Positron Emission Tomography in the management

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Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the ...... variabele fysiologische FDG stapeling ter hoogte van het gastrointestinaal systeem, alsook ... In dit onderzoek werd ook de betekenis bestudeerd van ...

Positron Emission Tomography in the management of Oesophageal and Colorectal cancer

Dr. Patrick Flamen

Promotor:

Prof. Dr. L. Mortelmans

Copromotor: Prof. Dr. E. Van Cutsem

Thesis submitted in fulfillment of the requirements for the degree of « Doctor in de Medische Wetenschappen »

2001

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Promotor

Prof. Dr. L. Mortelmans Nucleaire Geneeskunde UZ Gasthuisberg; Katholieke Universiteit Leuven

Copromotor

Prof. Dr. E. Van Cutsem Interne Geneeskunde (Maag-Darmziekten) UZ Gasthuisberg; Katholieke Universiteit Leuven

Jury Prof. Dr. S. Larson Nuclear Medicine Memorial Sloan-Kettering Cancer Center New York, United States of America Prof. Dr. A. Bossuyt Nucleaire Geneeskunde Academisch Ziekenhuis; Vrije Universiteit Brussel Prof. Dr. R.A. Dierckx Nucleaire Geneeskunde Universitair Ziekenhuis; Rijksuniversiteit Gent Prof. Dr. N. Ectors Pathologische Ontleedkunde UZ Gasthuisberg; Katholieke Universiteit Leuven Prof. Dr. T. Lerut Thoraxheelkunde UZ Gasthuisberg; Katholieke Universiteit Leuven Prof. Dr. E. Ponette Radiologie UZ Gasthuisberg; Katholieke Universiteit Leuven

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Dankwoord Zoals de aanpak van digestieve tumoren een nauwe multidisciplinaire samenwerking vereist, zo ook is deze doctoraatsthesis het resultaat van de inspanningen van diverse persoonlijkheden die rechtstreeks of onrechtstreeks betrokken waren bij het inspireren, het coördineren, het verwerken en interpreteren van dit werk. Vooreerst dient Prof. Luc Mortelmans vermeld te worden die mij uiteindelijk overhaald heeft om vanuit de Vrije Universitieit van Brussel, vier jaar geleden ondertussen, de niet zo evidente overstap te wagen naar de Katholieke Universiteit van Leuven. Zijn ongebreidelde ambitie en enthousiasme voor het vakspecialisme Nucleaire Geneeskunde, zijn werklust en temperament, tezamen met zijn onmiskenbare persoonlijke charme en gevoel voor humor waren de laatste jaren voor mij een belangrijke en noodzakelijke basis voor het uiteindelijke welslagen van mijn verblijf op de Gasthuisberg. Als diensthoofd en promotor was en blijft hij voor mij een betrouwbare leidraad. Vanuit de medische nucleaire hoek had ik het geluk geflankeerd te worden door twee sterke persoonlijkheden met scherpe geesten met wie de dagelijkse samenwerking, op een vriendschappelijke basis, immer smetloos en gesmeerd verliep: Prof. Alex Maes en Dr. Sigrid Stroobants. Hun onvoorwaardelijke collegialiteit en vertrouwen zullen mij steeds bijblijven. De soms vurige en vaak diepgaande discussies over wetenschap, carrierewendingen, en allerhande levensfilosofische onderwerpen hebben de voorbije jaren ongetwijfeld een zekere invloed gehad op mijn denk- en handelswijze. Dit werk was onmogelijk geweest zonder de hulpvaardige aanwezigheid van de verschillende ‘activiteitencentra’ van de dienst Nucleaire Geneeskunde. Het was mij een waar genoegen om me de voorbije jaren behaaglijk te kunnen koesteren onder deze hooggekwalificeerde, vaak wereldgereputeerde personaliteiten. Hierbij doel ik op de radiofarmacie (Prof. Alfons Verbruggen, Prof. Guy Bormans, Apr. Bert Van Billoen, Dr. Tsjibbe De Groot), de ingenieurs en physici (Prof. Johan Nuyts, Prof. Patrick Dupont, Ir. Jan Baetens, Ir. Stefaan Vleugels), de assistentengroep, de technologen (onder de zeer geappreciëerde leiding van Ludo Verhaegen), en, zeker niet te vergeten, het secretariaat (Danny Vandenabele en Francine Reniers). Een bijzonder woord van dank ben ik verschuldigd aan alle leden van het multidisciplinaire team rond slokdarmkanker, Prof. Eric Van Cutsem, tevens copromotor, en Prof. Toni Lerut. Het zijn hun exploratieve breinen die de aanstoot gaven tot het, in primeur, opstarten van het onderzoek over het gebruik van positron emissie tomografie bij slokdarmtumoren. De wekelijkse kransen lieten mij toe om als diagnosticus op korte termijn vertrouwd te worden met de gangbare klinische aanpak en de bestaande diagnostische knelpunten. Een meer ideaal platform voor prospectieve researchprojecten kon ik me niet indenken. Hopelijk zal ik mij in de toekomst kunnen blijven laven aan hun ideeën en impulsen.

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Een bijzondere blijk van dank betuig ik aan mijn vroegere mentors van de dienst Nucleaire Geneeskunde van de Vrije Universiteit van Brussel: Prof. em. Marc Jonckheer, Prof. Axel Bossuyt en Prof. Philippe Franken. Zij hebben mij de beginselen bijgebracht van het vrije wetenschappelijke denken, het systematisch analyseren en publiceren van de onderzoeksresultaten. De fundamentele waarden, ook menselijke, die deze mensen en hun instelling me hebben toegeleverd zijn van onschatbare waarde geweest in mijn verdere professioneel en persoonlijk leven. Een bijzondere dankbetuiging gaat uit naar mijn gezin, Nathalie, Nora en Gilles, bij wie het leven dermate aangenaam en bevrijdend was dat het de geleverde inspanningen en opofferingen draaglijk en zinvol maakten. Mijn ouders ben ik zeer veel verschuldigd. Ik wil hen danken voor alle kansen die ze mij gegeven hebben. Prof. Jan Bernheim, mijn schoonvader, voor het leesbaar maken van mijn linguistische monsters, alsook voor de blijvende motivering tot academisch denken en werken.

Leuven, 31 mei 2001

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Publication List Additional value of whole-body positron emission tomography with fluorine-18-2-fluoro-2-deoxy-D-glucose in recurrent colorectal cancer. Flamen P, Stroobants S, Van Cutsem E, Dupont P, Bormans G, De Vadder N, Penninckx F, Van Hoe L, Mortelmans L. Journal of Clinical Oncolology 1999; 17(3):894-901 Utility of positron emission tomography for the staging of patients with potentially operable esophageal carcinoma. Flamen P, Lerut A, Van Cutsem E, De Wever W, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, De Leyn P, Van Raemdonck D, Coosemans W, Ectors N, Haustermans K, Mortelmans L. Journal of Clinical Oncolology 2000; 18(18):3202-10 A new imaging technique for colorectal cancer: Positron Emission Tomography. Flamen P, Van Cutsem E, Mortelmans L. Seminars in Oncology 2000; 27(5), Suppl 10:22-29 Histopathologic validation of lymph node staging with FDG-PET scan in cancer of the esophagus and gastroesophageal junction - A prospective study based on primary surgery with extensive lymphadenectomy. Lerut T, Flamen P, Ectors N, Van Cutsem E, De Wever W, Peeters M, Stroobants S, Dupont P, Bormans G, Hiele M, De Leyn P, Van Raemdonck D, Coosemans W, Haustermans K, Mortelmans L. Annals of Surgery 2000; 232:743-751 The Utility of Positron Emission Tomography (PET) for the Diagnosis and Staging of Recurrent Esophageal Cancer. P. Flamen, A. Lerut, E. Van Cutsem, J.P. Cambier, A. Maes, W. De Wever, M. Peeters, P. De Leyn, D. Van Raemdonck, L. Mortelmans. J Thoracic and Cardiovascular Surgery 2000; 120(6):1085-1092 Clinical value of whole-body positron emission tomography in potentially curable colorectal liver metastases. Topal B, Flamen P, Aerts R, D’Hoore A, Filez L, Mortelmans L, Penninckx F. European Journal of Surgical Oncology 2001; in press Unexplained rising Carcinoembryonic Antigen (CEA) in the postoperative surveillance of colorectal cancer: the utility of Positron Emission Tomography. Flamen P, Hoekstra OS, Homans F, Van Cutsem E, Maes A, Stroobants S, Peeters M, Penninckx F, Filez L, Bleichrodt R, Mortelmans L. European Journal of Cancer 2001; in press Positron Emission Tomography for assessment of the response to Induction radiochemotherapy in advanced oesophageal cancer. P. Flamen, E. Van Cutsem, A. Lerut, J-Ph. Cambier, K. Haustermans, G. Bormans, P. De Leyn, D. Van Raemdonck, W. De Wever, N. Ectors, A. Maes, L. Mortelmans. Annals of Oncology 2001; in press

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Table of Contents I. General Introduction A. Synergism between advances in diagnosis and the treatment of cancer

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B. Synergism between structure and metabolism in cancer diagnosis

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C. Positron Emission Tomography

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D. Biochemical foundations of the use of 18F-FDG as a marker in malignancy

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E. Intratumoural distribution of FDG at the cellular level

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F. Technical aspects of whole-body FDG-PET

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G. Clinical applications of metabolic imaging using FDG and PET

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H. General consideration on the diagnostic use of FDG-PET in oncology

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I. Scope and purpose of the thesis

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II. Positron Emission Tomography in Colorectal cancer A. Primary staging of colorectal cancer

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B. PET in the management of recurrent colorectal cancer

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1) Diagnosis and staging of recurrent cancer The clinical problem

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Materials and Methods

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Results

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Discussion

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2) Unexplained Elevation of CEA The clinical problem

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Materials and Methods

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Results

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Discussion

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C. The use of PET for therapy monitoring

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III. Positron Emission Tomography in Oesophageal Cancer

A. Preoperative Staging of Oesophageal cancer

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The clinical problem

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Patients and Methods

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Results

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Discussion

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B. Diagnosis and Staging of Recurrent Oesophageal cancer

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The clinical problem

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Materials and Methods

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Results

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Discussion

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C. Response Assessment after Induction Therapy of Oesophageal Cancer

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The clinical problem

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Materials and Methods

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Results

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Discussion

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IV. Summary

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V. Samenvatting

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VI. References

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Frequently used abbreviations CDM

Conventional Diagnostic Modalities

CDW

Conventional Diagnostic Workup

CR

Complete Remission

CRT

chemoradiation therapy

CT

Computed Tomography

EC

(O)esophageal cancer

EUS

Endoscopic Ultrasound

FDG

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GEJ

gastro-oesophageal junction

GI

gastro-intestinal

LN

lymph node

M+org

presence of organ metastasis

M+ly

presence of distant lymph node metastasis

ROI

region of interest

PET

Positron Emission Tomography

qCR

quasi-complete remission

SUV

Standard Uptake Value

TNM

Tumour Node Metastasis (classification)

TUR

Tumour-to-liver Uptake Ratio

TREUS

Transrectal Endoscopic Ultrasound

F-Fluoro-2-deoxy-D-glucose

Definition of the frequently used statistical terms TP

true-positive

TN

true-negative

FP

false-positive

FN

false-negative

sensitivity

TP / (TP + FN)

specificity

TN / (TN + FP)

accuracy

(TP + TN) / (TP + TN + FP + FN)

positive predictive value

TP / (TP + FP)

negative predictive value TN / (TN + FN)

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I. General Introduction A. Synergism between advances in diagnosis and the treatment of cancer Until recently, ‘unimodality' surgical treatment was the most frequent approach for patients with gastrointestinal (GI) malignancy. The absence of effective nonsurgical

techniques for tumour diagnosis and staging entailed that surgical

therapy frequently was undertaken after an only minimal preoperative investigation. A major development in the 1990's was the advent of dramatic improvements in nonoperative and minimally invasive approaches for the diagnosis and staging of GI malignancy. In particular, contrast enhanced spiral computed tomography (CT), endoscopic ultrasound (EUS), magnetic resonance imaging (MRI), and video assisted laparoscopy and thoracoscopy certainly represent major advances in this area. In addition, a new emphasis on ‘multimodality’ therapy, combining radiotherapy and/or chemotherapy, preceeding (neoadjuvant) or following (adjuvant) operative management, entailed that surgery is often no longer the sole therapeutic option. As these different therapeutic options became available, the risk appeared of over- or undertreating certain patients because of inaccurate estimation of the disease extent. Therefore, in this new 'multimodal' therapeutic era, more accurate pretherapeutic estimation of the disease stage, resectability and prognosis certainly constitute a prerequisite to optimally benefit overall survival and quality of life of the involved patients. Ideally, this would culminate in the so-called ‘patient-tailored’ treatment modality. This essential synergism between diagnostic and therapeutic improvements in the management of cancer constitutes the fundamental basis of the research work presented in this thesis.

B. Synergism between structure and metabolism in cancer diagnosis The technologic revolution in medical imaging during the last decades is certainly one of the cornerstones of progress in modern oncology. Recent developments in radiographic imaging have resulted in highly sensitive cross sectional imaging, providing ever increasing accuracy in detection and defining the extent of tumours. Importantly, it must be born in mind that the diagnosis

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provided by these techniques entirely depends on structural and morphometric characteristics of the tumour. Therefore, the accuracy of these so-called structure-based techniques is severely hampered by the fact that structural information alone does not always allow straightforward differentiation between malignant versus benign lesions. An example is the use of the lesion diameter as a criterium to diagnose tumoural lymph node involvement by CT or endoscopic ultrasound. Using such a criterium results in both imperfect sensitivity (normal-sized lymph nodes can harbour neoplastic cells) and specificity (reactive, inflammatory lymph nodes are often enlarged). A classic example is the presacral mass often seen on CT in the follow-up after resection of a rectal carcinoma. Based on structural characteristics, differentiation between postoperative fibrotic changes and local recurrent tumour is not feasible. A major contribution in this setting are the recent technical developements for obtaining a histologic diagnosis using CT- or EUS -guided biopsy. This allows a highly specific diagnosis, but it is prone to false-negativity due to frequent sampling errors, resulting in a low negative predictive value of this technique. Therefore, a strong need exists for sensitive noninvasive imaging techniques which can provide information on tissue metabolism. These metabolic imaging techniques can indicate the probable presence or absence of malignancy on the basis of observed differences in biologic activity. These examinations yield data independently from associated structural characteristics, and therefore allow the detection or monitoring of specific biochemical perturbations which are not associated with or preceed the anatomical changes. Historically, the two imaging modalities, radiology and nuclear medicine, evolved in two separate worlds, which were often considered as competitive. Only recently, clinicians and research people have come to appreciate the essential synergism between these two disciplines. Indeed, adding the information on metabolism provided by nuclear medicine techniques to the structural substrate provided by the radiographic methods, leads to the socalled correlative or anatomometabolic imaging, and can significantly improve cancer diagnostics.

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C. Positron Emission Tomography Positron emission tomography (PET) is the most sensitive and specific technique for in-vivo imaging of metabolic pathways and receptor-ligand interactions in the tissues of man.1 PET uses radioisotopes of natural elements, oxygen-15, carbon-11, nitrogen-13, and fluorine-18. These radioisotopes allow the synthesis of numerous positron-emitting radiopharmaceuticals. Depending on the selected radiopharmaceutical, PET imaging can provide quantitative information regarding blood flow (H215O), hypoxia (18F-misonidazole), DNA metabolism (11C-thymidine), glucose metabolism (18F-FDG), protein synthesis rate (11C-tyrosine), amino acid metabolism (11C-methionine), and receptor status. PET is destined to provide a unique contribution in the translation of molecular biology discoveries to measurements at a regional tissue level in human diseases and during their treatments. The biodistribution of the positron-emitting tracers is measured using a dedicated tomographic imaging device. A positron transverses a few millimeters through the tissue until it combines with an electron in the surrounding media. This generates a pair of photons which travel in nearly opposite directions (180° apart) with an energy of 511 keV each. These opposed photons can be detected by detector pairs installed in a ring shaped pattern. Photons that simultaneously (i.e. within a predefined time-window) interact with these detectors are registered as decay events (cfr. Figure 1). Based on these registrations, tomographic images of the regional radioactivity distribution are reconstructed (emission images). Figure 1.

block detector annihilation photons positron emission

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Through the early 1980's, PET scans were primarily used in research, and predominantly focussed on the neurosciences and cardiology. Improvements in the technology have had a significant impact on the quality of PET image reconstruction and display. Through the 1990's, in parallel to significant advances in the molecular biology of cancer, applications of PET became increasingly oriented towards oncology. The number of scientific reports on its use for imaging cancer rose exponentially during the last decade. In parallel to what happened in the United States, the increasing implementation of PET in the management of cancer at the major university hospitals in Belgium led to the acceptance of the additional value of PET by the referring physicians. This in turn contributed to the decision by the national health insurance authority to reimburse PET in specific indications in colorectal, head and neck, lung and ovarian cancer, lymphoma, melanoma, and brain tumours.

D. Biochemical foundations of the use of

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F-FDG as a marker in

malignancy The tracer most commonly used worldwide is fluorine-18-labeled 2-fluoro-2deoxy-D-glucose (FDG). This is a D-glucose molecule in wich a hydroxyl group in the 2-position is replaced by an

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F-label. The use of FDG for in vivo cancer

imaging is based upon the higher rate of glucose metabolism in cancer cells, a feature which was first described by Warburg several decades ago.2 After malignant transformation, cells demonstrate an increased expression of the epithelial glucose transporter proteins and an increase in the activity of the principal enzymes of the glycolytic pathway. After intravenous administration, FDG competes with plasma glucose for the glucose transporters in the cell membrane. Figure 2 illustrates the molecular basis underlying the use of FDG for imaging cancer

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Figure 2.

Normal cell Glucose 6-phosphatase

Neoplastic cell

FDG

Glucose 6-phosphatase

FDG-6-P Glycolytic pathway

FDG-6-P Hexokinase

Hexokinase

G6P Glucose 6-phosphatase

Glycolytic pathway G6P

D-glucose

Glucose 6-phosphatase

Because FDG lacks a hydroxyl group in the 2-position, its first metabolite, FDG6-phosphate, is not a substrate for the glucosephosphate isomerase, and therefore cannot be converted to the fructose analog. As most tumours have a low phosphatase activity, the negatively charged FDG-6-phosphate will accumulate intracellularly, resulting in a so-called ‘metabolic trapping.3 Under steady state conditions, the amount of FDG-6-phosphate accumulated is proportional to the rate of glucose utilisation.

E. Intratumoural distribution of FDG at the cellular level Viable cancer cells have an increased accumulation of FDG. In-vitro studies have shown that malignant transformation of normal cells by oncogenic viruses or chemical carcinogens leads within hours to an increase in glucose uptake by a factor five.4 In most tumours, this constitutes the major origin of the measured radioactivity. It has been shown that increased tumoural FDG uptake, although a function of the proliferative activity, is mainly related to the viable tumour cell number.5 However, when interpreting data on intensity of FDG accumulation in tumours, it has to be kept in mind that other intratumoural non-malignant cells present may significantly contribute to the total radioactivity. It is well known that a variable fraction of a tumour mass consists of non-neoplastic cells, such as

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stimulated leucocytes, macrophages and proliferating fibroblasts, which appear in association with growth or necrosis of tumour (Figure 3). Figure 3. Tumour mass model. non-neoplastic tissue

neoplastic tissue G1 proliferating cells

macrophages neutrophils

S G2

granulation tissue

M non-proliferating cells necrosis

FDG

/

( fibroblasts )

scar

Thymidine

Methionine

FDG, as a non cancer-specific tracer, also accumulate in these hypermetabolic cells, to a degree often even more marked than neoplastic cells.6 Because the viable non-neoplastic part can constitute a large percentage of the total tumour mass, the total amount of radioactivity measured by PET in the tumour is correspondingly increased. The advantage of this phenomenon is an increase of the overall diagnostic sensitivity of FDG-PET for detecting small tumoural foci due to the resulting signal amplification. The disadvantage is that specifically tumoural metabolism cannot be precisely assessed due to this contamination. This is a problem mainly in the field of therapy monitoring. The post-therapeutic FDG signal is then the resultant of several intratumoural changes. On one hand, death of tumour cells leads to a decreased FDG-accumulation, whilst the tumour mass may not (yet) have changed. On the other hand, however, inflammatory immune and scavenging reactions may be induced by the success of the therapy, and the invasion of the tumour by the inflammatory cells may raise the overall FDG uptake. The latter phenomena may thus cause underestimation of the effectivity of treatment.7 To avoid this, the use of more tumour-specific radiotracers (11Cmethionine;

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C-thymidine) has been proposed, tracers which should be less

sensitive to inflammatory contaminants.

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F. Technical aspects of whole-body FDG-PET The physics and practicalities of PET detection, signal processing and image generation are beyond the scope of this thesis; the reader is referred to an upto-date review by Phelps et al.8 A typical whole-body PET scan is started 60 minutes after the intravenous administration of 10 mCi dose of

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F-FDG. The axial field of view of the PET

system (10 to 15 cm) is extended by imaging in multiple bed positions, so as to cover the whole body.9 An acquisition time of 4-6 minutes per bed-position after a 10 to 15 mCi injection of FDG produces images of good resolution and contrast, in a total imaging time of 30 to 40 minutes. Current PET systems allow for the correction of soft-tissue attenuation. To achieve this, a set of corresponding images is acquired with an external source of radiation. This can be performed prior to injection of the tracer (“cold transmission”) or afterwards (“hot transmission”). At the present time, however, it is still debatable whether for diagnostic and staging purposes, attenuation correction is of any benefit in clinical whole-body FDG-PET imaging. If, however, semi- or fully quantitative assessment of FDG-metabolism is needed, e.g. for the assessment of the metabolic response to an antineoplastic treatment, correction for attenuation is crucial. The most widely used semi-quantitative index of FDG uptake is the standardised uptake value (SUV). For this, the measured tumour radiotracer concentration (Q) is normalised to the injected activity (Qinj) and to the body weight (W) of the patient: SUV = (Q x W) / Qinj More complex procedures, using kinetic modelling, are necessary to calculate the metabolic rate for glucose (MRgluc; µmoles/min/ml). For this, the delivery of the FDG at the tumour site (the input curve) has to be known. This is derived from a dynamic PET acquisition (providing the time course of the radioactivity) together with an arterial blood sampling following the FDG injection. Monitoring of the arterial FDG plasma concentration can be a burden to both the operator and patient. Various approaches have been proposed to provide a surrogate for this, including arterialised-venous sampling, measuring the arterial radiotracer concentration using the left ventricle (if it is in the imaging field-of-view) and a

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population estimate of the input function shape using a single or small number of blood samples.10

G. Clinical applications of metabolic imaging using FDG and PET The applications of imaging in oncology can generally be assigned to three major domains: staging disease at the initial diagnosis, staging recurrent disease, and assessment of response to treatment. The relative ‘weight’ of the structural and metabolic aspects of imaging strongly differs according to the specific diagnostic category. In general, the added value of metabolic information to diagnosis compared to the information provided by the structural modalities, is relatively higher in the follow-up of patients (i.e. after initial treatment) than in the initial, pre-treatment phase. Indeed, after surgery or radiochemotherapy, the normal anatomical planes are severely disrupted, and the normal structural characteristics of organs and tissues are often changed due to treatment- induced inflammatory and scavenging processes, thereby rendering structure-based diagnosis less accurate. The efficacy of metabolic imaging, on the other hand, is not significantly reduced under these circumstances. The area in which metabolic imaging constitutes, by far, the major part of diagnostic information is in the early monitoring of therapy. Preliminary results from several in vitro and in vivo experiments in different tumour models have recently shown that the change of FDG accumulation early after chemo- or radiotherapy, before any structural effects have occured, can predict the responsiveness of the tumour to the treatment.10 The unique contribution of PET in this indication will certainly constitute a major cornerstone of the future widespread implementation of PET in oncology. Several extensive overviews of the increasing number of clinical oncological applications of FDG-PET for cancer diagnosis, staging and therapy follow-up have recently been published.11,12,13,14

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H. General consideration on the clinical use of FDG-PET in oncology

1) Limitations of sensitivity A major limitation of PET is the limited spatial resolution of the imaging tool. For current PET instrumentations it is approximately 5 to 8 mm. Due to the partial volume effect, tracer activity in all lesions smaller than 2 times the spatial resolution of the imaging apparatus is underestimated. Below a threshold lesion diameter (depending on the intensity of tracer accumulation), the tracer uptake will no longer be distinguishable from the background activity, leading to falsenegative PET results. For the same reason, larger but necrotic tumour masses with only a small rim of viable tumour cells, as well as peritoneal metastases can be missed by FDG-PET. Ito et al, indeed demonstrated that the calculated FDG uptake values of local recurrent colorectal carcinomas as measured by PET, are strongly correlated with the diameter of the mass.15 Thus, the uptake values should be corrected for tumour volume. However, no practical or reliable method is yet available for this purpose. It is clear that future technological innovations that optimize the spatial resolution of the imaging method, thus reducing the false-negativity of small lesions, will significantly increase the additional diagnostic value of PET imaging in staging colorectal cancer. However, even with the maximal achievable spatial resolution of PET (around 2-3 mm), micrometastases, will ever remain underdiagnosed.

2) Limitations of specificity FDG is not a very tumour-specific substance, inasmuch as the leucocytes and macrophages of inflammatory processes also accumulate the tracer. This is a major source of false-positive diagnoses in the application of FDG-PET in oncology.16 In order to reduce the potentially negative impact of occasional false-positive FDG-PET results on patient management, it is mandatory to carefully select the candidates for an FDG-PET scan, excluding those with known inflammatory or infectious conditions, to closely correlate the FDG-PET images with data from conventional imaging methods (correlative imaging, cfr.

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higher), and to carefully confirm by other means the additional FDG-PET lesions that significantly alter patient management. Therefore, it is our believe that implementation of PET in patient care requires a multidisciplinary approach, with close interactions between radiologists, nuclear medicine physicians and referring oncologists or surgeons. Another pitfall in the interpretation of FDG-PET images is the highly variable physiologic tracer accumulation in the small intestine, colon, and ureters. The experience of the interpreters, however, generally allows to distinguish these normal variants from disease.

G. Scope and purpose of this thesis This thesis studied the use of whole-body FDG-PET in oesophageal and colorectal cancer. The three major domains of diagnostic imaging (staging at initial diagnosis, staging of recurrent disease, and therapy monitoring) of both cancers will be covered. The purpose of the research was to study the added value of metabolic imaging using FDG-PET in each of these domains. The specific clinical questions studied are similar for both tumour types: a) staging at initial diagnosis: - can FDG-PET provide a more accurate pre-treatment disease stage? - can FDG-PET guide treatment? - can FDG-PET predict prognosis / survival? B) staging recurrent disease - can FDG-PET povide earlier diagnosis? - can FDG-PET provide a more accurate estimate of disease extent? - can FDG-PET guide treatment ? C) monitoring of therapy - can FDG-PET predict the response rate to a specific treatment? - can FDG-PET assess the effects of a treatment? - is the response measured by FDG-PET correlated with prognosis?

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II. Positron Emission Tomography in Colorectal cancer

The first part of the thesis describes the use of FDG-PET in the management of colorectal cancer. Our personal research work mainly focused on its use in recurrent colorectal cancer. The sections about the the use of PET for primary cancer staging (section A) and therapy monitoring (section C) provide an overview of the available literature data.

A. Primary staging of colorectal cancer In patients with rectal cancer with a clinical stage T3-4 and /or lymph nodepositivity, neoadjuvant preoperative pelvic radiation +/- chemotherapy is often proposed as the prefered approach.17 The possible advantages of such therapy include a decrease in local recurrence rate, an increase of the chance of sphincter preservation, and an increased resectability rate. The major potential disadvantage of preoperative neoadjuvant therapy in patients with clinically resectable disease is possibly overtreating patients because of incorrect clinical staging (i.e. by including patients with stages pT1-2N0M0 or with metastatic disease). Therefore a most accurate preoperative TNM staging is required for assigning the optimal therapeutic modality to a particular patient. Transrectal endoscopic ultrasound (EUS) images the rectal wall in five layers, and is the most accurate modality for assessing the T-stage with reported accuracies between 75% and 95%.18 Presently no noninvasive techniques are available that can accurately determine the lymph node status before surgery. EUS has been proposed, but its accuracy is not higher than 60%-70% (low specificity: 55%) in rectal cancer, and it cannot be used for more proximal cancers.19 Spiral CT scan is presently the benchmark test for staging metastatic disease. However, assessing the nodal involvement with CT is inaccurate (accuracy range: 22% to 73%).20 In view of this, more accurate preoperative NM-staging would thus certainly have an impact on the perioperative therapeutic management. FDG-PET has been studied in this setting. The most important work in this area has been done by Abdel-Nabi et al.21 In this study, in 48 patients with colorectal cancer,

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the result of FDG-PET was compared to CT, surgical, and histopathologic findings. FDG-PET depicted all primary tumours (sensitivity: 100%, compared to 37% for CT). However, the specificity of PET was poor (43%), due to falsepositive FDG-uptake in inflammatory bowel conditions, benign adenomata, or after polypectomy. It was also found that the ability of FDG-PET for depicting regional lymph node metastasis was poor (sensitivity 29%, specificity 96%). Similar results were obtained for CT scan. The reasons for this high falsenegativity rate of FDG-PET was that the majority of these lymph nodes were located in the immediate vicinity of the primary tumour, and that some of these nodes had histologically only limited, micrometastatic invasion. The underlying reason for the inaccuracy of FDG-PET in this setting is clearly a limitation of the spatial resolution of the imaging apparatus. Does FDG-PET provide more accurate diagnosis of metastatic disease? The report by Abdel-Nabi indicated a superiority of FDG-PET for detection of metastatic disease in the liver.21 However, the study used conventional CT instead of the widely spread new generation spiral CT. Studies performed in recurrent colorectal cancer have indicated the superior sensitivity of spiral CT compared to FDG-PET for detection of liver metastasis.22 There are no reports of studies that focussed on the use of whole-body FDG-PET in comparison to state of the art conventional imaging modalities for the detection of distant metastatic (Stage IV) disease in a preoperative setting. Therefore, we conclude that there are no data to support the routine use of FDG-PET for preoperative TNM staging of colorectal cancer at the initial diagnosis.

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B. FDG-PET in the management of recurrent colorectal cancer 1) Diagnosis and staging of recurrent cancer

THE CLINICAL PROBLEM In patients with colorectal cancer the recurrence rate after apparently curative resection of the primary tumour is 30-40%, predominantly occurring within 3 years following surgery.23 Approximately 10% of first colorectal cancer recurrences are isolated locoregional failures, and an additional 15% to 20% are metastatic deposits, predominantly located in the liver, that are potentially resectable for cure.24 In those patients, for resection of liver metastases or pelvic recurrence to be curative, it is imperative that there be no unrecognized foci of tumoural disease outside the operation field. Presently, using standard preoperative diagnostic procedures, surgical treatment of recurrences lead to cure in 25-40% of the patients.25,26 Although the value of the conventional diagnostic modalities (CDM) has improved in this setting, there still is a need for a highly accurate and noninvasive imaging modality to detect inoperable disease and select patients for curative surgery. Recently, FDG-PET has been advocated

as

a

promising

tool

for

staging

recurrent

colorectal

adenocarcinoma.27,28,29 The major impediments for the widespread application of this unique metabolic imaging tool is its limited availability due to high cost and complexity. Therefore, definition of patient subsets most likely to benefit from this technique in a realistic environment of competing, state of the art diagnostic modalities is mandatory. The purpose of this first retrospective study was to evaluate the additional value of whole-body FDG-PET scan as a complementary staging modality to conventional diagnostic methods in patients with known or suspected recurrence of colorectal carcinoma.

MATERIALS AND METHODS Patient Population From June 1991 to June 1996, the nuclear medicine department at the University Hospital of Leuven performed a whole-body FDG-PET scan in 172

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consecutive patients with a clinical suspicion of recurrent colorectal cancer or for the preoperative staging in case of previously proven recurrence. Only patients with a clinical and radiological follow-up by the clinician at the university hospital

were

considered

(n=124).

Patients

who

underwent

previous

chemotherapeutic treatment for advanced disease (n=8), and those with known inflammatory bowel disease (n=6) were also discarded. Patients with a time interval between the abdominal CT scan and the PET scan of more than 2 months were also excluded (n=7). The selected group consisted of 103 patients (62 men and 41 women), with a mean age of 61 year (range: 35 to 81 yr.). All patients had undergone a surgical resection of a primary adenocarcinoma located in the colon (n= 24) or in the rectum (n= 79). The mean time interval between primary surgery of the colorectal cancer and the FDG-PET scan was 580 days (range: 2 months to 11 yr).

Conventional Diagnostic Modalities All patients underwent a work-up with conventional diagnostic modalities including an abdominal spiral CT scan and a chest radiography. Depending on the specific clinical problem, other appropriate investigations were also performed: plasma CEA measurement (n=81), chest CT scan (n=42), endoscopy (n=52), transrectal endoscopic ultrasonography (TREUS) (n=25), and magnetic resonance imaging of the liver (n=20).

Positron Emission Tomography Whole-body FDG-PET scans were performed within 2 months of CDM's using a dedicated PET camera. All patients fasted for at least 6 hours prior to FDG-PET scanning. A dose of 370 to 550 MBq 18F-FDG was administered intravenously. After tracer injection patients were kept well hydrated and received a diuretic in order to minimize image artifacts from urinary stasis in the renal collecting system and ureters. During the time between injection and scanning (sixty minutes), patients were asked to lie comfortably in order to avoid muscular tracer accumulation. All FDG-PET images were reconstructed using an iterative reconstruction algorithm. Attenuation correction was not performed.

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Data Analysis Transaxial, coronal and sagittal views of the emission scans were evaluated by visual inspection on a high-resolution display monitor by two experienced nuclear medicine physicians (SS,LM). At the time of the interpretation the observers were fully aware of the results of the CDM, but completely blinded to the final outcome of the patient. Areas of marked focal FDG accumulation greater than the background activity of the examined organ were interpreted as sites of malignant disease. Equivocal FDG-PET readings were classified as negative. The results of CDM were drawn from the patient records. Suspected lesions identified by one of the CDM or FDG-PET were grouped into 4 regions: local (i.e. the postoperative site), abdominal cavity (including mesenterial, peritoneal and retroperitoneal metastases), liver (divided in right and left lobe), and extra-abdominal organs. Region-based analysis. For every region, the concordance between CDM and FDG-PET findings was verified. In case of a discordance, the FDG-PET result was compared to the true lesion status, obtained by histopathology or clinical follow-up of more than 12 months, and classified as a true-positive, falsepositive, true-negative or false-negative result. Then, the additional value of FDG-PET imaging on regional diagnosis was calculated as the ratio (%) between the sum of correct FDG-PET discordances and the total number of regions. For the patient-based analysis, six patient subsets were defined: 1) resectable local recurrence; 2) resectable recurrence limited to one lobe of the liver; 3) extended disease: inoperable patients with lesions in more than one region, with bilobar liver metastasis, or with abdominal lymph node metastasis; 4) completely normal CDM findings despite clinical suspicion of recurrent disease; 5) elevated plasma carcinoembryonic antigen (CEA) levels with otherwise normal CDM findings; 6) inconclusive CDM findings. The diagnostic impact of performing an additional FDG-PET scan on the patients' staging was assessed by verifying the discordances between CDM and FDG-PET according to this patient classification. Based upon the true patient status, obtained by histopathology or clinical follow-up of more than 12 months, the discordant

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FDG-PET

results

were

categorized

as

correctly

upstaging,

correctly

downstaging, falsely overstaging, or falsely understaging the patient. Then, the additional value of FDG-PET imaging on patient staging was calculated as the ratio (%) between the sum of correct FDG-PET discordances and the total number of patients.

Statistical analysis The relative number of true and false discordant results between whole-body FDG-PET and the CDM was compared by a McNemar test for correlated proportions.

RESULTS

Region-based analysis. Table 1 shows the distribution of the discordances between CDM and FDG-PET per anatomical region and the methodology used to define the true lesion status. A total number of 40 regional discordances were found in 103 patients. The true lesion status of these discordances was determined by histologic examination in 22 (55%) cases, and by follow-up in 18 (45%) cases.

Table 1. Distribution of the discordances between CDM and FDG-PET scan readings listed per anatomical region, and the methods used to define the true lesion status. Number of discordances

Locoregional Liver Abdominal cavity Extra-abdominal organs Total

16 7 8 9 40

True lesion status defined by histology 10 3 5 4 22 (55 %)

True lesion status defined by follow-up 6 4 3 5 18 (45 %)

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In case of a discordance between FDG-PET and CDM , PET was correct in 35 lesions, and incorrect in 5 lesions. The difference in accuracy of both modalities, and thus the additional diagnostic value of FDG-PET, was statistically significant (p

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