describes the distribution
and characteristics of these patients. We did this classification with and without using the
typical cut-off SUV max ≥2.5 to see the differences that occurred by using cut-off
points.
It‟s important to note that whether we used or did not use this cut-off point, there were
scans which had neither bone nor LN metastasis but just had other soft tissue metastasis
like in lungs, liver etc. Such cases are denoted as soft tissue dominant disease. Table 15
contains detailed distribution of predominance in both groups.

Classification of Predominance

The information of baseline FDG PET-CT scans on these 70 patients was collected along
with the details on their clinical variables. Based on the baseline FDG PET-CT scan, the
patients were split into having either osseous/ nodal/ mixed dominant metastasis. We
applied a cut-off point SUVmax ≥2.5 for defining a lesion as seen on the PET scan.
Bone predominant disease was defined when a patient had only bony metastasis or when
difference between number of bone and LN lesions was >3 (ex. 8 bony mets and 3 LN
mets). Similarly, we classified the patient as having a LN predominant or a mixed
predominant disease. If the patient had both bone and LN lesions and the difference
between them was not > 3 then it was classified as having mixed lesions. Only baseline
FDG PET-CT scans were used for making this classification and for analysis.

83
Table 15: Distribution and characteristics of group 1 & 2 patients.

Group 1 Group 2

Total patients 35 35
- 4 scans 28 21
- 3 scans 3 7
- 2 scans 4 7
Classification without using
cut-point SUV max >2.5
- Bone 21 17

- LN 6 12
- Mixed (LN+bone) 5 4
- No * 3 2
- Prostate bed # 12 5
Classification using
cut-point SUVmax >2.5
- Bone 18 16
- LN 5 9
- Mixed (LN+bone) 4 4
- No * 8 6
- Prostate bed # 12 5
PSA (ng/ml) ~ 19.6 33.1
(4.09-147.95) (10.01-97.15)
Calcium (mg/dl) ~ 9.3 (9.2-9.5) 9.2 (8.9-9.7)

Alkaline Phosphatase (IU/L) ~ 78 (53-107) 83 (62-143)

Gleason score ~ 8 (7-9) 8 (7-9)

~ Baseline PSA, calcium, alk phos and Gleason score values are presented as Median
(25
th
- 75
th
percentile).

# denotes lesions in the prostatic bed. None of these patients had undergone a radical
prostatectomy.

* indicates the soft tissue dominant scans and also those which did not classify in any of
the mentioned categories after applying SUVmax ≥ 2.5 cut point.

84
Statistical analysis & Results

Univariate and multivariate logistic regression models were used to determine the role of
clinical variables in predicting a bone vs. non-bone dominant metastasis. The univariate
predictor model shows that PSA and Alkaline Phosphatase levels are statistically
significantly associated in predicting a predominant osseous compared to nodal
metastasis, based on the information provided from baseline FDG PET-CT scan and
baseline clinical parameters. Odds of predicting a bone predominant disease was 7.33
and 9 times higher when the PSA levels were 4.1 – 20 and >20 ng/ml respectively, with a
p-value of 0.004. Alkaline Phosphatase level of > 140 IU/L had a 5.83 times higher
chance of predicting a bone predominant disease compared to non-bone disease and it
was also statistically significant with a p-value of 0.029. Gleason score and having a
lesion in prostatic bed were not significantly associated in predicting dominant type of
metastasis on FDG PET-CT scans (p-values were 0.69 and 0.82 respectively).

Table 16: Univariate logistic regression for presence of bone disease when
SUV≥2.5 was used as cut point (pts with prostate bed lesions included N=70).

Variable Odds ratio (95% CI) p-value
Group 0.79 (0.30-2.05) 0.63
PSA 0.004
≤4 1.00
4.1-20 7.33 (1.47-36.7)
>20 9.00 (2.10-38.6)
Alka phosphase 0.029
≤140 1.00
>140 5.83
Gleason 0.92 (0.60-1.41) 0.69
Prostate bed lesion 1.00 0.82
1.15 (0.36-3.61)

85

PSA = Alk Phos = Gleason score
180 ng/ml 522 IU/L = 8

Figure 30: FDG PET-CT and Bone scan images demonstrating a case where high
serum PSA and Alkaline Phosphatase levels were associated with a predominant
osseous metastasis.

Baseline FDG PET-CT and Bone scan images in a 69 year-old male with hormone-
refractory metastatic prostate cancer, diagnosed originally in 1997, with a biopsy proven
adenocarcinoma of the prostate, Gleason score 4+4. The sagittal PET and CT images as
well as the bone scan images show that this patient had widespread osseous metastatic
lesions in axial and appendicular skeleton. The PSA and Alkaline Phosphatase levels at
baseline were 180 ng/ml and 522 IU/L respectively which goes with the derived results
that PSA levels > 20 ng/ml and alkaline Phosphatase level > 140 IU/L are associated
with statistically significant higher risk of predicting a bone predominant disease on FDG
PET-CT scan compared to having a non-bone predominant metastasis.

86

PSA = 0.51 Alk Phos = 51 Gleason = 8

Figure 31: FDG PET-CT scan images demonstrating a case where low serum
PSA and Alkaline Phosphatase levels were associated with a predominant lymph
node metastasis.

Baseline FDG PET-CT scan images in a 67 year old male with hormone-sensitive
metastatic prostate cancer, diagnosed originally with adenocarcinoma of the prostate in
1995, with a Gleason score 4+3. This patient had a predominant nodal metastasis, with
multiple metabolically active LN‟s found in retro-peritoneum and pelvic regions. The
PSA and Alk phos levels at baseline in this patient were 0.51 ng/ml and 51 IU/L
respectively which goes with our results that lower PSA and Alkaline Phosphatase
levels predict a nodal (non-bone) predominant metastasis compared to bony metastasis
on FDG PET-CT scan.

Conclusion

PSA and Alkaline Phosphatase levels are important clinical variables in predicting
osseous vs. nodal predominant metastasis on FDG PET-CT scans.

87
CONCLUSIONS

The conclusions derived from the various analyses done for addressing the scientific
questions mentioned in the aims of this thesis are as follows:

Chapter 3: A pictorial view of the various sites of metastasis from prostate cancer as

seen on FDG PET/CT scan.

The diagnostic accuracy of FDG PET scan was similar to the conventional imaging
modalities (CT scan and Tc 99m MDP bone scintigraphy) used for diagnosis and
evaluation of metastatic lesions from malignant prostate cancer.

Chapter 4: Detection of lymphadenopathy in metastatic prostate cancer:
18
F-FDG PET

vs. CT

The use of hybrid PET-CT imaging systems will afford enhanced diagnostic information
and increased diagnostic confidence by providing precise localization of metabolic
abnormalities and by characterizing the metabolism of morphologic abnormalities.
Integrated FDG PET-CT has the potential to be more effective tool compared to PET
and CT alone for detection of lymph node metastasis in patients with malignant prostate
cancer.

Chapter 5: Imaging evaluation of osseous metastasis in prostate cancer: comparison of
FDG-PET, CT and Bone scan.
18F-FDG PET-CT is a reasonably sensitive and specific modality for detection of bone
metastasis in patients with high-risk prostate cancer in comparison to the conventional
88

Tc99m MDP bone scintigraphy. CT images obtained as a part of PET-CT were helpful in
yielding the precise the location of bone lesions and thus avoiding misdiagnosis of bone
metastasis.

Chapter 6: Diagnostic accuracy of FDG PET-CT scans in evaluating response to

treatment in metastatic prostate cancer.

As a single modality, FDG PET is promising as an outcome measure in prostate cancer
as it can show treatment effects that are usually described by a combination of PSA, bone
scintigraphy and soft tissue imaging.

Chapter 7: Clinical determinants of node vs. bone dominant metastatic disease on

FDG PET-CT

PSA and Alkaline Phosphatase levels may predict osseous vs. nodal predominant

metastasis on FDG PET-CT scan, in men with malignant cancer of the prostate.

89
FUTURE PERSPECTIVES

We would further investigate the diagnostic and prognostic utility of PET-CT with the
most commonly available tracer, FDG, in metastatic prostate cancer on a larger
population of patients. We plan to correlate the treatment induced changes of glucose
metabolism in metastatic prostate cancer lesions to the changes in various conventional
clinical, laboratory and diagnostic imaging parameters such as serum PSA level, lesion
size, time to androgen independence, and survival. Our long range objective is to obtain
pilot data to investigate the ability of the hybrid PET and CT imaging systems for
assessing treatment response in patients with metastatic prostate cancer in comparison to
conventional imaging.

The use of FDG-PET in prostate cancer should be considered since the first NOPR data
clearly suggest that FDG-PET can influence the clinical management of men with
prostate cancer, although the influence is believed to be less in comparison to other
cancers. To reliably predict patient outcome it is necessary to explore the optimal time
point and the standards for evaluation of FDG PET scans during therapy for prostate
cancer.

90

ACCEPTED / IN REVIEW / IN PREPAPRATION ABSTRACTS,
PAPERS & PRESENTATIONS ON THIS THESIS

Jadvar H, Desai B, Conti PS, Dorff T, Groshen S, Pinski J, Quinn D, Ye W: “Detection of
lymphadenopathy with FDG PET-CT in men with metastatic prostate cancer”, Proc SNM
57th Ann Meeting, Salt Lake City, UT; In: J Nucl Med 51 (Supp 2): 126p;

2010. [NIH-NCI R01-CA1116101 Support]

Jadvar H, Desai B, Pinski J, Quinn D, Groshen S, Conti P: “Comparison of PET with

FDG, CT and bone scan in osseous metastatic prostate cancer”, J Nucl Med; 2010. (In
Preparation) [NIH-NCI R01-CA111613-01 Support]

Jadvar H, Desai B, Pinski J, Quinn D, Groshen S, Conti P: “Clinical determinants of
node versus bone dominant metastatic disease in prostate cancer”, J Nucl Med; 2010. (In
Preparation) [NIH-NCI R01-CA111613-01 Support]

Jadvar H, Desai B, Pinski J, Quinn D, Groshen S, Conti P: “[F-18]fluorodeoxyglucose
PET-CT of lymphadenopathy in castrate-sensitive and castrate-resistant prostate
cancer”, J Nucl Med; 2010. (In Preparation)[NIH-NCI R01-CA111613-01 Support]

Jadvar H, Desai B, Conti PS, Groshen S, Pinski J, Quinn D: “Clinical predictors of bone
disease on FDG PET/CT in men with metastatic prostate cancer”, RSNA 96th Scientific
Assembly & Ann Meeting,Chicago, IL, 2010. [NIH-NCI R01-CA1116101 Support]
(Accepted)

Jadvar H, Desai B: “A pictorial review of FDG PET/CT in prostate cancer”, Proc
RSNA 96th Scientific Assembly & Ann Meeting, Chicago, IL, 2010. [NIH-NCI R01-
CA1116101 Support] (Accepted)

91
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Abstract (if available)

Abstract The aims of present thesis are:1)To provide a pictorial view of the various sites of metastasis from prostate cancer as detected by FDG PET-CT scan and to compare its diagnostic potential with the conventional gold standard imaging modalities (CT and Tc 99m-MDP bone scintigraphy).2)To assess the diagnostic utility of 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET) compared to Computed Tomography (CT) in detection of lymph node metastasis in men with metastatic prostate cancer.3)To compare the diagnostic utility of FDG-PET, CT and Bone scans in evaluation of osseous metastasis in men with malignant prostate cancer.4)To determine the effects of clinical variables (PSA, calcium, Gleason score, Alkaline Phosphatase) in predicting a bone vs. non-bone (LN+ soft tissue) dominant disease on FDG PET/CT in men with metastatic prostate cancer.5)To identify interesting cases depicting the role of 18F-FDG PET scan for evaluation of response to treatment in metastatic prostate cancer.-Castrate-sensitive patients-Castrate- resistant patients

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University of Southern California Dissertations and Theses

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Asset Metadata

Creator Desai, Bhushan B. (author)

Core Title FDG PET-CT in metastatic prostate cancer

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical and Biomedical Investigations

Publication Date 08/06/2010

Defense Date 06/30/2010

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag castrate-resistant,castrate-sensitive,FDG,OAI-PMH Harvest,PET-CT,prostate cancer,PSA

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Jadvar, Hossein (committee chair), Groshen, Susan (committee member), Pinski, Jacek (committee member)

Creator Email bhushand@usc.edu,dr.bhushandesai@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m3319

Unique identifier UC1171895

Identifier etd-Desai-3912 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-369514 (legacy record id),usctheses-m3319 (legacy record id)

Legacy Identifier etd-Desai-3912.pdf

Dmrecord 369514

Document Type Thesis

Rights Desai, Bhushan B.

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu