PREDICTING THE BIOLOGY OF

COLORECTAL LIVER METASTASES:

FDG-PET/CT ASSESSMENT

A thesis submitted for the subject

Advanced Medical Science

Written by
Marco Kwok

Liver Tumours (00997)

The University of Melbourne
Department of Surgery,
Austin Hospital, Heidelberg, Australia

Date of submission: May 2011

Declaration

Student Statement

I, Marco Kwok, certify that the work presented in this thesis is, to the best of my
knowledge and belief, my original work and contains no material published or written by
another person except as acknowledged in the text.

I certify that the contents of this thesis are in compliance with the University’s Advanced
Medical Science (AMS) thesis guidelines and that the material presented has not been
submitted previously for a degree at this or any other University.

Signature:

Date: 20 May 2011

Supervisor Statement

This research project has been approved and is ready for submission.

Signature:

Date: 20 May 2011

Acknowledgments
I would like to take this opportunity to express my gratitude to the various individuals who
have supported me in writing this thesis.

Firstly, Mr Vijayaragavan Muralidharan has undoubtedly been most central to the

completion of this project. He has provided constant guidance and support over the past
year despite his absurdly demanding schedule as a surgeon. It has been a pleasure learning
and working so closely with him. His enthusiasm for this project has been most contagious,
and has helped me make the most of my AMS year.

Cathy Malcontenti-Wilson also deserves tremendous thanks for all her help she has given
me. Her radiant personality was always a warm welcome at the lab, and her insight and
expertise were valuable to me both academically and personally. I would like to wish her
great health and happiness in the years to come.

Dr. Sze Ting Lee and Dr. Lawrence Lau have also assisted me with many practical aspects
of this study. Without them, the project would definitely not have run so smoothly. The
opportunity to work with these two clinicians was also remarkable and has made me glad I
chose my career in the medical field.

Importantly, I would not have felt so at home if it was not for all the great people at the
Department of Surgery. I have never met a group of people so gifted at cooking (and
sharing) food. In particular I would like to thank Stephanie Gan, Shir Lin Koh, Linh
Nguyen and Shu Wen Wen for putting up with me this past year and for keeping me sane
while I underwent the ordeal of writing this thesis.

Last but not least I would like to thank Professor Christopher Christophi for bringing
together all the wonderful people that make up the department. It has been an absolute
privilege to be able to complete my research at this institute and, where circumstances allow,
I hope to be able to return again in the future.
Table of Contents
!!!!

Declaration ................................................................................................................................. ii
Acknowledgments .................................................................................................................... iii
Table of Contents ..................................................................................................................... iv
List of Tables and Figures ....................................................................................................... vi
Table of Abbreviations ........................................................................................................... vii
Abstract .................................................................................................................................... viii
1 INTRODUCTION ..................................................................................................1
1.1 COLORECTAL LIVER METASTASES .................................................................... 2
1.1.1 Current Treatment ........................................................................................................ 2
1.1.2 Risk of Treatment and the Selection of Patients ..................................................... 5
1.2 CANCER STAGING AND PROGNOSTICATION ..................................................... 7
1.2.1 TNM Staging ................................................................................................................. 7
1.2.2 Prognostic Scoring Systems ........................................................................................ 8
1.2.3 Tumour Biology ............................................................................................................ 9
1.2.4 Imaging in the Staging of Colorectal Liver Metastases......................................... 11
1.3 POSITRON EMISSION TOMOGRAPHY ............................................................... 12
1.3.1 Basis of PET................................................................................................................ 12
1.3.2 Current role of FDG-PET in CRLM management .............................................. 12
1.3.3 FDG-PET and Prognostication ............................................................................... 13
1.4 AIMS AND HYPOTHESES .................................................................................. 15
1.4.1 Hypothesis ................................................................................................................... 15
1.4.2 Aim ............................................................................................................................... 15

2 METHODS............................................................................................................ 16
2.1 Study Design and Ethics Approval ............................................................................. 17
2.2 Patient Cases ................................................................................................................... 17
2.3 Data Extraction .............................................................................................................. 17
2.4 Follow Up and Missing Data ....................................................................................... 18
2.5 18F-FDG PET/CT Scan Acquisition and Analysis .................................................. 18
2.6 Statistical Analysis .......................................................................................................... 19

3 RESULTS .............................................................................................................. 21
3.1 DESCRIPTIVE STATISTICS .................................................................................22
3.1.1 Patient Characteristics ................................................................................................ 22
3.1.2 Primary Tumour ......................................................................................................... 22
 3.1.3 Liver Metastases .......................................................................................................... 22
3.1.4 Surgical Resection ....................................................................................................... 22
3.1.5 PET Metabolic Parameters ....................................................................................... 23
3.1.6 Prognostic Scores ....................................................................................................... 23
3.1.7 Survival Outcomes ..................................................................................................... 25
3.2 RECEIVER-OPERATOR CHARACTERISTICS .........................................................27
3.2.1 PET Metabolic Parameters ....................................................................................... 27
3.2.2 Prognostic Scores ....................................................................................................... 29
3.2.3 Time-dependent ROC analysis ................................................................................. 30
3.2.4 Optimal Cutoff Points ............................................................................................... 31
3.3 KAPLAN-MEIER SURVIVAL CURVES .................................................................32
3.3.1 PET Metabolic Parameters ....................................................................................... 32
3.3.2 Prognostic Scores ....................................................................................................... 36
3.4 UNIVARIATE AND MULTIVARIATE ANALYSIS (COX REGRESSION) ...................39

4 DISCUSSION ........................................................................................................42
5 CONCLUSION .....................................................................................................49

BIBLIOGRAPHY.......................................................................................................50
List of Tables and Figures

TABLE 1.1: CRITERIA OF PROPOSED PROGNOSTIC SCORING SYSTEMS ................................. 8

TABLE 3.1: PET METABOLIC PARAMETER DISTRIBUTION ..................................................... 23
TABLE 3.2: OVERALL SURVIVAL OUTCOMES .......................................................................... 26
TABLE 3.3: AREAS UNDER THE CURVE (AUC) OF PET PARAMETERS ................................... 28
TABLE 3.4: AREAS UNDER THE CURVE (AUC) OF PROGNOSTIC SCORES ............................. 30
TABLE 3.5: OPTIMAL CUTOFF POINTS / SENSITIVITY / SPECIFICITY .................................. 31
TABLE 3.6: MULTIVARIATE ANALYSIS OF PROGNOSTIC PREDICTORS ................................ 39
TABLE 3.7: UNIVARIATE ANALYSIS OF POTENTIAL PROGNOSTIC PREDICTORS ................ 40

FIGURE 3.1: CORONAL PET IMAGES OF PATIENTS WITH CRLM ............................................ 24

FIGURE 3.2: DISTRIBUTION OF PROGNOSTIC RISK SCORES IN THE COHORT ...................... 25
FIGURE 3.3: KAPLAN-MEIER SURVIVAL CURVES BY OS AND RFS IN ENTIRE COHORT ....... 26
FIGURE 3.4: ROC CURVES BY PET PARAMETERS (SUVMAX, SUVMEAN, MTV, TGV).............. 27
FIGURE 3.5: ROC CURVES BY PROGNOSTIC SCORES ................................................................ 29
FIGURE 3.6: AUC OVER TIME PLOTS OF PET PARAMETERS BY OS AND RFS ......................... 30
FIGURE 3.7: KAPLAN-MEIER SURVIVAL CURVES OF PET PARAMETERS BY OS ..................... 33
FIGURE 3.8: KAPLAN-MEIER SURVIVAL CURVES OF PET PARAMETERS BY RFS ................... 34
FIGURE 3.9: KAPLAN-MEIER SURVIVAL CURVES OF TGV BY QUARTILES ............................. 35
FIGURE 3.10: KAPLAN-MEIER SURVIVAL CURVES OF MTV BY QUARTILES ............................. 36
FIGURE 3.11 KAPLAN-MEIER SURVIVAL CURVES OF PROGNOSTIC SCORES BY OS .............. 37
FIGURE 3.12: KAPLAN-MEIER SURVIVAL CURVES OF PROGNOSTIC SCORES BY RFS ............ 38
Table of Abbreviations
AUC Area under curve
CI Confidence interval
CEA Carcinoembryonic Antigen
CRC Colorectal cancer
CRLM Colorectal liver metastases
CT Computed Tomography
FDG Fluorodeoxyglucose
EGFR Epidermal growth factor reception
FOLFOX Folinic acid, Fluorouracil, Oxaliplatin
FOLFIRI Folinic acid, Fluorouracil. Irinotecan
HR Hazard ratio
MTV Metabolic tumour volume
OS Overall survival
RFS Recurrence-free survival
ROC Receiver-Operator characteristics
PET Positron Emission Tomography
SUV Standardized uptake value
TGV Total glycolytic volume (also known as TLG – total lesion glycolysis)
VEGF Vascular endothelial growth factor
 THE UNIVERSITY OF MELBOURNE

Predicting the Biology of Colorectal Liver Metastases:

FDG-PET/CT Assessment

Abstract
Author: Marco Kwok
Project Supervisors:
Mr Vijayaragavan Muralidharan1, Dr. Sze-Ting Lee2,3, Professor Christopher Christophi1,
Mrs. C. Malcontenti-Wilson1
1
The University of Melbourne Department of Surgery, Austin Hospital, Victoria, Australia.
2
Department of Nuclear Medicine & Centre for PET, Austin Hospital, Victoria, Australia.
3
Ludwig Institute for Cancer Research, Austin Hospital, Victoria, Australia.

BACKGROUND
Colorectal liver metastases (CRLM) develop in up to a half of colorectal cancer patients and
is a major contributor to the mortality of this disease. Treatment for CRLM is associated
with increased morbidity and must therefore be adapted to the patient’s risk of relapse and
predicted survival. However, tools developed in the past to stratify patients into risk groups
have been generally inconsistent and limited in their prognostic capacities.

Biological characteristics of tumours have been increasingly appreciated as a major

determinant of patient outcomes. Intense glucose uptake by tumours on novel imaging
techniques such as positron emission tomography (PET) has been correlated with poorer
patient survival and may reflect biological aggressiveness in certain tumours, such as lung
carcinoma. However, this has yet to be demonstrated in CRLM, and may serve to be a
promising alternative to traditional prognostic indicators.

OBJECTIVE
To assess the prognostic utility of preoperative PET-based metabolic measurements as a
surrogate indicator of tumour biology, and compare these measurements to previously
proposed prognostic scoring systems.

METHODS
This study retrospectively reviewed thirty patients who had 18F-FDG PET/CT imaging
studies performed before liver resection and after neoadjuvant chemotherapy for colorectal
liver metastases. Several semiquantitative parameters known as mean and maximum
standardized uptake value (SUVmean & SUVmax), metabolic tumour volume (MTV) and
tumour glycolytic volume (TGV) were measured from the PET scans, and four prognostic
scores proposed by Fong (MSKCC), Iwatsuki (Pittsburgh), Nordlinger, and Rees
(Basingstoke) were applied to the patients. The prognostic value of these factors was
estimated using univariate and multivariate Cox proportional regression analysis. Receiver-
operator characteristics (ROC) analysis was conducted to assess their discriminative abilities
and determine optimal cut-off points for each PET parameter. These cut-off points were
then used to compare survival differences between FDG-uptake groups by Kaplan-Meier
survival analysis.

RESULTS
On univariate analysis, patient age, size of largest metastasis, TGV, MTV, Pittsburgh and
Basingstoke scores were found to be significant predictors of survival. When adjusted for
other variables, only TGV was determined to be an independently predictive of overall
survival (OS) (P=0.002) and recurrence-free survival (RFS) (P=0.001). Each unit of TGV
produced 1.9% and 1.3% increased hazard of death and recurrence respectively (HR:
1.019[95% CI: 1.007-1.032] for OS and HR: 1.013 [95% CI: 1.005-1.021] for RFS). Of the
PET parameters, SUV measurements showed poor discriminative performance compared
to MTV and TGV. Prognostic scores were significantly discriminative with death as an
endpoint but not recurrence. Patients with high FDG uptake tumours had significantly
reduced OS and RFS than low uptake patients when assessed with MTV and TGV, but not
SUV.

CONCLUSION
This study found that a high TGV on PET after neoadjuvant chemotherapy is an
independent predictor of poor prognosis in preoperative patients. Assessing the burden of
metabolically active tumour with volumetric PET parameters may provide a unique
advantage over current prognostic scoring systems in optimizing therapeutic selection in
patients.
Section 1

INTRODUCTION
1 INTRODUCTION 2

1.1 Colorectal Liver Metastases

Colorectal cancer (CRC) is amongst the most common malignancies in both men and
women worldwide1 with high incidences seen in major developed countries in North
America, Europe, and Australia. CRC is a significant health burden with over 13 000 new
cases diagnosed annually in Australia alone.2

While screening initiatives have successfully enabled earlier detection of this cancer,
metastatic disease to the liver remains the most frequent cause of mortality in CRC. In
around 25% of patients, colorectal liver metastases (CRLM) are observed even at the initial
presentation of the disease. A further 25% of patients will develop metachronous liver
metastases following treatment for the primary CRC.3 Left untreated, the median survival in
patients with metastatic disease to the liver is approximately 8 months.4

1.1.1 Current Treatment

SURGERY
Surgical treatment of CRLM involves resection of the lesion and the surrounding liver
parenchyma with margins clear of microscopic disease. The procedure was first successfully
performed by Cattell in 1943 back when a nihilistic attitude to treating CRLM was
prevalent.5 Since then, evidence supporting the benefits of resection has grown, and despite
significant improvements in other modes of therapy, surgery remains accepted as the only
current intervention that is potentially curative.

Surgical resection of liver metastases is a safe procedure and has the potential to prolong
long-term survival. With better insight into liver segmental anatomy and continuing
refinement in surgical and anaesthetic techniques, perioperative overall mortality has been
shown to be less than 2%.6 Survival benefits of surgery have been well documented in
numerous studies with 5-year survival rates of 30% to 50% in patients undergoing the
1 INTRODUCTION 3

procedure.7,8 This is in stark contrast to the rather poor prognosis of those who do not
receive treatment or are treated with a palliative intent.

However, while the survival benefits are substantial in those with surgically resectable
tumours, these individuals constitute only 20% to 30% of the patient population.4 The
majority of CRLM patients present with inoperable disease, which is determined by a
number of factors. First is the technical ability to resect all hepatic metastases. Resection
must be conducted leaving sufficient liver volume for postoperative recovery of liver
function, but this may not be feasible when the number and distribution of the metastases
is unfavourable.9 Patient must also be medically fit to undergo major surgical procedures.
Finally, as metastatic colorectal cancer is a systemic disease, the presence of extrahepatic
metastases may signify poor tumour biology. Patients with extrahepatic disease have been
demonstrated to have a higher risk of tumour recurrence and death, and are classically
precluded from surgical treatment.10,11

Yet even without the evidence of extrahepatic disease, tumour recurrence remains a
significant issue in those undergoing hepatic resections. A large number of patients relapse
soon after surgery due to the presence of micrometastases that are neither detectable by
routine clinical imaging, nor amenable to any form of surgical intervention.4 Although some
patients will benefit from a repeat resection, the majority will have metastatic disease that
excludes them from further surgery. Because of this, a multimodal and multidisciplinary
approach that extends beyond surgical procedures is vital in achieving optimal outcomes
for patients.

SYSTEMIC CHEMOTHERAPY
Complementing surgical interventions with systemic chemotherapy has been a key shift in
the management strategy of CRLM. Significant improvement has been made to the menu
of chemotherapeutic agents available for liver metastases, evolving from early treatment
with 5-fluorouracil and leucovorin, to the eventual inclusion of oxaliplatin (FOLFOX) and
irinotecan (FOLFIRI) to the combination. The efficacy of chemotherapy in reducing
tumour burden is now well established and its use in conjunction with surgery is strongly
encouraged for the majority of CRLM patients.